The Case Against Antidepressants

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FunkOdyssey

Well-Known Member
I decided to create a new thread to compile some of the evidence against the use of antidepressant drugs to treat depression. In my mind, the most compelling reason to avoid them is that they may worsen the condition over time, so we will begin there.

The following paper suggests poor-long term outcomes of drug treatment, depression-inducing effects, development and acceleration of bipolar disorder, tolerance to antidepressants, resistance to later trials of the same antidepressant, and withdrawal syndromes may all be attributed to the "oppositional model of tolerance". The idea here is that the body's adjustments to restore homeostasis oppose the drug's acute effects and persist after the drug is withdrawn.

J Clin Psychiatry
2003 Feb;64(2):123-33.

Can long-term treatment with antidepressant drugs worsen the course of depression?​

Giovanni A Fava 1

Abstract​

Background: The possibility that antidepressant drugs, while effectively treating depression, may worsen its course has received inadequate attention.

Method: A review of the literature suggesting potential depressogenic effects of long-term treatment with antidepressant drugs was performed. A MEDLINE search was conducted using the keywords tolerance, sensitization, antidepressive agents, and switching. This was supplemented by a manual search of Index Medicus under the heading "antidepressant agents" and a manual search of the literature for articles pointing to paradoxical effects of antidepressants.

Results: A number of reported clinical findings point to the following possibilities: very unfavorable long-term outcome of major depression treated by pharmacologic means, paradoxical (depression-inducing) effects of antidepressant drugs in some patients with mood and anxiety disturbances, antidepressant-induced switching and cycle acceleration in bipolar disorder, occurrence of tolerance to the effects of antidepressants during long-term treatment, onset of resistance upon rechallenge with the same antidepressant drug in a few patients, and withdrawal syndromes following discontinuation of mood-elevating drugs. These phenomena in susceptible individuals may be explained on the basis of the oppositional model of tolerance. Continued drug treatment may recruit processes that oppose the initial acute effects of a drug and may result in loss of clinical effect. When drug treatment ends, these processes may operate unopposed, at least for some time, and increase vulnerability to relapse.

Conclusion: The possibility that antidepressant drugs may worsen the course of depression needs to be tested, even though its scientific exploration is likely to encounter considerable methodological and ideological difficulties. The clinical implications of this hypothesis in depression are considerable. Antidepressant drugs are crucial in the treatment of major depressive episodes. However, appraisal of paradoxical effects that may occur in susceptible patients during long-term treatment may lead to more effective use of the drugs.

 
Defy Medical TRT clinic doctor

Systemlord

Member
I think the problem with antidepressants is they work for short-term and then the body builds tolerance forcing you to switch to another drug and a repeat cycle of having to find another drug for relief, all while what's causing the depression isn't being addressed and is like a runaway train.

Antidepressants treat the symptoms, not the cause.
 

readalot

Member
Amazing how easily one gets offered and Rx'ed an AD or SSRI in an in network PCP provider's office. They must really work. Never tried one, any recommendations....

Mirtazipine
Lexapro

Throw a little clonazepam in there too?

Serious anxiety and panic now that coincide with exercise intolerance and ectopic beats during exercise. All docs recommend an AD along with some beta blocker and maybe some benzo in there as well. Twenty years with major depression and never took the plunge down AD lane. Seriously considering it.
 
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FunkOdyssey

Well-Known Member
This paper coins a term for the phenomenon of antidepressant-induced depression: tardive dysphoria.

Med Hypotheses
2011 Jun;76(6):769-73.
doi: 10.1016/j.mehy.2011.01.020. Epub 2011 Apr 2.

Tardive dysphoria: the role of long term antidepressant use in-inducing chronic depression​

Rif S El-Mallakh 1, Yonglin Gao, R Jeannie Roberts

Abstract​

Background: Treatment-resistant and chronic depression appear to be increasing. The recent identification of antidepressant tachyphylaxis, the loss of antidepressant efficacy over time, is only a partial explanation. This is an emerging evidence that, in some individuals, persistent use of antidepressants may be prodepressant.

Methods: A literature search of PubMed utilizing the terms: antidepressant tachyphylaxis, treatment-resistant depression, chronic depression, and antidepressant tolerance was performed, and relevant articles were used.

Results: Depressed patients who ultimately become treatment resistant frequently have had a positive initial response to antidepressants and invariably have received these agents for prolonged time periods at high doses. Parallels between this course and tardive dyskinesia are noted. It is proposed that neuroplastic processes related to dendritic arborization may underlie the treatment resistant depression that occurs in the setting of chronic antidepressant use. Since the prodepressant effect is seen after prolonged antidepressant use, the term tardive dysphoria is proposed.

Conclusions: Tardive dysphoria, needs to be considered in studies of treatment resistant depression, and should be examined in blinded, randomized antidepressant discontinuation trials.

Quotes from the full-text:
For many patients recurrence of depressive symptoms may occur despite ongoing antidepressant treatment [17]. When optimization of treatment fails, such patients are noted to have treatment-resistant depression (TRD). TRD may comprise 30–50% of people with major depressive illness [17,18]. The cause of TRD is unknown, but its prevalence appears to be increasing. In 2006, a meta-analysis reported that nearly 40% of depressed patients had TRD [19].

Tachyphylaxis

Tachyphylaxis (also known as antidepressant tolerance, antidepressant ‘‘poop-out’’, or ‘‘breakthrough depression’’) is a condition in which patients experience a good initial antidepressant response which is lost over time with repeated or prolonged antidepressant treatment [23,26–28]. This phenomenon is distinct from an initial non-response or a partial response. Up to 80% of patients diagnosed with major depressive disorder will experience a recurrence of depressive episode despite constant maintenance dose of an antidepressant [12,23,29,30]. Attempts to treat these individuals frequently result in poor response and the rise of TRD [30].

Once initial treatment response is lost, subsequent improvement is unlikely. If patients with TRD respond to a subsequent antidepressant, the extent of improvement is inferior to the initial response [33]. Patients who lost response to a MAOI not only did not respond to subsequent treatment, but reported greater extent of depression after relapse than before the new treatment was initiated [34,35].

Antidepressant-induced depression

The possibility of antidepressant-induced depression was introduced by Fava [36]. He suggested that a neurobiochemical mechanism increasing vulnerability to depression might play a role in this phenomenon and contribute to the observed worsening long-term outcome of major depression [24]. Other authors have also introduced similar ideas [25,37].

Several studies support these assertions. Van Scheyen [38] naturalistically followed 84 depressed adults and found that long term treatment with TCAs increased the likelihood of a depressive recurrence. Long term treatment with imipramine is associated with worsening mood in mildly depressed patients [39]. Anxious patients without a history of a mood disorder may develop depression after long-term treatment with antidepressants for their anxiety disorder [40,41]. In a recent study 27% of patients without any history of a mood disorder who had received antidepressants for an average of 29 months for panic disorder, developed a cyclothymic illness that persisted for 1 year after antidepressant discontinuation [42]. Normal controls receiving antidepressants in research studies were reported to experience depression [43].

These effects may be analogous to the observations that antidepressant treatment in bipolar disorder could destabilize the illness [44]. An antidepressant-associated chronic irritable depressive (ACID) state has been reported in bipolar and bipolar spectrum patients given long-term antidepressants [45,46]. In some of these patients antidepressant discontinuation was associated with slow and gradual improvement of the depressive symptoms. In a random assignment study, antidepressant continuation in rapid cycling bipolar subjects who achieved remission with initial antidepressant treatment tripled the likelihood of a future depression compared to patients who discontinued the antidepressant over the subsequent year of treatment [47].

Sharma [25] speculated that a prodepressant effect of antidepressants may occur because continued drug treatment may induce processes that are the opposite of what the medication originally produced. He believed this process may even cause a worsening of the illness, continue for a period of time after discontinuation of the medication, and may not be reversible [24]. The field of psychiatry is familiar with such a process in the case of tardive dyskinesia.

Tardive dysphoria (TDp)

It is proposed that tardive dysphoria (TDp) is an abnormal dysphoric state that develops in some predisposed individuals with prolonged antidepressant treatment. Patients with this syndrome may comprise a significant fraction of TRD subjects. TDp is defined as a chronic, frequently treatment resistant, depressive state with onset in the setting of ongoing, persistent antidepressant treatment. Antidepressants may be initially administered for any reason (e.g., anxiety or depression), but afflicted subjects with a history of a recurrent major depressive disorder would have historically experienced an initial positive response to antidepressant medication (generally with their first exposure). The depressive state is perpetuated (and possibly worsened) by continuing the antidepressant. It is believed that SRI antidepressants might be selectively associated with the development of TDp. Discontinuation
of the antidepressant results in a slow and gradual improvement of the chronic depressive symptoms. However, in some individuals who have experienced TDp for a very prolonged period of time, discontinuation of antidepressant may not result in reversal of the symptoms. This is superficially similar to TD. Subjects who ultimately develop TDp will have frequently had an initial positive response to antidepressants, helping to cement adherence. Depression recurs in 9–57%, or perhaps as high as 93% in the effectiveness trial STARD (relapse and dropout of study) [59], of patients despite ongoing antidepressant treatment [23]. In such patients, an increase in dose [60,61], change to another antidepressant agent [62,63] or adding another antidepressant [64,65] may be effective in 30–60% of patients. However, there is evidence that switch may not be helpful [66], and if patients do respond relapse occurs within 6 months in some 20% [61]. Ultimately, 30–50% of such patients will develop TRD [17,18]. In the subset of such patients who have developed TDp, ongoing attempts to treat the depression with antidepressants perpetuate the TRD, and may ultimately make the chronic depression permanent.

TDp is different from conditioned tolerance [67] in that it is not merely the loss of the drug effect, but viewed as an active process in which a depressive picture is caused by continued administration of the antidepressant. In conditioned tolerance, environmental and behavioral conditional compensatory responses mediate tolerance by in the presence of cues usually associated with the drug [67].

 

FunkOdyssey

Well-Known Member
This study finds a higher rate of psychiatric re-hospitalization and longer duration of stay among antidepressant users than non-users:

Front Psychiatry. 2019; 10: 79.
doi: 10.3389/fpsyt.2019.00079

Antidepressant Use During Acute Inpatient Care Is Associated With an Increased Risk of Psychiatric Rehospitalisation Over a 12-Month Follow-Up After Discharge​

Michael P. Hengartner,1,* Silvia Passalacqua,1 Andreas Andreae,2 Thomas Heinsius,2 Urs Hepp,2 Wulf Rössler,3,4,5 and Agnes von Wyl1

Abstract​

Background: Some evidence suggests that antidepressants may relate to poor outcomes in depression. The aim of this study was, therefore, to examine, whether antidepressant use may worsen the long-term outcome in real-world psychiatric patients with both primarily affective and non-affective mental disorders.

Methods: Based on a total of n = 151 inpatients with a mixed range of diagnoses enrolled at two psychiatric hospitals in Zurich, Switzerland, matched pairs of n = 45 antidepressant users and n = 45 non-users were selected via nearest neighbor propensity score matching. Pairs were matched according to 14 clinically relevant covariates assessing psychosocial impairments, functioning deficits and illness severity. The two outcomes of interest were the number and total duration of all rehospitalisations over a 12-month follow-up after discharge from the hospital based on the official clinical registry.

Results: Altogether 35.6% of antidepressant users were rehospitalised at least once, as compared to 22.2% in matched non-users. Two or more rehospitalisations occurred in 22.2% of antidepressant users but only in 2.2% of non-users. In antidepressant users, the mean total duration of rehospitalisations was 22.22 days, as compared to 8.51 in matched non-users. According to Poisson regression analyses, antidepressant use during acute inpatient care prospectively relates to both a higher risk (incidence rate ratio [IRR] = 3.64, 95% confidence interval [95%-CI] = 1.71–7.75, p = 0.001) and a longer duration (IRR = 2.61, 95%-CI = 1.01–6.79, p = 0.049) of subsequent rehospitalisations. These findings were consistently replicated when traditional multivariable regression analysis was applied to the full sample. Findings also replicated when patients with affective and non-affective disorders were analyzed separately.

Conclusions: Our findings raise the possibility that, in the long-term, antidepressants may impair recovery and increase the risk of rehospitalisation in patients with both primarily affective and non-affective disorders. More work is required to explore possible aetiopathological pathways leading to psychiatric rehospitalisation.

From full-text:

Interpretation of Findings​

Several long-term trials suggest that antidepressants may not produce clinically meaningful long-term benefits (1416). In accordance with mounting evidence from observational studies, our findings even raise the possibility that antidepressant pharmacotherapy may increase relapse rates and impair recovery in the long run (20, 21, 23, 24, 26). These findings are in accord with a comprehensive meta-analysis of long-term clinical trials by Andrews et al. (9), which shows that patients with major depression who recovered on placebo have a lower relapse rate upon treatment discontinuation than patients who recovered on drugs. These findings conflict with the results from discontinuation trials (7), which aim at estimating long-term relapse prevention in continuously drug-treated patients compared to patients whose medication was discontinued rapidly and replaced by placebo.

Although recommendation for maintenance therapy is mostly based on these discontinuation trials, their validity is poor due to several limitations (5, 6). Since antidepressant discontinuation can cause severe withdrawal reactions, including depression-like symptoms such as lethargy, fatigue, irritability, suicidal ideation, and sleep problems (44), withdrawal reactions are easily misdiagnosed as depression relapse (8, 13, 44). The higher relapse rates in participants switched to placebo could thus be the result of neurobiological adaptations due to prior pharmacotherapy, a condition that was referred to as oppositional tolerance (4, 9). Moreover, preventive effects reported in discontinuation trials apply only to patients who favorably respond to antidepressant, but not to non-responders and spontaneous remitters (16).

As there appears to be an association between antidepressant use and rehospitalisation rates, it is important to propose plausible causal mechanisms that may account for such a relationship. Although we were not able to assess these mechanisms in our study, possible pathways have been described in the literature. Owing to pharmacodynamic alterations in neurobiological functions, including reduction of receptor density in response to increased neurotransmitter concentration (45), affective and psychosomatic disturbances following long-term antidepressant use are possibly iatrogenic, that is, attributable to drug-induced neurobiological adaptations (4, 9, 10). These treatment-emergent adverse effects of psychotropic medications may develop following antidepressants discontinuation of mostly long-term use and in some patients withdrawal is severe to an extent that they develop protracted post-withdrawal affective disorders (44, 46). In other instances continuing antidepressant therapy after initial response may cause new mental disorders, which has also been referred to as behavioral toxicity (46).

Meta-analyses of placebo-controlled randomized trials indeed suggest that some rehospitalisations in treatment-adherent antidepressant users are possibly due to adverse drug reactions. For instance, in patients with mood and anxiety disorders, antidepressants may trigger psychomotor agitation and mania (47, 48) or suicidal acts (49, 50). Moreover, in healthy volunteers without mental disorders, relative to placebo, antidepressant use has been associated with a significantly increased risk of adverse mental events, including agitation, sleep problems, nervousness, and abnormal thinking (51, 52). These iatrogenic psychological disturbances may possibly account for the increased rate and duration of rehospitalisations observed in the present study, but more work is required to establish causal aetiopathological mechanisms.

 

FunkOdyssey

Well-Known Member
Ther Adv Psychopharmacol. 2020; 10: 2045125320970325.
Published online 2020 Nov 2. doi: 10.1177/2045125320970325

May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance​

Giovanni A. Fava

Abstract​

In recent years there has been a considerable debate on antidepressant drugs. Continued drug treatment with antidepressant medications may stimulate processes that run counter to the initial acute effects of a drug. The oppositional model of tolerance may explain loss of treatment efficacy during maintenance treatment and the fact that some side effects tend to occur only after a certain time. These processes may also direct the illness into a treatment-unresponsive course, including manifestations of bipolar disorder or paradoxical reactions. When drug treatment ends, oppositional processes no longer encounter resistance, resulting in potential onset of new withdrawal symptoms, persistent post-withdrawal disorders, hypomania, and resistance to treatment if it is reinstituted. In all these cases, antidepressant medications may constitute a form of iatrogenic comorbidity, which increases chronicity and vulnerability to depressive episodes. Antidepressant medications are essential drugs for the treatment of major depressive episodes. They are less likely, however, to provide protection for relapse prevention. Current prescription practices need to be reformulated in light of consideration of vulnerabilities and adverse effects of treatment. The oppositional model of tolerance provides a conceptual framework for weighing all these elements in the individual case. The model does not appear to apply to all patients who undergo treatment with AD, but only to a part of them. Studying the variables that are associated with such occurrence in certain patients and not in others would be one of the most important tasks of current therapeutic research. Current diagnostic systems in psychiatry do not consider the iatrogenic components of psychopathology, and can be applied to only patients who are drug free. They are suited for a patient who no longer exists: most of the cases that are seen in psychiatric clinical practice receive psychotropic drugs and such treatment is likely to affect prognosis and treatment choices.

oppositional model of tolerance.png


Quotes from full-text:

Loss of antidepressant efficacy​

The return of depressive symptoms during maintenance antidepressant treatment has been object of two recent reviews.11,12 The term “tachyphylaxis” (the progressive reduction in response to a given dose of medication after repeated administration of a pharmacologically or physiologically active substance) has also been used to characterize relapse during maintenance treatment or clinical deterioration marked by symptoms such as apathy and fatigue.1113 The use of this latter term is, however, questionable, since its Greek root connotes a fast, rapid loss of effect; on the contrary, the phenomenon increases with duration of treatment. In a meta-analysis of maintenance treatment studies, the risk of relapse increased progressively from 23% within 1 year to 34% in 2 years and 45% in 3 years.14 As a result, the term “tachyphylaxis” should be avoided and substituted by “loss of clinical effects” or “loss of efficacy”.

A potential explanation for loss of treatment efficacy may be that AD are effective for the treatment of the acute episode, but not in maintenance treatment. Accordingly, it would not represent actual loss of treatment effects, but the absence of prophylaxis by AD. However, this possibility runs counter the fact that the phenomenon is not generalized, since it involves a segment of the treated population that increases progressively over time.11,12,15

A clinically intuitive strategy for addressing the problem is to increase the dosage of the AD. In a randomized controlled study,16 fluoxetine was administered at 20 mg daily or 90 mg weekly dose. About one-third of patients relapsed within an average of 107 days of maintenance treatment. The effectiveness of increasing the medication if relapse took place was assessed: 57% of patients receiving the daily dosage and 72% those with the weekly dosage displayed a response to the dose increase. One patient out of five who initially responded to dose increase relapsed again during the 25-week trial.16 It is conceivable that more relapses would have occurred if the trial continued, as reported in recurrent depression.17 The findings in a placebo-controlled trial of duloxetine were pretty similar.18 However, in two pilot controlled investigations,19,20 psychotherapy (in one case a modified form of cognitive behavior therapy and in another family therapy) without changing the drug regimen was significantly more effective than dose increase in yielding a persistent remission in depressed patients who experienced a loss of clinical effect while being treated with AD.

Resistance to antidepressant drugs​

The term “resistance” is generally applied to either depressive illness (an episode which does not respond to drugs or psychotherapy) or to lack of response to a previously effective pharmacological treatment when the same medication is started again after a drug-free period. The former use is the most common, but the latter also occurs in a considerable number of cases.21 In a recent systematic review on lack of response to re-challenge,22 the range of response failures was broad (between 4.9% and 42.9% across studies). In a large observational study,23 failure to respond to the same medication that was used in a previous episode was found to occur in a quarter of cases. Prior use of AD has been found to be related to resistance to AD that differed from those administered during the first trials.24,25 In an investigation on 122 patients who, after initially responding to fluoxetine, were assigned to placebo,26 resistance was examined. About half of patients relapsed. After re-initiation of fluoxetine, 38% of depressed patients did not respond at all or displayed an initial response followed by relapse.26

The data available thus indicate that, when drug treatment is reinstituted, the patient may not respond to the same antidepressant that improved depressive symptoms initially. In patients who respond to the same AD that was used in the previous episode, a loss of therapeutic effect may then ensue.23 This suggests that loss of efficacy and resistance to treatment may be connected and have a common underlying mechanism.

The lack of differentiation between an illness episode that is unresponsive to a certain treatment and the lack of response to a previously effective therapy is likely to generate confusion. Such confusion is increased by the assumption that treatment was right in the first place and failure to respond is blamed on patients’ characteristics.21 “Treatment resistance” thus prompts switching and augmentation of AD. Yet, these therapeutic strategies may trigger a “cascade iatrogenesis”, instead of reconsideration of the entire process21: was treatment appropriate in the first place? Clinical outcome is the result of several interacting variables: living conditions, patient characteristics, illness features and previous therapeutic experience, self-management (the degree of collaboration of the patient in behavioural and lifestyle terms), and treatment setting (e.g. physician’s attitude and attention, illness behavior).21 Some of these factors may be therapeutic, whereas other factors may be counter-therapeutic. In some patients the interactive combination of treatment variables may lead to clinical improvement; in other cases, the net result will produce no effect; in another segment of the clinical population, it may cause worsening of the condition.

Paradoxical effects​

In 1968, Di Mascio et al. investigated the effects of imipramine on individuals who were very heterogeneous as to depression levels, using a double-blind placebo-controlled procedure.27 Imipramine induced an increase in depression in subjects with the lowest scores of depression. This early pilot trial suggested the possibility that, when depressive symptoms are minimal, antidepressant medications may do more harm than good. As a result, use of AD may be associated with the appearance of new symptoms and exacerbation of baseline clinical picture (paradoxical effects). Improvement may result from antidepressant discontinuation.10

The occurrence of paradoxical effects was reported in double-blind placebo-controlled investigations that were concerned with fluoxetine and sertraline.28,29 Indeed, the concept of antidepressant-induced tardive dysphoria points to the fact the symptomatology may be reversed by tapering or discontinuing the AD.30

During treatment of panic disorder by fluvoxamine,31 the onset of depressive symptoms in 7 of 80 patients (9%) was reported. It is of considerable interest that these patients had no past or current history of depression before fluvoxamine therapy. The symptoms improved when fluvoxamine was stopped and tricyclic antidepressants (TCA) or clonazepam were substituted as treatment. Depressive symptoms reappeared again when fluoxetine was administered.28 Similar observations were made with the use of TCA in anxiety disorders.32 Raja described nine patients who had an initial good response to treatment with AD.33 However, such response was followed by loss of efficacy, resistance, and worsening with subsequent treatment. These oppositional manifestations appeared to be closely connected and part of the same syndrome.

Switching to bipolar disorder​

Treatment with AD has been associated with mania or other forms of excessive behavioral activation.34 These manifestations may simply unveil bipolar disorder that had not been recognized or may be predominantly iatrogenic, since they may also occur in patients who lack any previous history or genetic predisposition to bipolar illness. In the early 1980s, Koukopulos et al. observed how treatment by AD may change course from unipolar to bipolar illness.35 They suggested that mania induced by antidepressants may not simply be a temporary and fully reversible phenomenon when treatment is discontinued, but that AD trigger complex biochemical mechanisms of permanent illness deterioration. Bader and Dunner pointed to the association between antidepressant-induced mania and treatment-resistant depression in patients who lacked a family history of bipolar disorder.36

A systematic review and meta-analysis explored hypomania, mania, and behavioral activation of children and adolescents during AD treatment.37 It disclosed that rates of excessive arousal-activation with antidepressants were very significantly higher both in anxiety (13.8%) and depression (9.8%), than with placebos (5.2 versus 1.1%, respectively).37 As a result, behavioral activation, hypomania, and mania are a consistent risk regardless of individual or family history of bipolar illness. Such risk runs counter the widespread clinical use of antidepressants in anxiety disorders, particularly in younger patients.

Despite initial denial, the view that AD may worsen the course of bipolar disorder has achieved wide currency.34 AD, however, may induce episode acceleration also in unipolar depression.

Goodwin has illustrated its potential mechanism: “If the natural sequence of recurrent unipolar illness goes from depression to recovery and then eventually to the next episode, treatments that accelerate recovery of the index depression could also accelerate the onset of the next episode” (p.43).38

Withdrawal syndromes​

Withdrawal symptoms following discontinuation of antidepressant treatment were soon recognized after the introduction of these drugs.39 They have been described with any type of AD, but particularly with SSRI, venlafaxine, and duloxetine.4045 In the past they have been labeled as “discontinuation syndromes”, with the aim of avoiding any hint to the dependence potential of SSRI that may affect marketing. However, this position is no longer tenable in view of current evidence that indicates that the clinical phenomena pertain to withdrawal syndromes and do not differ from those that occur with other psychotropic drugs.4045 Hengartner et al. remarked that the first systematic review on SSRI appeared only in 2015,40,46 and the first on serotonin-noradrenaline reuptake inhibitors (SNRI) in 2018,42 after nearly 200 meta-analyses on the efficacy of new generation antidepressants. The withdrawal syndrome encompasses a broad range of somatic symptoms (e.g. headache, dizziness, flu-like symptoms, nausea).4045 Psychological symptoms may occur as well: agitation, anxiety, panic attacks, dysphoria, irritability, confusion, and worsening of mood.40,45 Symptoms typically begin within 3 days of stopping antidepressant medication or initiating medication taper. Untreated symptoms may be mild and resolve spontaneously in 1–3 weeks; in other cases they may persist for months or even years,4045 leading to what has been defined as persistent post-withdrawal disorder.41,45

Discontinuation of antidepressant medications may also trigger hypomania or mania, despite concurrent mood-stabilizing treatment.47 The syndrome has a very variable course: it may be self-limiting, or may abate when AD are started again, or may require specific anti-manic treatment. Mood elevation may also occur with antidepressant dose decrease,48 and patients who failed to respond to mood stabilizers in combination with antidepressants may improve on discontinuation of the antidepressants.49

Withdrawal symptoms are likely to be misunderstood as indications of relapse and may lead to starting treatment with AD again, perpetuating the problem.50

Refractoriness​

The Sequenced Treatment Alternatives to Relieve Depression Study (STAR*D) provided an important confirmation of the oppositional model of tolerance.51 The original aim of the trial was to test the best pharmacological strategies for obtaining remission in major depression. Patients entered a first open trial of medication (citalopram), with aggressive dosing and an extended duration of treatment. Only 37% of patients reached remission and the proportion that responded and stayed well for a year was 15%.51,52 Patients who did not recover after the first trial of medication were submitted to three sequential steps involving switching, augmentation or combination strategies, based on existing evidence. The rate of remission cumulatively after all four sequential steps was 67%; however, when persistent recovery (also including relapse rates while on treatment) was considered, the cumulative rate was 43%. Therapeutic efforts after step one (open treatment with citalopram) yielded only an additional 6% of sustained recovery. Remission rates decreased after each treatment step, despite the fact that each step of the trial was carefully conceived to increase the likelihood of response in patients who did not remit.51 In each sequential treatment step, the rates of relapse (while still on medication) increased in patients who achieved remission. Further, after each treatment step intolerance to treatment increased (as evidenced by dropouts for any reason during the first 4 weeks, or side effects afterwards).

If we interpret the STAR*D findings in light of the oppositional tolerance model2,10,15: pharmacological manipulations, either by switching or augmentation may propel depressive illness into a more refractory phase, characterized by higher rates of relapse while on treatment, lower remission to subsequent treatments, as well as higher intolerance to further treatment (steps 3 and 4). Such trends were confirmed by another trial:53 the higher was the number of prior antidepressant treatments, the greater the likelihood of depressive relapse.

It has been suggested the undiagnosed bipolarity in depressed patients may be an explanation for treatment resistance and refractoriness and the current diagnostic systems differentiating unipolar and bipolar depression fail to acknowledge intermediate areas.54,55 However, undiagnosed bipolarity may explain only part of the spectrum of clinical phenomena, and, inadvertently, shifts the blame to a faulty diagnosis and incorrect use of AD. Hypomanic and manic switches upon antidepressant treatment may occur also with proper and accurate assessment, and are only one of the several manifestations of tolerance. Not surprisingly, they tend to cluster with other manifestations (Table 1).

Conclusion​

At 26 years after the formulation of a largely speculative hypothesis concerned with the iatrogenic effects of AD,1 the evidence I have reviewed indicates that use of these medications may have the potential to worsen long-term outcome of mood and anxiety disorders in individual cases. Similar mechanisms, subsumed under the concept of supersensitivity psychosis, may apply to the use of antipsychotics in schizophrenia and mood disorders.78,79 The oppositional model of tolerance is also consistent with the use of psychotropic medications as recreational drugs.80

If we take into consideration the potential benefits, the likelihood of responsiveness, and the potential adverse events and vulnerabilities entailed by oppositional mechanisms, we would be inclined to target the application of AD only to the most severe and persistent cases of depression for the shortest possible time, and avoid their utilization in anxiety disorders (unless a major depressive disorder is present or other treatments have been ineffective).81

AD were found to be effective in the treatment of severe depression, but the better tolerability of newer AD has expanded their original indications. Their use has been prolonged to maintenance and prevention of relapse of depression, and has been extended to long-term treatment of anxiety disorders.81 However, if treatment is prolonged beyond 6 months, phenomena such as tolerance, episode acceleration, sensitization and paradoxical effects may ensue. The hidden costs of using the AD may then outweigh their apparent gains, particularly when the likelihood of responsiveness is low.81

Therapeutic strategies that are found to be effective in the short term are not necessarily the most suitable for long-term treatment. Unfortunately, a largely untested assumption (what makes the patients feel better is the best for keeping him/her well) has hindered the progress of pharmacological research in depression, with neglect of drugs that may be effective for maintenance treatment and not for the treatment of the acute episode.82

Antidepressant medications are essential drugs if the proper indications are endorsed. However, currently, prescriptions are driven by an overestimated consideration of potential benefits, little attention to the likelihood of responsiveness and neglect of potential vulnerabilities to the adverse effects of treatment.81 The oppositional model of tolerance still awaits adequate pre-clinical and clinical research testing. However, it provides a conceptual framework for unifying adverse clinical phenomena that may occur in patients and for weighing benefits and harms when using AD.

The model does not appear to apply to all patients who undergo treatment with AD, but to only a fraction of them. Studying the variables that are associated with such occurrence in certain patients and not in others would be one of the most important tasks of current therapeutic research. Current diagnostic systems in psychiatry do not consider the iatrogenic components of psychopathology, and can be applied only to patients who are drug free. They are suited for a patient who no longer exists: most of the cases that are seen in psychiatric clinical practice receive psychotropic drugs and such treatment is likely to affect prognosis and treatment choices.

 

FunkOdyssey

Well-Known Member
I'll post some studies now that address the question of whether antidepressant drugs are actually effective.

Are Antidepressants as Effective as Claimed? No, They Are Not Effective at All

Joanna Moncrieff, MBBS, MRCPsych, MSc, MD1
(Can J Psychiatry 2007;52:96–97)

Antidepressant drugs are claimed to have specific effects on depressive symptoms. It is assumed that they do this by acting on an abnormal brain state that gives rise to depression. In contrast, I suggest that there is no evidence for this position. The effects of antidepressants seen in depression trials can easily be accounted for by nonspecific pharmacologic and psychological actions.

Short-Term Studies

There are thousands of randomized controlled trials (RCTs) comparing antidepressants with placebo, using various measures of depression. Metaanalyses of these have generally come to the conclusion that, overall, they show a small advantage for antidepressants. However, this obscures enormous heterogeneity among published study results, with many trials finding no difference between antidepressant medication and placebo. In addition, we know that negative trials are less likely to be published than positive ones and that positive outcomes are selectively reported within trials. A recent metaanalysis that included unpublished studies found that the difference between antidepressants and placebo amounted to less than 2 points on the Hamilton Depression Rating Scale (HDRS).1

There are 2 reasons why the small difference found in this and other recent metaanalyses does not necessarily imply that antidepressants have a truly “antidepressant” effect. First, all rating scales contain items—such as sleeping difficulties, anxiety, and agitation—that are not specific to depression and that are likely to respond to nonspecific sedative effects associated with many antidepressants. For example, the HDRS contains 6 such items; these can score a total of 16 points (a score of 19 to 20 points indicates severe depression as defined by the American Psychiatric Association). Therefore, improvements according to rating scales may simply reflect nonspecific effects and do not necessarily imply any change in mood, per se. Second, antidepressants are active drugs and, as such, produce a range of physiological effects when ingested. These effects may indicate to assessors or trial participants whether they are taking the antidepressant or the placebo; thus, the double-blind design is often penetrated in trials of antidepressants and other psychotropic agents. This is especially likely to happen in contemporary trials in which subjects are forewarned in detail about the randomized design, the use of placebo, and the nature of likely side effects. Patients on antidepressants may therefore experience an amplified placebo effect as a consequence of suspecting that they are taking the active drug. Similarly, raters may inflate ratings for individuals they suspect to be taking the active drugs on the basis of reported side effects. This amplified placebo effect is difficult to demonstrate empirically, but several metaanalyses have found that trials with more rigorously blind conditions demonstrated lower medication effects, compared with placebo, than other trials.2,3 These metaanalyses have been criticized with some justification, partly owing to the low quality of the included trials. Nevertheless, although critics are right to point out that the effects of placebo amplification have not been conclusively demonstrated, neither have they been refuted.

Therefore, the clinical significance of small differences in rating scale scores in RCTs comparing antidepressants with placebo is unclear. These differences could easily be accounted for by nonspecific pharmacologic effects, such as sedation, or by amplified placebo effects. Evidence from other sources does not suggest that antidepressants have a beneficial impact on the outcome of depression. Naturalistic studies indicate that people treated with antidepressants do less well than people who are not treated with them, even after controlling for the severity of the original condition.4 Despite the enormous increase in antidepressant prescribing in the West over the last decade and a half, epidemiologic evidence suggests that the prevalence of depressive episodes is higher than ever.5 Evidence on suicide and absence due to sickness does not suggest that antidepressant use has contributed to reducing the consequences of depression. Despite some claims that antidepressants have contributed to falling suicide rates, there is abundant evidence that suicide trends are long-standing and independent of patterns of antidepressant use. 6 Rates of sickness absence due to depression increased substantially in the United Kingdom during the 1990s, when antidepressant prescribing was soaring.

Long-Term Studies

The fact that many people appear to relapse after discontinuing long-term maintenance treatment with antidepressants for recurrent depression is often perceived as strong evidence for the efficacy of antidepressants. However, the evidence does not warrant this conclusion. Studies of maintenance or long-term treatment are effectively discontinuation studies. They take a group of individuals who have improved on antidepressants and randomize some of them to have the antidepressant withdrawn and replaced by placebo, usually quite rapidly. Thus the placebo group is really an antidepressant discontinuation group. It is now well recognized that antidepressants are associated with a discontinuation syndrome, but this was not widely acknowledged when most maintenance studies were done. Discontinuation symptoms potentially invalidate maintenance trials, first, because they may be mistaken for early signs of relapse in their own right and, second, because they may unblind participants, making them more vulnerable to relapse through a “nocebo effect”—the inverse of the placebo effect—wherein negative expectations cause physical illness or psychological distress. Negative expectations are likely in participants in maintenance trials, given that by definition they initially “responded” to antidepressants and are therefore likely to believe in their efficacy.

Viguera et al7 have suggested that antidepressant withdrawal may increase vulnerability to relapse in its own right, independent of the course of the underlying condition, as is the case for lithium withdrawal. In a metaanalysis of maintenance trials, these authors found that relapses tended to cluster after withdrawal, with declining risk thereafter, suggesting that the event of withdrawal is associated with relapse. In addition, the risk of relapse was constant whether patients had been taking antidepressants for 3 weeks or 4 years. This also suggests a withdrawal-related effect, since a greater length of stability would generally be expected to predict a lower relapse rate if withdrawal were merely revealing the underlying course of the disorder.

An Alternative View of the Action of Antidepressants

Elsewhere, I have suggested that psychiatric drugs should be viewed as acting not by targeting and redressing abnormal biochemical states but by causing abnormal drug-induced states.8 These drug-induced states, such as the sedation and indifference produced by neuroleptics in acute psychosis, may be useful in some acute psychiatric conditions. Different antidepressants produce a range of drug-induced effects. Tricyclic antidepressants cause profound sedation and cognitive impairment. The effects of selective serotonin reuptake inhibitors are less pronounced, but they appear to cause both mild stimulant and sedating effects. There is no evidence other than that derived from RCTs that antidepressants elevate mood. In volunteer studies, they either cause dysphoria or they have no effect; nor, for reasons spelled out above, do the results of RCTs with patients suffering from depression confirm that antidepressants affect mood in patients either, other than possibly through amplified placebo effects. Although many drugs are known to cause short-term, context-dependent euphoria or mood elevation, there is no evidence that any drugs, including antidepressants, can produce long-term mood elevation.9 Sedative effects may be useful in the short term in some cases of depression accompanied by agitation, sleep impairment, or anxiety. However, it is difficult to think of any other recognized drug-induced effects that are desirable in depression.

Conclusion

I suggest that the term “antidepressant” is a misnomer. The small advantage that antidepressants have over placebo in RCTs is easily accounted for by nonspecific psychological and pharmacologic effects. Other evidence does not confirm that antidepressants have a clinically significant effect. We have no reason to suppose that any drugs can reverse the diverse problems that are labelled as depression. We need to emphasize other ways of responding to people who seek help from psychiatrists when they are distressed. The quest for the magic bullet for depression may be a wild goose chase.

References

1. Kirsch I, Moore TJ, Scoboria A, et al. 2002. The emperor’s new drugs: an analysis of antidepressant medication data submitted to the US Food and Drug Administration. Prevention and Treatment [Internet]. [cited 30 Nov 2006] (1). Available from: http://www.content.apa.org/journals/pre/5/1/23.
2. Moncrieff J, Wessely S, Hardy R. Meta-analysis of trials comparing antidepressants with active placebos. Br J Psychiatry. 1998;172:227–231.
3. Greenberg RP, Bornstein RF, Greenberg MD, et al. A meta-analysis of antidepressant outcome under “blinder” conditions. J Consult Clin Psychol. 1992;60(5):664–669.
4. Brugha TS, Bebbington PE, MacCarthy B, et al. Antidepressants may not assist recovery in practice: a naturalistic prospective survey. Acta Psychiatr Scand. 1992;86(1):5–11.
5. Patten SB. The impact of antidepressant treatment on population health: synthesis of data from two national data sources in Canada. Popul Health Metr. 2004;2(1):9.
6. Moncrieff J, Kirsch I. Efficacy of antidepressants in adults. BMJ. 2005;331(7509):155–157.
7. Viguera AC, Baldessarini RJ, Friedberg J. Discontinuing antidepressant treatment in major depression. Harv Rev Psychiatry. 1998;5(6):293–306.
8. Moncrieff J, Cohen D. Rethinking models of psychotropic drug action. Psychother Psychosom. 2005;74(3):145–153.
9. Moncrieff J, Cohen D. Do antidepressants cure or create abnormal brain states? PLoS Med. 2006;3(7):e240.

 

FunkOdyssey

Well-Known Member
The following paper claims that most, if not all, benefits of antidepressants are due to placebo effect:

Z Psychol. 2014; 222(3): 128–134.
doi: 10.1027/2151-2604/a000176

Antidepressants and the Placebo Effect​

Irving Kirsch

Abstract​

Antidepressants are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin in the brain. Indeed, their supposed effectiveness is the primary evidence for the chemical imbalance theory. But analyses of the published data and the unpublished data that were hidden by drug companies reveals that most (if not all) of the benefits are due to the placebo effect. Some antidepressants increase serotonin levels, some decrease it, and some have no effect at all on serotonin. Nevertheless, they all show the same therapeutic benefit. Even the small statistical difference between antidepressants and placebos may be an enhanced placebo effect, due to the fact that most patients and doctors in clinical trials successfully break blind. The serotonin theory is as close as any theory in the history of science to having been proved wrong. Instead of curing depression, popular antidepressants may induce a biological vulnerability making people more likely to become depressed in the future.

Introduction​

On February 26, 2008, an article about antidepressants that my colleagues and I wrote was published in the journal PLoS Medicine (Kirsch et al., 2008). That morning, I awoke to find that our paper was the front page story in all of the leading national newspapers in the United Kingdom. A few months later, Random House invited me to expand the article into a book, entitled The Emperor’s New Drugs: Exploding the Antidepressant Myth, which has since been translated into French, Italian, Japanese, Polish, and Turkish (Kirsch, 2009). Two years later, the book, and the research reported in it, was the topic of a five-page cover story in the influential American news magazine, Newsweek. And 2 years after that, it was the focus of a 15-min segment on 60 Minutes, America’s top-rated television news program. Somehow, I had been transformed, from a mild-mannered university professor into a media superhero – or super villain, depending on whom you asked. What had my colleagues and I done do warrant this transformation?

To answer that question, we have to go back to 1998, when a former graduate student, Guy Sapirstein, and I published a meta-analysis on antidepressants in an online journal of the American Psychological Association (Kirsch & Sapirstein, 1998). When they were new, meta-analyses were somewhat controversial and our article was accompanied by an editorial warning to that effect – not unlike the suicide warning that the US Food and Drug Administration (FDA) requires for antidepressants. But now meta-analyses are published in all of the major medical journals, where they are widely considered to be the best and most reliable way of making sense of the data from studies with different and sometimes conflicting results.

When Sapirstein and I began our analysis of the antidepressant clinical trial data, we were not particularly interested in antidepressants. Instead, we were interested in understanding the placebo effect. I have been fascinated by the placebo effect for my entire academic career. How is it, I wondered, that the belief that one has taken a medication can produce some of the effects of that medication?

It seemed to Sapirstein and me that depression was a good place to look for placebo effects. After all, one of the prime characteristics of depression is the sense of hopelessness that depressed people feel. If you ask depressed people to tell you what the worst thing in their life is, many will tell you that it is their depression. The British psychologist John Teasdale called this being depressed about depression (Teasdale, 1985). If that is the case, then the mere promise of an effective treatment should help to alleviate depression, by replacing hopelessness with hopefulness – the hope that one will recover after all. It was with this in mind that we set out to measure the placebo effect in depression.

We searched the literature for studies in which depressed patients had been randomized to receive an inert placebo or no treatment at all. The studies we found also included data on the response to antidepressants, because that was the only place one finds data on the response to placebo among depressed patients. I was not particularly interested in the drug effect. I assumed that antidepressants were effective. As a psychotherapist, I sometimes referred my severely depressed clients for prescriptions of antidepressant drugs. Sometimes the condition of my clients improved when they began taking antidepressants; sometimes it did not. When it did, I assumed it was the effect of the drug that was making them better. Given my long standing interest in the placebo effect, I should have known better, but back then I did not.

Analyzing the data we had found, we were not surprised to find a substantial placebo effect on depression. What surprised us was how small the drug effect was. Seventy-five percent of the improvement in the drug group also occurred when people were give dummy pills with no active ingredient in them. Needless to say, our meta-analysis proved to be very controversial. Its publication led to heated exchanges (e.g., Beutler, 1998; Kirsch, 1998; Klein, 1998). The response from critics was that these data could not be accurate. Perhaps our search had led us to analyze an unrepresentative subset of clinical trials. Antidepressants had been evaluated in many trials, the critics said, and their effectiveness had been well established.

In an effort to response to these critics, we decided to replicate our study with a different set of clinical trials (Kirsch, Moore, Scoboria, & Nicholls, 2002). To do this, we used the Freedom of Information Act to request that the Food and Drug Administration (FDA) send us the data that pharmaceutical companies had sent to it in the process of obtaining approval for six new generation antidepressants that accounted for the bulk of antidepressant prescriptions being written at the time. There are a number of advantages to the FDA data set. Most important, the FDA requires that the pharmaceutical companies provide information on all of the clinical trials that they have sponsored. Thus, we had data on unpublished trials as well as published trials. This turned out to be very important. Almost half of the clinical trials sponsored by the drug companies have not been published (Melander, Ahlqvist-Rastad, Meijer, & Beermann, 2003; Turner, Matthews, Linardatos, Tell, & Rosenthal, 2008). The results of the unpublished trials were known only to the drug companies and the FDA, and most of them failed to find a significant benefit of drug over placebo. A second advantage of the FDA trials in the FDA dataset is that they all used the same primary measure of depression – the Hamilton depression scale (HAM-D). That made it easy to understand the clinical significance of the drug-placebo differences. Finally, the data in the FDA files were the basis upon which the medications were approved. In that sense they have a privileged status. If there is anything wrong with those trials, the medications should not have been approved in the first place.

In the data sent to us by the FDA, only 43% of the trials showed a statistically significant benefit of drug over placebo. The remaining 57% were failed or negative trials. Similar results have been reported in other meta-analyses (Turner et al., 2008), including one conducted by the FDA on the clinical trials of all antidepressants that it had approved between 1983 and 2008 (Khin, Chen, Yang, Yang, & Laughren, 2011). The results of our analysis indicated that the placebo response was 82% of the response to these antidepressants. Subsequently, my colleagues and I replicated our meta-analysis on a larger number of trials that had been submitted to the FDA (Kirsch et al., 2008). With this expanded data set, we found once again that 82% of the drug response was duplicated by placebo. More important, in both analyses, the mean difference between drug and placebo was less than two points on the HAM-D. The HAM-D is a 17-item scale on which people can score from 0 to 53 points, depending on how depressed they are. A six-point difference can be obtained just by changes in sleep patterns, with no change in any other symptom of depression. So the 1.8 difference that we found between drug and placebo was very small indeed – small enough to be clinically insignificant. But you don’t have to take my word for how small this difference is. The National Institute for Health and Care Excellence (NICE), which drafts treatment guidelines for the National Health Service in the United Kingdom, has established a three-point difference between drug and placebo on the HAM-D as a criterion of clinical significance (NICE, 2004). Thus, when published and unpublished data are combined, they fail to show a clinically significant advantage for antidepressant medication over inert placebo.

I should mention here the difference between statistical significance and clinical significance. Statistical significance concerns how reliable an effect is. Is it a real effect, or is it just due to chance? Statistical significance does not tell you anything about the size of the effect. Clinical significance, on the other hand, deals with the size of an effect and whether it would make any difference in a person’s life. Imagine, for example, that a study of 500,000 people has shown that smiling increases life expectancy – by 5 min. With 500,000 subjects, I can virtually guarantee you that this difference will be statistically significant, but it is clinically meaningless.

The results of our analyses have since been replicated repeatedly (Fountoulakis & Möller, 2011; Fournier et al., 2010; NICE, 2004; Turner et al., 2008). Some of the replications used our data; others analyzed different sets of clinical trials. The FDA even did its own meta-analysis on all of the antidepressants that they have approved (Khin et al., 2011). But and despite differences in the way the data have been spun, the numbers are remarkably consistent. Differences on the HAM-D are small – always below the criterion set by NICE. Thomas P. Laughren, the director of the FDA’s psychiatry products division, acknowledged this on the American television news program 60 Minutes. He said, “I think we all agree that the changes that you see in the short-term trials, the difference in improvement between drug and placebo is rather small.”

And it is not only the short-term trials that show a small, clinically insignificant difference between drug and placebo. In their meta-analysis of published clinical trials, NICE (2004) found that the difference between drug and placebo in the long-term trials were no larger than those in short-term trials.

Severity of Depression and Antidepressant Effectiveness​

Critics of our 2002 meta-analysis argued that our results were based on clinical trials conducted on subjects who were not very depressed (e.g., Hollon, DeRubeis, Shelton, & Weiss, 2002; Thase, 2002). In more depressed patients, they argued, a more substantial difference might be found. This criticism led my colleagues and I to reanalyze the FDA data in 2008 (Kirsch et al., 2008). We categorized the clinical trials in the FDA database according to the severity of the patients’ depression at the beginning of the trial, using conventionally used categories of depression. As it turns out, all but one of the trials were conducted on moderately depressed patients, and that trial failed to show any significant difference between drug and placebo. Indeed, the difference was virtually nil (0.07 points on the HAM-D). All of the rest of the trials were conducted on patients whose mean baseline scores put them in the “very severe” category of depression, and even among these patients, the drug-placebo difference was below the level of clinical significance.

Still, severity did make a difference. Patients at the very extreme end of depression severity, those scoring at least 28 on the HAM-D, showed an average drug-placebo difference of 4.36 points. To find out how many patients fell within this extremely depressed group, I asked Mark Zimmerman from the Brown University School of Medicine to send me the raw data from a study in which he and his colleagues assessed HAM-D scores of patients who had been diagnosed with unipolar major depressive disorder (MDD) after presenting for an intake at a psychiatric outpatient practice (Zimmerman, Chelminski, & Posternak, 2005). Patients with HAM-D scores of 28 or above represented 11% of these patients. This suggests that 89% of depressed patients are not receiving a clinically significant benefit from the antidepressants that are prescribed for them.

Yet this 11% figure may overestimate the number of people who benefit from antidepressants. Antidepressants are also prescribed to people who do not qualify for the diagnosis of major depression. My neighbor’s pet dog died; his physician prescribed an antidepressant. A friend in the US was diagnosed with lumbar muscle spasms and was prescribed an antidepressant. I have lost count of the number of people who have told me they were prescribed antidepressants when complaining of insomnia – even though insomnia is a frequently reported side effect of antidepressants. About 20% of patients suffering from insomnia in the United States are given antidepressants as a treatment by their primary care physicians (Simon & VonKorff, 1997), despite the fact that “the popularity of antidepressants in the treatment of insomnia is not supported by a large amount of convincing data, but rather by opinions and beliefs of the prescribing physicians” (Wiegand, 2008, p. 2411).

Predicting Response to Treatment​

Severity of depression is one of the few predictors of response to treatment. Type of antidepressant little if any impact on treatment response. As summarized in a 2011 meta-analysis of studies comparing one antidepressant to another:

On the basis of 234 studies, no clinically relevant differences in efficacy or effectiveness were detected for the treatment of acute, continuation, and maintenance phases of MDD. No differences in efficacy were seen in patients with accompanying symptoms or in subgroups based on age, sex, ethnicity, or comorbid conditions… Current evidence does not warrant recommending a particular second-generation antidepressant on the basis of differences in efficacy (Gartlehner et al., 2011, p. 772).
Although type of medication does not make a clinically significant difference in outcome, response to placebo does. Almost all antidepressant trials include a placebo run-in phase. Before the trial begins, all of the patients are given a placebo for a week or two. After this run-in period, the patients are reassessed, and anyone who has improved substantially is excluded from the trial. That leaves patients who have not benefitted at all from placebo and those who have benefited only a little bit. These are the patients who are randomized to be given drug or kept on placebo. As it turns out, the patients who show at least a little improvement during the run-in period are the ones most likely to respond to the real drug, as shown not only by physician ratings, but also by changes in brain function (Hunter, Leuchter, Morgan, & Cook, 2006; Quitkin et al., 1998).

How Did These Drugs Get Approved?​

How is it possible that medications with such weak efficacy data were approved by the FDA? The answer lies in an understanding of the approval criteria used by the FDA. The FDA requires two adequately conducted clinical trials showing a significant difference between drug and placebo. But there is a loophole: There is no limit to the number of trials that can be conducted in search of these two significant trials. Trials showing negative results simply do not count. Furthermore, the clinical significance of the findings is not considered. All that matters is that the results are statistically significant.

The most egregious example of the implementation of this criterion is provided by the FDA’s approval of vilazodone in 2011. Seven controlled efficacy trials were conducted. The first five failed to show any significant differences on any measure of depression, and the mean drug-placebo difference in these studies was less than ½ point on the HAM-D, and in two of the three trials, the direction of the difference actually favored the placebo. The company ran two more studies and managed to obtain small but significant drug-placebo differences (1.70 points). The mean drug-placebo difference across the seven studies was 1.01 HAM-D points. This was sufficient for the FDA to grant approval, and the information approved by the FDA for informing doctors and patients reads, “The efficacy of VIIBRYD was established in two 8-week, randomized, double-blind, placebo-controlled trials.” No mention is made of the five failed trials that preceded the two successful ones.

The failure to mention the unsuccessful trials was not merely an oversight; it reflects a carefully decided FDA policy dating back for decades. To my knowledge, there is only one antidepressant in which the FDA included information on the existence of negative trials. The exception is citalopram, and the inclusion of the information followed an objection raised by Paul Leber, who was at the time the director of the FDA Division of Neuropharmacological Drug Products. In an internal memo dated May 4, 1998, Leber wrote:

One aspect of the labeling deserves special mention. The [report] not only describes the clinical trials providing evidence of citalopram’s antidepressant effects, but make mention of adequate and well-controlled clinical studies that failed to do so… The Office Director is inclined toward the view that the provision of such information is of no practical value to either the patient or prescriber. I disagree. I believe it is useful for the prescriber, patient, and 3rd-party payer to know, without having to gain access to official FDA review documents, that citalopram’s antidepressants effects were not detected in every controlled clinical trial intended to demonstrate those effects. I am aware that clinical studies often fail to document the efficacy of effective drugs, but I doubt that the public, or even the majority of the medical community, is aware of this fact. I am persuaded that they not only have a right to know but that they should know. Moreover, I believe that labeling that selectively describes positive studies and excludes mention of negative ones can be viewed as potentially “false and misleading.” (Leber, May 4, 1998).
Hooray for Paul Leber. I have never met or corresponded with this gentleman, but because of this courageous memo, he is one of my heroes.

The Serotonin Myth​

Over the years, I have noticed something very strange in the antidepressant literature. When different antidepressants are compared with each other, their effects are remarkable similar. I first noticed this when Guy Sapirstein did our 1998 meta-analysis of the published literature. When we first saw how small the actual drug effect was, we thought we might have done something wrong. Perhaps we had erred by including trials that had evaluated different types of antidepressants. Maybe we are underestimating the true effectiveness of antidepressants by including clinical trials of drugs that were less effective than others.

Before submitting our paper for publication, we went back to the data and examined the type of antidepressant used each trial. Some were selective serotonin reuptake inhibitors (SSRIs), others were tricyclic medications, we lumped together the trials on antidepressant drugs that were neither SSRIs nor tricyclics and called them “other antidepressants.” And then we noticed that there was a fourth category of drugs in the trials were had analyzed. These were trials in which drugs that are not thought to be antidepressants at all – tranquilizers and thyroid medications, for example – were given to depressed patients and evaluated for their effect on depression.

When we analyzed the drug and placebo response for each type of drug, we found another surprise awaiting us. It did not matter what kind of drug the patients had been given in the trial. The response to the drug was always the same, and 75% of that response was also found in the placebo groups. I recall being impressed by how unusual the similarity in results was, but I have since learned that they are not unusual at all. I have since encountered this phenomenon over and over again. In the STAR*D trial, which, at a cost of $35,000,000, is the most costly clinical trial of antidepressants ever conducted, patients who did not respond to the prescribed SSRI were switched to a different antidepressant (Rush et al., 2006). Some were switched to a SNRI (serotonin-noradrenalin-reuptake-inhibitor), a drug that is supposed to increase norepinephrine as well as of serotonin in the brain. Others were switched to an NDRI (norepinephrine-dopamine reuptake inhibitor), which is supposed to increase norepinephrine and dopamine, without affecting serotonin at all. And still others were simply given a different SSRI. About one out of four patients responded clinically to the new drug, but it did not matter which new drug they were given. The effects ranged from 26% to 28%; in other words, they were exactly the same regardless of type of drug.

The most commonly prescribed antidepressants are SSRIs, drugs that are supposed to selectively target the neurotransmitter serotonin. But there is another antidepressant that has a very different mode of action. It is called tianeptine, and it has been approved for prescription as an antidepressant by the French drug regulatory agency. Tianeptine is an SSRE, a selective serotonin reuptake enhancer. Instead of increasing the amount of serotonin in the brain, it is supposed to decrease it. If the theory that depression is caused by a deficiency of serotonin were correct, we would expect to make depression worse. But it doesn’t. In clinical trials comparing the effects of tianeptine to those of SSRIs and tricyclic antidepressants, 63% of patients show significant improvement (defined as a 50% reduction in symptoms), the same response rate that is found for SSRIs, NDRIs, and tricyclics, in this type of trial (Wagstaff, Ormrod, & Spencer, 2001). It simply does not matter what is in the medication – it might increase serotonin, decrease it, or have no effect on serotonin at all. The effect on depression is the same.

What do you call pills, the effects of which are independent of their chemical composition? I call them “placebos.”

Antidepressants as Active Placebos​

All antidepressants seem to be equally effective, and although the difference between drug and placebo is not clinically significant, it is significant statistically. This leads to the obvious question: What do all of these active drugs have in common that make their effect on depression slightly, but statistically significantly, better than placebo?

One think that antidepressants have in common is that they all produce side effects. Why is that important? Imagine that you are a subject in a clinical trial. You are told that the trial is double blind and that you might be given a placebo. You are told what the side effects of the medication are. The therapeutic effects of the drug may take weeks to notice, but the side effects might occur more quickly. Would you not wonder to which group you had been assigned, drug or placebo? And noticing one of the listed side effects, would you not conclude that you had been given the real drug? In one study, 89% of the patients in the drug group correctly “guessed” that they had been given the real antidepressant, a result that is very unlikely to be due to chance (Rabkin et al., 1986).

In other words, clinical trials are not really double blind. Many patients in clinical trials realize that they have been given the real drug, rather than the placebo, most likely because of the drug’s side effects. What effect is this likely to have in a clinical trial? We do not have to guess at the answer to this question. Bret Rutherford and his colleagues at Columbia University have provided the answer. They examined the response to antidepressants in studies that did not have a placebo group with those in studies where they did have a placebo group (Rutherford, Sneed, & Roose, 2009). The main difference between these studies is that in the first case, the patients were certain they were getting an active antidepressant, where as in the placebo-controlled trials, they knew that they might be given a placebo. Knowing for sure that they were getting an active drug boosted the effectiveness of the drug significantly. This supports the hypothesis that the relatively small difference between drug and placebo in antidepressant trials are at least in part due to “breaking blind” and discerning that one is in the drug group, because of the side effects produced by the drug.

What to Do?​

To summarize, there is a strong therapeutic response to antidepressant medication. But the response to placebo is almost as strong. This presents a therapeutic dilemma. The drug effect of antidepressants is not clinically significant, but the placebo effect is. What should be done clinically in light of these findings?

One possibility would be to use antidepressants as active placebos. But the risks involved in antidepressant use render this alternative problematic (Andrews, Thomson, Amstadter, & Neale, 2012; Domar, Moragianni, Ryley, & Urato, 2013; Serretti & Chiesa, 2009). Among the side effects of antidepressants are sexual dysfunction (which affects 70–80% of patients on SSRIs), long-term weight gain, insomnia, nausea, and diarrhea. Approximately 20% of people attempted to quit taking antidepressants show withdrawal symptoms. Antidepressants have been linked to increases in suicidal ideation among children and young adults. Older adults have increased risks of stroke and death from all causes. Pregnant women using antidepressants are at increased risk of miscarriage, and if they don’t miscarry, their offspring are more likely to be born with autism, birth malformations, persistent pulmonary hypertension, and newborn behavioral syndrome. Furthermore, some of these risks have been linked to antidepressant use during the first trimester of pregnancy, when women may not be aware that they are pregnant. Perhaps the most surprising health consequence of antidepressant use is one that affects people of all ages. Antidepressants increase the risk of relapse after one has recovered. People are more likely to become depressed again after treatment by antidepressants than after treatment by other means – including placebo treatment (Andrews et al., 2012; Babyak et al., 2000; Dobson et al., 2008). Furthermore, the degree to which the risk of relapse increases depends on the degree to which the particular antidepressant used changes neurotransmission in the brain. Given these health risks, antidepressants should not be used as a first-line treatment for depression.

Another possibility is to prescribe placebos. They are almost as effective as antidepressants, but elicit far fewer side effects. Surveys indicated that many physicians do in fact prescribe placebos (Raz et al., 2011; Tilburt, Emanuel, Kaptchuk, Curlin, & Miller, 2008). The conventional wisdom is that for a placebo to be effective, patients must believe they are receiving active medication, which entails deception. Besides being ethically questionable, the practice of deceiving patients runs the risk of undermining trust, which may be one of the most important clinical tools that clinicians have at their disposal. But is the conventional wisdom correct? My colleagues and I have tested and confirmed the hypothesis that placebos can be effective even when given openly, without deception, when given in the context of a warm therapeutic relationship and with an honest but convincing rationale as to why they should be effective (Kaptchuk et al., 2010). Our study targeted irritable bowel syndrome, rather than depression, but a small pilot study suggests that it might also work in the treatment of depression (Kelley, Kaptchuk, Cusin, Lipkin, & Fava, 2012). Until this is confirmed, however, placebo treatment is not a viable option.

Fortunately, placebos are not the only alternative to antidepressant treatment. My colleagues and I have conducted a meta-analysis of various treatments for depression, including antidepressants, psychotherapy, the combination of psychotherapy and antidepressants, and “alternative” treatments, which included acupuncture and physical exercise (Khan, Faucett, Lichtenberg, Kirsch, & Brown, 2012). We found no significant differences between these treatments or within different types of psychotherapy. When different treatments are equally effective, choice should be based on risk and harm, and of all of these treatments, antidepressant drugs are the riskiest and most harmful. If they are to be used at all, it should be as a last resort, when depression is extremely severe and all other treatment alternatives have been tried and failed.

 

FunkOdyssey

Well-Known Member
This paper claims antidepressants are ineffective and increase risk of suicide and all-cause mortality:

Front Psychiatry. 2017; 8: 275.
doi: 10.3389/fpsyt.2017.00275

Methodological Flaws, Conflicts of Interest, and Scientific Fallacies: Implications for the Evaluation of Antidepressants’ Efficacy and Harm​

Michael P. Hengartner1,*

Abstract​

Background

In current psychiatric practice, antidepressants are widely and with ever-increasing frequency prescribed to patients. However, several scientific biases obfuscate estimates of antidepressants’ efficacy and harm, and these are barely recognized in treatment guidelines. The aim of this mini-review is to critically evaluate the efficacy and harm of antidepressants for acute and maintenance treatment with respect to systematic biases related to industry funding and trial methodology.

Methods

Narrative review based on a comprehensive search of the literature.

Results

It is shown that the pooled efficacy of antidepressants is weak and below the threshold of a minimally clinically important change once publication and reporting biases are considered. Moreover, the small mean difference in symptom reductions relative to placebo is possibly attributable to observer effects in unblinded assessors and patient expectancies. With respect to trial dropout rates, a hard outcome not subjected to observer bias, no difference was observed between antidepressants and placebo. The discontinuation trials on the efficacy of antidepressants in maintenance therapy are systematically flawed, because in these studies, spontaneous remitters are excluded, whereas half of all patients who remitted on antidepressants are abruptly switched to placebo. This can cause a severe withdrawal syndrome that is easily misdiagnosed as a relapse when assessed on subjective symptom rating scales. In accordance, the findings of naturalistic long-term studies suggest that maintenance therapy has no clear benefit, and non-drug users do not show increased recurrence rates. Moreover, a growing body of evidence from hundreds of randomized controlled trials suggests that antidepressants cause suicidality, but this risk is underestimated because data from industry-funded trials are systematically flawed. Unselected, population-wide observational studies indicate that depressive patients who use antidepressants are at an increased risk of suicide and that they have a higher rate of all-cause mortality than matched controls.

Conclusion

The strong reliance on industry-funded research results in an uncritical approval of antidepressants. Due to several flaws such as publication and reporting bias, unblinding of outcome assessors, concealment and recoding of serious adverse events, the efficacy of antidepressants is systematically overestimated, and harm is systematically underestimated. Therefore, I conclude that antidepressants are largely ineffective and potentially harmful.

Introduction​

Treatment guidelines for major depression (MD) in Europe and the United States typically recommend antidepressant medication with or without psychotherapy (1). In particular, the American Psychiatric Association (APA) advises antidepressants as first-line treatment for all forms of MD, including mild episodes (2). The APA further recommends antidepressants not only for acute treatment but also for continuation therapy (approximately 4–9 months) and maintenance therapy (several years up to indefinite time). Overall, the APA treatment guidelines for adult MD provide are very favorable risk–benefit analysis for selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), suggesting that these drug classes are highly effective, well tolerated, and safe. However, paradoxically the massive increase in antidepressant prescription rates over the last three decades did not translate into measurable public health benefits (35). From a public mental health perspective, we would expect that effective antidepressants reduce the prevalence and burden of MD, unless the scientific evidence is unreliable. In the following, I will therefore provide a critical re-examination of antidepressants’ efficacy and safety. I will mostly rely on evidence from randomized controlled trials (RCTs), as these are considered gold-standard to establish causality and efficacy of clinical interventions. Although RCTs are less prone to bias than observational studies, they also have limitations, in particular in industry-funded pharmacological research (68). A special emphasis will hence be given to the unduly ties between scientific psychiatry and the pharmaceutical industry (911). I will first examine antidepressants’ efficacy for acute treatment, proceed with a review of their efficacy for continuation and maintenance therapy, and close with an outline of severe harms. Scientific biases will be discussed in context, as they substantially inflate antidepressants’ public health significance.

Acute Therapy​

Research funded by the pharmaceutical industry is systematically biased toward their marketed products (1215). That is, the estimated efficacy of pharmaceutical products is significantly higher when the research was funded by the industry compared to non-industry funding, but this difference is not attributable to differences in the study quality (13, 14). For instance, research funded and conducted by the NIMH largely failed to demonstrate a clear difference between antidepressants and placebo, despite adequate sample sizes and strong RCT methodology [e.g., Ref. (16, 17)]. Research conducted by authors with financial conflicts of interest (COI) related to the pharmaceutical industry is likewise systematically biased in favor of the industry’s vested interests (1820). That is, efficacy of pharmacological treatments is overestimated, whereas harms are underreported. Due to the pervasive entanglement of psychiatry with the pharmaceutical industry (911, 21), these biases undermine the validity of the scientific literature on antidepressants’ efficacy. For instance, it is now clearly established that many industry-funded antidepressant trials were never published, and if published, some results were inadequately presented in a favorable way (15, 22, 23). That is, trials with negative results are either not published or negative results are distorted to appear positive (7, 24). Outcome reporting bias is a common scientific flaw and means that authors conceal the effect of the prespecified primary efficacy outcome and instead choose to report the most convenient from different secondary outcomes (25). Also, harms and serious adverse events of antidepressants are often not reported, and such concealment is strongly related to authors’ financial COI and industry funding (26). Another common flaw is to report efficacy based on drug-placebo differences in response and remission rates (27). To come at binary constructs such as response and remission, continuous symptom rating scales are dichotomized along arbitrary cut-offs. However, methodologists have vigorously advised against the use of dichotomization (2830) because it produces, among others, systematically inflated effect sizes (3133). Most short-term efficacy RCTs were conducted to receive marketing approval from regulatory agencies. To ensure that drug-placebo differences in the outcome are clearly attributable to the intervention, efficacy RCT use preselected groups of participants tested under ideal clinical settings (34). Therefore, trial conditions markedly deviate from real-world clinical settings, and the included participants are not representative of the patient population seen in routine clinical practice. Specifically, RCT exclude a majority of MD patients due to comorbid disorders and suicidal ideation (35). Included participants are less impaired and have a higher level of functioning (36, 37), and it has been demonstrated that they respond better to antidepressants than the average real-world patient (36).

Meta-analyses that include unpublished trials and that examine mean differences in continuous depression rating scales report statistically significant but marginally small differences between antidepressants and placebo (23, 3840). More recent studies have suggested that drug-placebo differences are larger when instead of heterogeneous sum-scores, which also include somatic symptoms, only depressive core symptoms were considered (41, 42). However, the results barely support this conclusion, because estimated effect sizes are still small and considered clinically insignificant per convention. But what exactly means clinically significant? In general, clinical significance refers to an effect size d or g > 0.5 or a difference >3 points on the Hamilton Depression Scale for Depression (HAMD) (38). However, empirical evidence has suggested that at least 7 points on the HAMD or an effect size >0.87 is necessary for a clinician to observe a minimal improvement in depression symptoms (43). Based on these criteria, the efficacy of antidepressants is impossible to discern from placebo effects in any meta-analysis conducted thus far.

Some authors deem the small difference between antidepressants and placebo a methodological artifact (27, 4446). For instance, Chen et al. (47) re-analyzed a double-blind RCT with the treatment arms antidepressant (sertraline), St John’s Wort, and placebo, with respect to patients’ treatment beliefs. Depression symptom reduction did not differ between treatment arms. However, independent of actual treatment received, patients who believed they receive placebo showed less improvement, and patients who correctly guessed that they receive placebo improved even less. One hypothesis states that the assumption of blinding is violated even in double-blind RCT, because both patients and outcome assessors may correctly guess who receives placebo due to a suspicious lack of side effects (44). Such unblinding effects inflate the apparent efficacy of antidepressants, because unblinded outcome assessors systematically overestimate the efficacy of experimental interventions (48, 49). Taking into account the unblinding bias, Gotzsche (50) calculated that the average efficacy of antidepressants does not differ from placebo. More reliable than differences in subjective rating scales are objective outcomes such as premature treatment termination. Several meta-analyses did not detect a noticeable difference between antidepressant and placebo arms with respect to overall dropout rates in short-term RCT (5153). Assuming that patients prematurely terminate a free treatment only if they perceived it as useless or even harmful (54), these findings indicate that the average patient experiences no clear benefits from antidepressants.

Continuation and Maintenance Therapy​

There are two trial designs to examine effects of long-term antidepressant use. The first is the long-term parallel-arm efficacy trial, where responders to both antidepressants and placebo are followed up. The second, much more common design, is the discontinuation trial, where antidepressant responders are randomly assigned to either continued therapy or rapid discontinuation and switching to placebo. In a recent meta-analysis of long-term parallel-arm RCT of 6–8 months duration, no difference between groups was found with respect to both remission and treatment discontinuation rates (55). Meta-analyses of discontinuation trials suggest that long-term antidepressant use may prevent relapse, but only very few trials have empirically examined that effect for 2 years or more (56, 57). In addition, effects in discontinuation trials are difficult to interpret, because they exclusively include participants who remitted during acute open-label antidepressant treatment. Therefore, it is not known how many patients would have relapsed if they had remitted spontaneously, i.e., without prior acute antidepressant therapy (55). This is a serious issue, because it has been argued that antidepressants prospectively increase the relapse rate due to pharmacodynamics (58, 59). Another problem with discontinuation trials is the rapid discontinuation of antidepressants and immediate switching to placebo given the ambiguous nature of subsequently emerging symptoms (60). Research has shown that antidepressants may cause severe withdrawal symptoms after discontinuation (61, 62), which in some cases persist for months and therefore are easily misdiagnosed as depression relapse (63). That is, a substantial portion of depression relapses in discontinuation trials are in fact discontinuation or withdrawal syndromes. In support of this notion, it has been shown that rapid discontinuation of antidepressants, relative to gradual tapering, prospectively increases the risk of depression reoccurrence (64), but note that even very slow tapering may cause severe mood disturbances (61, 63). It has further been shown that the preventive effects of antidepressants dissipate after 1–3 months (65). At the latest after 6 months, the risk of re-occurrences is identical in antidepressant and placebo arms (66).

Some authors suggest that long-term antidepressant use may increase the vulnerability for (recurrent) depression due to neurochemical sensitization (58, 59). In support of this thesis, a recent meta-analysis revealed that the relapse risk after antidepressant discontinuation correlates positively with the duration of preceding acute therapy (57). That is, the longer antidepressant treatment, the higher the relapse risk after discontinuation. Moreover, several meta-analyses showed that psychotherapy reduces the long-term relapse risk significantly more than pharmacotherapy, despite both therapies being equally effective during acute therapy (67, 68). A systematic review of observational long-term studies found that maintenance therapy conveys no clear benefits: antidepressant users had no better long-term outcome than non-users (69). In an observational study of patients with remitted recurrent depression, maintenance therapy related to a higher recurrence rate than discontinuation (70). Other observational studies likewise suggest that antidepressant use may worsen the long-term outcome (71, 72), but causality is uncertain due to confounding by indication. A few highly cited epidemiologic studies reported that long-term antidepressant medication relates to lower relapse rates, but these have been shown to be methodologically flawed: when properly analyzed, maintenance therapy is not associated with lower relapse rates (73). Finally, according to the re-analysis of STAR*D (54), only 5.8% of all patients who entered continuation therapy were still in remission after 12-month follow-up. A total of 37.4% of remitted patients, and altogether 64.4% of improved patients had a relapse within the first 12 months of continuation therapy.

Severe Harm​

In children, adolescents and young adults up to 25 years, several meta-analyses of short-term RCT have confirmed that antidepressants, relative to placebo, significantly increase suicide risk (7477). Moreover, there is now increasing evidence from several RCT and a few well-controlled observational studies that antidepressants may increase suicide risk in adults of any age. On the basis of Bayes’ statistics, Aursnes et al. (78) calculated that paroxetine, compared to placebo, may cause suicide with a certainty of 98–99%. Baldessarini et al. (79) meta-analyzed long-term RCT for adult MD and found a markedly increased rate of completed and attempted suicides in antidepressant arms compared to placebo. With respect to suicidality, i.e., suicide attempts, self-harm, and suicidal ideation combined, a meta-analysis found that antidepressants convey a 2.5 times increased risk (80). Another meta-analysis found that paroxetine increases suicidality in adults aged 18 years and older by a factor 2.6 (51). Gunnell et al. (81) found weak meta-analytic evidence for a slightly increased risk of self-harm in antidepressant users, but not with respect to suicides or suicidal ideation. The recent meta-analysis by Sharma et al. (75) did not find increased suicidality in adult antidepressant users relative to placebo. In contrast to that, Stone et al. (76) meta-analyzed data from pharmaceutical companies submitted to the FDA and found that suicidality was slightly increased in placebo groups for adults aged 25–64 years (relative risk: 1.3), and it was even markedly increased in adults aged 65 years and older (relative risk: 2.7). These findings suggest that antidepressants may protect against suicide in middle-aged and older adults, which conflicts with the findings of all other meta-analyses detailed above. However, the work by Stone et al. (76) was criticized, because many cases of suicidality were evidently missing in antidepressant treatment arms (50). In accordance, many authors concluded that industry-funded trials are unreliable, as they willingly underreport cases of suicidality in antidepressant arms (80, 81), for instance by coding suicide attempts as “emotional lability” (75).

Just as the apparent efficacy of antidepressants is overestimated due to publication and reporting biases (15, 23), the pharmaceutical industry conceals harms by underreporting serious adverse events (14, 52, 82). Because RCT typically excludes severely impaired persons with suicidal ideation (35, 36), they run the risk to overlook a pernicious risk. Therefore, industry-funded research systematically underestimates the harm caused by their marketed drugs (14). Although scientifically less stringent (due to confounding by indication), I therefore need to consider well-controlled observational studies conducted by researchers without COI. An advantage of observational studies is that they can encompass much longer time frames than the short-term RCT typically lasting only 6–8 weeks. Due to much larger samples, observation studies allow for detecting harms occurring at low absolute frequency (34). A large naturalistic study with close to 240,000 persons with MD aged between 20 and 64 years found that antidepressant users committed 2.6 times more often suicide than non-users (83). Another well-controlled observational study based on a national register of 5,866 suicides showed that antidepressant use increases the odds of committing suicide 2.7 times in women and 4.3 times in men, with a clear increase in risk with higher age (84). Finally, several ecologic studies supposedly show a negative correlation between national antidepressant sales/prescriptions and suicide rates (suggesting that antidepressants prevent suicide), but these studies are substantially flawed (85) and some were clearly disconfirmed (3, 5).

Naturalistic studies with high power have further shown that antidepressant use prospectively relates to all-cause mortality. For instance, in a study with over 60,000 patients with MD aged 65 years and older, it was shown that over a mean follow-up of 5.0 years, prescription of tricyclics increase the relative mortality rate by 16%, SSRI by 54%, and other antidepressants (mostly SNRI) by 66% (86). In another prospective observational study including over 136,000 postmenopausal women, it was shown that SSRI increase the relative mortality rate by 32% and tricyclics by 67% (87). Finally, a recent meta-analysis showed that antidepressants increase the all-cause mortality risk by 33% in the general population with no difference between SSRI and tricyclics (88). Due to thorough multivariate statistical modeling, it is unlikely that confounding by indication may account for all these effects. Moreover, in psychiatric outpatients, antidepressant use is higher in persons with low distress (89), whereas in primary care, most antidepressants are prescribed to persons without a psychiatric diagnosis (90). Hence, it is possible that confounding by indication may even underestimate the true harm attributable to antidepressant use. Therefore, a reasonable conclusion is that antidepressants disrupt adaptive bodily processes such as digestion, immune function, tissue repair, metabolism, etc., which may lead to premature death (91, 92).

Conclusion​

The results of this mini-review suggest that the efficacy of antidepressants is systematically overestimated, while potential harms are underreported and neglected. Despite these alarming findings, thought leaders within mainstream psychiatry and official treatment guidelines strongly recommend antidepressant use for acute and long-term therapy. However, mainstream psychiatry is closely tied to the pharmaceutical industry, and most leading psychiatric experts receive substantial amounts of financial support from the industry (9, 11, 21). Thus, it is crucial to reiterate that industry-funded trials and research conducted by authors with financial COI is systematically biased toward the pharmaceutical industry’s vested interests (13, 14, 20). The strong alliance between scientific psychiatry and the pharmaceutical industry is problematic and should be subjected to close scrutiny (911, 24). Moreover, there is an ongoing debate, whether antidepressant therapy is more efficacious in severe, rather endogenous MD compared to milder, reactive MD (27). Some meta-analytic evidence suggests that this is indeed the case (93), but other failed to replicate this finding (40). Finally, the evidence reviewed in this article relied mostly on RCT, which are also subject to bias (34, 94). Theoretically, these biases could result in an underestimation of antidepressant efficacy, but evidence from real-world effectiveness trials strongly argues otherwise, since real-world patients are more impaired and respond significantly worse to antidepressant therapy (36, 37). Finally, it has been argued that the efficacy of antidepressants is underestimated in more recent trials due to marked increases in placebo responses over time. However, that claim is false. A recent meta-analysis has clearly shown that the placebo response rate has been stable for almost 30 years now (95). As concerns treatment recommendations, my reading of the literature is that some patients may benefit from acute pharmacotherapy, but on average clinical benefits are debatable and should be weighed against adverse side effects (38, 39, 51). Continuation and maintenance therapy is not recommended due to an apparent lack of clear clinical benefits (54, 55, 96), coupled with a possibly increased vulnerability to chronic depression (58, 97), increased suicide risk (79, 83), and, in particular in older adults, higher all-cause mortality (86, 88, 98).

 

FunkOdyssey

Well-Known Member
The following paper claims that long-term, CBT is far more effective than drugs in the treatment of mental illness, and that drug treatments are actually making a variety of mental illnesses worse:

EMBO Mol Med. 2016 Oct 4;8(10):1115-1117.
doi: 10.15252/emmm.201606650. Print 2016 Oct.

From neuroleptics to neuroscience and from Pavlov to psychotherapy: more than just the "emperor's new treatments" for mental illnesses?​

Jürgen Margraf 1, Silvia Schneider 1

Abstract​

After decades of proclaimed therapeutic breakthroughs, neither neurobiology nor neuroscience has led to better long‐term outcomes for any of the major mental disorders. This contrasts with the long‐term efficacy of psychosocial interventions and points to the necessity to focus on sustained success, broaden our concept of mental health problems, and resist the temptations of marketing.

“The drugs don't work” was one of the hit singles from The Verve's album Urban Hymns, released in 1997. The song was written by lead singer Richard Ashcroft relating to his drug abuse, but it might well relate to the modern treatments for mental illnesses. More than half a century after neuroleptics, antidepressants, benzodiazepines, antipsychotics, behavior therapy, and cognitive treatment were introduced, it is prudent to ask whether “the drugs don't work”.

During the past 50 years, the industrialized world has seen a dichotomy between loudly proclaimed therapeutic breakthroughs and rapidly rising numbers of people on disability payments because of mental illness. We hear that antipsychotic, antidepressant, and anti‐anxiety drugs as well as behavior therapy and newer treatments have radically improved what was described as a dismal fate of people suffering from mental disorders. Simultaneously, the percentage of disabled mentally ill patients in the USA has risen by more than 600% since the 1950s (Whitaker, 2010) and similar rates are seen in European countries. Most epidemiologists agree that this “epidemic” is not caused by increased incidence. Moreover, the once rapid succession of new therapeutic developments seems to have halted, at least in pharmacology, as big companies are withdrawing from research on mental disorders.

How can this apparent contradiction be explained? Could it be that therapeutic progress is much less than we think or are being told? Could it be that the course of depression, anxiety, schizophrenia, or ADHD has been altered for the worse? Could it be that we cannot make therapeutic progress because the concept of mental illness and its treatment is deeply flawed? There are strong reasons to assume that all three suspicions are in fact true.

So, what do we know about the efficiency of pharmacological and psychological treatments? In regard to short‐term outcomes, pharmacotherapy is clearly inferior to cognitive behavior therapy (CBT) in treating anxiety disorders; for depression, the two modalities appear to be roughly equivalent, and most clinicians would argue that drug treatments are superior to psychotherapy for treating psychotic disorders. Neither drugs nor CBT show convincing efficacy against ADHD.

However, mental disorders are fluctuating and chronic conditions. What really counts therefore is lasting improvement. Here, the picture looks radically different: Lasting success after the end of treatment has only been shown for psychotherapy (typically CBT), whereas the effects of drug treatments vanish rapidly once the drugs are withdrawn. This is obvious for anxiety disorders, depression, and ADHD and may also apply to schizophrenia.

There are now plenty of data and evidence that, in the long term, the drugs do not work.

CBT undoubtedly outperforms drug treatments (benzodiazepines, antidepressants) for anxiety disorders such as panic and phobias. Since the 1980s, Western governments have also been warning that benzodiazepines are addictive and should not be used on a long‐term basis. Moderate to strong withdrawal syndromes, worsened anxiety, cognitive impairment, and functional decline are consistent consequences of long‐term use, and there is a clear dose–response relationship. Regarding depression, it was initially claimed that 70% of the patients responded to antidepressants and 30% to placebo. Today, these numbers are actually closer to 40 and 30% (Khan & Brown, 2015). The average effect size of antidepressants in trials submitted to the FDA is 0.30 (Gibertini et al, 2012), and when looking at clinical significance and “real‐world” patients, they are on average not better than placebo (Kirsch, 2010). Even more dubious results in children and adolescents led official institutions such as the UK's MHRA to conclude that most selective serotonin reuptake inhibitors (SSRIs) to treat depression are both ineffective and harmful.

With respect to long‐term results after end of treatment, psychotherapy, especially CBT, generally outperforms antidepressants (Voderholzer & Barton, 2016): For patients with major depression, relapse after withdrawal is the rule for antidepressants (50–80%, average around 60%) but the exception for psychotherapy (20–50%, on average around 30%). For anxiety disorders, the differences are even more pronounced: The lines for the effects of placebo and of active drugs cross shortly after treatment. In contrast, positive effects remain stable for most patients who had CBT and some even experience further gains. Similarly, it is now clear that stimulants show no long‐term efficacy against ADHD. Generally, adding psychotherapy to antidepressants yields better long‐term results, but adding antidepressants to psychotherapy does not improve the outcome of treatment. In fact, the combination of exposure—the hallmark CBT treatment—and benzodiazepines or tricyclics works less well than exposure alone for treating anxiety.

So perhaps, we should not withdraw medications at all? This is exactly what has happened during the past decade in the developed countries, and it has had a host of negative long‐term effects. Psychotropic medications are classically given for long periods of time, in reality often much longer than officially acknowledged. It is easily understandable that taking psychoactive drugs would alter the targeted neurotransmitter systems over time. Among negative clinical outcomes of long‐term antidepressant use are increasing chronicity and heightened relapse rates for depression and an elevated risk of moving from unipolar to bipolar affective disorder, especially in younger patients (Fava, 2003; Whitaker, 2010; Andrews et al, 2012). The continued use of antidepressants may also propel depression to a more malignant and treatment‐unresponsive course. Compensatory neural adaptations after drug withdrawal may result in “withdrawal symptoms and increased vulnerability to relapse” (Fava, 2003). In adolescents, use of stimulants and antidepressants may lead to juvenile bipolar illness. The negative effects of benzodiazepines need not be discussed again here.

What about neuroleptics to treat schizophrenia? Remarkably, seminal WHO studies established that the long‐term outcome of schizophrenia is consistently much better in “developing countries”, where only 15.9% of patients were continuously maintained on neuroleptics, than in “developed countries”, where 61% of patients received this treatment. Moreover, the outcomes for patients in the USA have gotten worse since the 1970s and were no better in 1994 than they had been in 1900 (Hegerty et al, 1994). Potential biological explanations for these disappointing results include drug‐induced dopaminergic supersensitivity, shrinkage of the frontal lobes, enlargement of the basal ganglia and a progressive loss of frontal white matter volume associated with a worsening of negative symptoms, increased functional impairment, and cognitive decline. Long‐term use of older neuroleptics, atypical antipsychotics, and clozapine is associated with smaller brain tissue volumes (white and gray matter) that cannot be attributed to severity of illness or substance abuse. In addition, there is the well‐known risk of permanently dysfunctional dopaminergic pathways, which result in tardive dyskinesia, tardive psychosis, and tardive dementia.

Most worrisome, however, are the effects in the developing brain of children and adolescents. Most mental disorders begin before the age of 14 and continue to evolve over the whole life span. Brain development persists into the early 20s and coincides with a main risk period for mental disorders and for negative effects of interfering with neurobiology. Basic animal research shows for instance that antipsychotic treatment during the childhood/adolescent period has long‐term effects on depressive‐like, anxiety‐like, and locomotor behaviors in adult rats (De Santis et al, 2016). Many other findings in animals support similar risks, and there are emerging data in humans, for instance, with respect to heightened suicide risk after SSRI treatments.

Given the enormous investments into research for the past 60 years, why are we not more successful in treating mental disorders? One reason may be the ill‐advised biological notion of mental illnesses. First, the “myth of chemical imbalance” (Kirsch, 2010). Based on the effects of drugs on various neurotransmitter systems, it was assumed that mental disorders result from deficiencies in these systems. This has now become a standard narrative to “explain” mental disorders to patients or the public at large. In order to qualify as a causal factor, however, the assumed pathophysiology would have to exist before the onset of the mental disorder. In contrast to various psychosocial risk factors, this has not been shown convincingly. Concerning the monoamine deficiency theory, for instance, “the incongruence between the scientific literature and the claims made in FDA‐regulated SSRI advertisements is remarkable, and possibly unparalleled” (Lacasse & Leo, 2005).

Second, the reification of diagnostic constructs (“depression”) as distinct illness categories leads to an uncritical acceptance of supposed qualitative differences between “health” and “illness”, whereas research shows equivocal or even outright contradictory results. Categories with dubious validity miss the relevant dimensions of human behavior to the great detriment of scientists, clinicians, and patients. One prominent alternative approach, the US National Institute's of Mental Health′s Research Domain Criteria, aims to develop a classification based on behavioral dimensions and neurobiological measures. Its units of analysis, however, range only from genes to self‐reports, curiously omitting the social level.

Third, although we have broadened our view since George Engel introduced the bio‐psycho‐social model of illness in 1977, we have interpreted this with an increasingly narrow focus on biology and “bottom‐up” causal pathways, largely neglecting “top‐down” causal pathways. This is in stark contrast to the clearly established relationships of mental health problems with psychosocial factors. Recent findings show that the effect of social factors is largely mediated by psychological mechanisms—sense of control, mental activity, delay of gratification, self‐efficacy, and so on. Moreover, there are now reliable findings that improving social factors also improves mental health in a lasting way.

After decades of proclaimed therapeutic breakthroughs and promises of imminent better treatments based on translation of basic science into clinical practice, neither neurobiology nor neuroscience has led to measurably better long‐term outcomes for any of the major mental disorders (Margraf & Zlomuzica, 2015). Although psychotropic drugs are by far the most often used treatment modality in industrialized countries, there is no compelling evidence for the long‐term stability of their small to moderate short‐term results. The scant follow‐up evidence points to high relapse rates once medication is withdrawn and substantial negative outcomes if it is not withdrawn.

What needs to be done? First, we need better collaboration in the right places: We need to tighten the interlocking of etiological and therapeutic research strategies and of the bio‐, psycho‐, and social levels of analysis of mental disorders. Second, we need a broad and a narrow focus. While we should not give up investigating clearly defined and measured biological processes, we need to complement this by a “broader” focus on psychological and social processes. Third, we need to push back on marketing. The marketing power of Big Pharma and parts of the life sciences and medicine enjoyed remarkable economic success with a more than fivefold increase in sales of psychotropic drugs in the USA since the 1980s. Today, almost a quarter of American women in their 40s and 50s regularly take antidepressants. Lastly, we need to focus on the doable. Rather than chasing chimeras—“magic bullet” pills or fashionable new psychotherapies—we need to make sure that treatments with proven long‐term efficacy reach those who need them.

A great example for a pragmatic approach that has achieved measurable success for millions of patients is the UK′s IAPT (Improving Access to Psychological Therapies) program, which provides evidence‐based short‐term psychotherapy for anxiety and depression. Indeed, the major problem in psychotherapy, in contrast to drug treatment, is not efficiency but availability for those in need and the quality of treatment. The cost is not a major issue: A standard CBT to treat anxiety disorders, for instance, costs less per year than a drug regimen.

A realistic assessment of our current treatment options and the close cooperation of clinicians and neuroscientists would help us to overcome the current stagnation and put us back on the track forward.

 

FunkOdyssey

Well-Known Member
This paper argues you really can't call our current crop of antidepressant drugs antidepressants, because that isn't what they usually do. They more reliably cause particular side effects than relieve depression. Antiaphrodisiacs may be a more accurate term:

Scientifica (Cairo). 2012; 2012: 965908.
Published online 2012 Jun 4. doi: 10.6064/2012/965908

Relabeling the Medications We Call Antidepressants​

David Antonuccio 1 , 2 ,* and David Healy 3

Abstract​

This paper raises the question about whether the data on the medications we call antidepressants justify the label of antidepressant. The authors argue that a true antidepressant should be clearly superior to placebo, should offer a risk/benefit balance that exceeds that of alternative treatments, should not increase suicidality, should not increase anxiety and agitation, should not interfere with sexual functioning, and should not increase depression chronicity. Unfortunately, these medications appear to fall short on all of these dimensions. Many of the “side effects” of these medications have larger effect sizes than the antidepressant effect size. To call these medications antidepressants may make sense from a marketing standpoint but may be misleading from a scientific perspective. Consumers deserve a label that more accurately reflects the data on the largest effects and helps them understand the range of effects from these medications. In other words, it may make just as much sense to call these medications antiaphrodisiacs as antidepressants because the negative effects on libido and sexual functioning are so common. It can be argued that a misleading label may interfere with our commitment to informed consent. Therefore, it may be time to stop calling these medications antidepressants.

1. Introduction​

The medications we call antidepressants are incredibly popular. According to pharmaceutical consulting firm IMS Health, worldwide revenue estimates for antidepressants topped $20 billion in 2008, with almost $12 billion annually in the USA alone [1]. Estimates are that about 1 in 8 adult Americans had taken an antidepressant in the prior 10 years [2]. Of those taking antidepressants, about 60% indicate they have taken them for more than 3 months; 46% have taken them for more than a year. The CDC [3] found that antidepressant use has increased almost 400% in the USA since 1988, making antidepressants the most frequently used medications by people aged 18–44. The CDC study [3] also found that 11% of Americans aged 12 and older took antidepressants during the 2005–2008 study period. Less than 1/3 of Americans taking one antidepressant and less than 1/2 of those taking multiple antidepressants have seen a mental health professional in the prior year. Almost 25% of American women aged 40 to 59 are taking antidepressants. According to IMS Health [1], in 2010 more than 250 million prescriptions for antidepressants were filled in the USA, making them the number 2 most popular class of drug, just behind lipid regulators. One reason for their popularity is that primary care doctors are prescribing more than 73% of all antidepressants, most of the time without noting a psychiatric diagnosis [4]. In other words, these medications are being prescribed for the symptoms of depression, not just the diagnosis of depression.

2. An Antidepressant Should Be Clearly Superior to Placebo​

These medications were originally developed because of a possible psychotropic drug effect that might be beneficial to patients diagnosed with depression [5]. To be labeled an antidepressant, a medication should be consistently and clearly superior to a sugar pill. Several meta-analyses have been conducted examining randomized controlled trials to determine whether this is so.

Kirsch et al. [6] used the Freedom of Information Act (FOIA) to access 38 randomized controlled trials (RCTs) involving 6944 patients from the USA Food and Drug Administration (FDA) database. These were all the RCTs used in the initial approval of the six most popular antidepressants. These included all of the available studies for fluoxetine, paroxetine, sertraline, venlafaxine, nefazodone, and citalopram, published or not. The modal duration of treatment was 6 weeks. This analysis showed that placebo duplicated 82% of the antidepressant response. This means that the placebo patients did almost as well as the patients on active medication. The average difference between the active drug and the placebo was less than 2 points on the Hamilton Depression Rating Scale (HDRS) [7]. Only 43% of the trials favored the antidepressant over placebo.

Kirsch et al. [8] conducted a subsequent meta-analysis of antidepressants that included all studies submitted to the FDA, whether published or not, for fluoxetine, nefazodone, venlafaxine, and paroxetine. The meta-analysis was limited to these 4 medications because the researchers decided to include studies only on those medications for which mean change scores were available on all trials. This analysis examined depression severity in relation to response. The results showed that the active drug only had clinically significant benefit (using the threshold for a clinically significant difference of ≥3 on the HDRS established by the National Institute for Clinical Excellence (NICE)) for those patients with an initial HDRS score greater than 28. In other words, Kirsch and colleagues conclude that the antidepressants had a clinically meaningful impact only on depressed patients in the very severe range.

Fournier et al. [9] conducted a similar meta-analysis in which they analyzed 6 RCTs comparing a selective serotonin reuptake inhibitor (SSRI) and placebo. These researchers restricted their analysis to those studies that did not use a placebo washout (i.e., the common practice of offering all study participants a placebo for 2 weeks, and excluding placebo responders from the study). This was done to make sure that the studies were not biased against the placebo condition. They also only included studies for which they were able to get individual level data from the original researchers. This was done to ensure that no data were excluded in the analysis. Most meta-analyses use summary statistics generated from study publications rather than individual level data that can be independently analyzed. They were able to get individual level data on 718 patients. The analysis showed that antidepressants did not cause clinically meaningful benefits compared with placebo (also using the NICE threshold for a clinically significant difference of ≥3 on the HDRS) until patients had an initial intake HDRS score of 25. The authors note that this represents less than 30% of patients who seek treatment in clinical settings. In other words, similar to the Kirsch et al. [8] findings, Fournier et al. [9] concluded that only patients with very severe depression seemed to experience meaningful benefit from the antidepressant compared with a sugar pill.

Through the Freedom of Information Act, Turner and his colleagues [10] reviewed 74 trials of 12 antidepressants submitted to and approved by the FDA. They found that selective publication of results of antidepressant drug trials has resulted in biased conclusions about the effectiveness of antidepressant drugs. Of the 74 FDA-registered studies in the report, 38 (51%) were found to have positive results, all but 1 of which were published. There were 36 studies the FDA found to have negative results. Of these, 3 were published with negative results (8%), 22 were not published, and 11 (33%) were published as if the results had been positive—directly conflicting with the FDA conclusions concerning outcome. Thus, while 94% of publications on antidepressants report success, the actual rate is 51%. Turner et al. [10] also found that the published literature inflated effect sizes (compared with effect sizes that include all of the FDA data) from 11% to 69%, averaging 32%. The authors point out that such selective and inflated reporting is misleading health care professionals and patients about the effectiveness of these medications. Of all the human subjects who participated in the studies included in this meta-analysis, 3449 never had their data published. An additional 1843 human subjects had their data positively spun in conflict with the FDA analysis. This was often accomplished by emphasizing positive secondary outcomes or by omitting nonsignificant prespecified primary outcomes altogether. Not publishing data or spinning data contrary to actual results would seem to be a violation of the IRB contract with human subjects [11]. Given that the FDA requires only 2 positive studies for approval of a psychotropic medication, many of the approved antidepressant medications have more negative studies than positive ones, for example bupropion, citalopram, paroxetine, and sertraline [10].

Based on the foregoing analyses, it would seem that medications called antidepressants are not more effective than a sugar pill at relieving depression for the vast majority of patients who take them. To be clear, it appears that many depressed patients improve on antidepressants, but this is also true of those who take placebos. However, the real-world outcomes with antidepressants may actually be much worse than those in the placebo-controlled trials. The STAR*D [12] study, a large (N = 4.041 depressed patients) and well-funded (35 million dollars from NIMH) study, was designed to mimic the real word. Depressed patients who were not helped by their first antidepressant received up to three additional trials with pharmacologically distinct treatments. This was designed to maximize the likelihood of obtaining and maintaining remission of depression via antidepressant medication. The medications used alone or in combination were Celexa, Zoloft, Effexor, Wellbutrin, Remeron, and Pamelor. Surprisingly, the data show that after a year of continuation treatment following remission, of the 4,041 patients who entered the study, only 108 (3%) had a sustained remission—all the other patients either dropped out or relapsed [12]. These actual results are in stark contrast to the STAR*D publicized cumulative remission rate of 67% theoretically attainable after four acute treatment steps.

The results of STAR*D suggest that while the placebo-controlled studies provide evidence of an effect (i.e., a signal that the medication might be effective), this may not translate into effectiveness in the real world [13]. Furthermore, there is evidence that SSRIs are not effective with melancholic depression [14]. These patients tend not to qualify for the trials in the first place (i.e., most suicidal patients are excluded by design).

3. Antidepressants Should Offer a Risk/Benefit Balance That Exceeds That of Alternatives​

For medications to be considered true antidepressants, they should clearly offer benefit that exceeds the risks and side effects. To determine this, it is important to examine studies that compare these medications to credible nondrug interventions. Several studies allow such a comparison. Dimidjian et al. [15] randomly assigned 241 patients with major depression to paroxetine, cognitive therapy, behavioural activation, or placebo. The active treatments lasted 16 weeks while, for ethical reasons, the placebo treatment was limited to 8 weeks. All of the active treatments were superior to placebo after 8 weeks with behavioral activation having the best outcome in terms of response and remission at 16 weeks, followed by cognitive therapy, followed by paroxetine. After the acute phase of treatment, patients in the paroxetine condition were randomly assigned to continued placebo or continued paroxetine for one year. The cognitive therapy and behavioral activation conditions had treatment discontinued. The continued paroxetine condition and the discontinued psychotherapy conditions had similar survival rates (i.e., 55% to 65% of remitted patients remained remitted), while the newly assigned placebo patients deteriorated more rapidly (i.e., 40% remained in remission). After 1 year of follow-up, the patients who were continued on paroxetine had their medication stopped. They relapsed at a very high rate (i.e., only 15% sustained remission) while the discontinued behavioral activation and cognitive therapy patients did much better (i.e., about 50% of the remitted patients sustained remission). These authors concluded that the psychotherapy conditions had a clear cost advantage over medication at about 9 months after treatment initiation because of a more enduring benefit for the psychotherapies and the ability to discontinue treatment for most patients.

Several other well-controlled trials have shown that psychotherapeutic interventions offer more enduring benefit than medications called antidepressants, even for severe depression [eg., [1620]]. Even for patients who have “responded” to these medications, almost half indicate that they would not take them again due to unwanted psychological side effects such as narrowing of affect, not feeling like oneself, loss of creativity, and an inability to cry [21]. Physical side effects most often reported included sexual dysfunction, dry mouth, jitteriness, nausea, headaches, sweating, dizziness, lethargy, and inability to sleep [21].

4. An Antidepressant Should Not Increase Suicidality​

The FDA analysis of the SSRI and SNRI database of medications called antidepressants trials in depressed youth (24 trials involving a total of 4,400 patients) found suicidal ideation and behavior in approximately 4% of those patients randomly assigned to the antidepressant compared with 2% of those randomly assigned to placebo [22]. While the risk of increased suicidality appears to be relatively low (i.e., two extra suicidal patients for every 100 treated with an antidepressant compared with a placebo) and no patients actually completed suicide in the FDA database of controlled trials, the stakes are clearly high. Another analysis using different statistical methods found 3% suicidality in the medication conditions versus 2% suicidality in the placebo conditions [23]. Unfortunately, data concerning potential risk are limited because randomized trials involving antidepressants have typically excluded suicidal patients. The acceptability of the risk/benefit profile with fluoxetine, the only antidepressant to show evidence of some benefit in depressed youth and the only antidepressant approved by the FDA for use with depressed children and adolescents, involves value judgments about the cost of harm-related and psychiatric-related adverse events. A legitimate question is ‘‘How many children should benefit from an antidepressant to justify one extra child harmed by an antidepressant?”

Whittington et al. [24] reviewed all of the available data (published and unpublished) from controlled trials of SSRIs in depressed youth. This meta-analysis concluded that the risk benefit profile (number needed to treat to benefit one extra patient (NNTB), versus number needed to treat to cause a serious adverse harm event in one extra patient (NNTH)) was favorable for fluoxetine but was unfavorable for paroxetine, sertraline, citalopram, and venlafaxine [25]. This analysis from Whittington et al. [24] did not include the Treatment for Adolescents with Depression Study (TADS), which did not show an advantage of fluoxetine alone compared with placebo.

5. Antidepressants Should Not Increase Anxiety and Agitation​

The Treatment of Adolescent Depression Study [26], conducted more recently than the studies included in the Whittington et al. [24] review, offers some of the most complete data relevant to the short-term relative risks of treating patients with psychotherapy alone, medication alone, the combination, or a placebo. Despite the fact that suicidality decreased across all four arms of this study, the fluoxetine condition had a significantly higher rate of harm-related adverse events (such as suicidal ideation), physiological side effects (diarrhea, insomnia, and sedation), and psychiatric adverse events (irritability, mania, and fatigue) compared with placebo or CBT alone. Using the global response measure from the TADS study, the NNTB is about three in the combined condition, five for fluoxetine alone, and 12 for CBT alone, all compared to placebo. In terms of harm-related adverse events, the NNTH is approximately 20 in the fluoxetine-containing conditions in comparison to nonmedication conditions. When considering psychiatric-related adverse events, the NNTH is approximately 10 in the fluoxetine alone condition compared with placebo and only about five compared with CBT alone. In other words, when considering psychiatric adverse events, a practitioner would only have to treat 5 patients with fluoxetine to harm one extra patient compared with treating those same 5 patients with CBT. Adding together the risk for psychiatric and physiological side effects and harm-related events reduces the NNTH for fluoxetine even further.

Follow-up to TADS found no significant differences in depression outcome in the three treatment groups at 36 weeks [27] or at 5 years [28]. However, the fluoxetine condition had significantly more suicidal events than CBT alone or the combination treatment at 36 weeks [27]. As concerning as this information may be, there are data to suggest that TADS [26, 27] underestimated the actual suicidality risk by prescribing antidepressants to some patients in the placebo or CBT conditions following the acute treatment phase [29]. When these newly prescribed patients had a suicidality event, it was apparently charged against their original nondrug assignment in the data analysis (uncovered by Goran Hogberg, see [30]) rather than the medication (see figure 1 in [29]). Therefore, those on medication in TADS may have been more than 4 times as likely to have a suicidality event compared with those who were not, rather than about twice as likely as originally thought.

Psychiatric adverse events are not a trivial concern. Preda et al. [31] found that more than 8% of patients admitted to the Yale psychiatric facility were admitted for antidepressant-induced mania. Such adverse events can be frightening, costly, and extremely disruptive to a patient's life.

6. An Antidepressant Should Not Interfere with Sexual Functioning​

Sexual side effects caused by antidepressant medications appear to be a bigger problem than first thought in the original clinical trials. Premarket trials estimated that 2–16% of patients taking SSRIs and SNRIs experienced sexual dysfunction [32]. Montejo et al. [33] examined outpatients (610 women and 412 men) with previously normal sexual function who were being treated with antidepressants from April 1995 to February 2000. All patients were interviewed with the Psychotropic Sexual Dysfunction Questionnaire. Sexual dysfunction was reported by 62% of the men and 57% of the women. Women reported more severe symptoms. Dysfunctions included decreased libido, delayed orgasm, inability to have an orgasm, or decreased arousal. The SSRIs and venlafaxine resulted in the highest rates of dysfunction. Comparable rates of sexual dysfunction have been found in a more recent study [34]. There is even evidence that some patients may experience genital anesthesia or pleasureless orgasm, a problem that for some patients may persist even after the medication is discontinued [32].

7. Antidepressants Should Not Increase Depression Chronicity​

Through a mechanism known as “oppositional tolerance” [35, 36], it has been suggested that antidepressant medications may actually cause persistence of depression symptoms in some patients. This phenomenon has been referred to as “tardive dysphoria” [37]. Some intriguing clues about the possibility of this phenomenon may have appeared in one of the early landmark comparative studies. For example, in the NIMH collaborative depression study, patients who had received imipramine (a tricyclic medication) were more likely to seek treatment during the follow-up period, had a higher probability of relapse, and had fewer weeks of minimal or no symptoms compared with those who had taken placebo [38]. In a recent analysis to determine the safety of the placebo condition in the TADS study, Kennard et al. [39] actually found that participants initially assigned to placebo had a lower utilization of crisis intervention during follow-up than those initially assigned to the active drug conditions.

The SSRIs were developed to act on the serotonin system by interfering with serotonin reuptake. However, the brain quickly (as soon as 2 days in animal studies) compensates for this increase in serotonin through the process of downregulation or reduction in the number of serotonin receptors [40, 41]. The permanence of these changes and the potential long-term consequences are not clear. Fava [42] speculated almost 20 years ago that the receptor changes, similar to those found in tardive dyskinesia, may in some cases be irreversible, and may increase the biological vulnerability to depression in some patients following drug withdrawal, especially after long-term use. Baldessarini [43] has suggested that since some studies show a shorter time to relapse after drug discontinuation than would be expected from pretreatment history and the rate of drug removal predicts the time to the first recurrent episode, the combination of long-term drug treatment followed by withdrawal may be a causal factor in depression recurrence. He goes on to raise the possibility that it may take months to reestablish a predrug level of neurophysiological and neuropsychological homeostasis. Further research is needed to evaluate this possible risk.

8. Conclusions​

On all of the identified dimensions for what a medication should accomplish to be called an antidepressant, current medications we call antidepressants seem to fall short. They are not clearly superior to placebo for the vast majority of patients for whom they are prescribed. The risks appear to outweigh the benefits for many patients, risks that are serious enough to warrant black box warnings about increased suicidality for patients under the age of 25 issued by the FDA and other regulatory bodies. There is now worldwide consensus that these medications increase the risk of suicidality. They may even increase the chronicity of depression in some patients. Anxiety, agitation, gastrointestinal problems, and sexual dysfunction are the most common side effects.

If we do not call these medications antidepressants, what are some alternative labels that may better fit the existing data? The effect sizes for many of the “side effects” are larger than the antidepressant effect sizes. Using labels like antiaphrodisiac medications, agitation enhancers, insomnia inducers, suicidality inducers, mania stimulators, or gas busters obviously would not offer the same marketing appeal. Though tongue in cheek, we consider these possible labels to be more accurate than the commonly used label of “antidepressant.” It could be argued that the outcomes with the largest effect sizes should be offered as the primary label for a medication. Though the data reviewed in this paper appear not to adequately support the label of antidepressant, as long as these medications continue to be called antidepressants, prescribers will feel a moral obligation to offer them to their patients who are suffering from depression. Of course, the drug industry does not have an incentive to change the label. However, we feel patients ought to be informed of these possible alternative labels because they may apply equally well if not better. The main point is that calling these medications antidepressants is a marketing decision that does not appear to be consistent with the scientific data.

 

FunkOdyssey

Well-Known Member
This paper claims the relapse prevention trials that form the basis of long-term antidepressant treatment are fatally flawed due to withdrawal symptoms. In other words, people often become depressed due to the discontinuation syndrome associated with stopping the drug, rendering the conclusions invalid:

Ther Adv Psychopharmacol. 2020; 10: 2045125320921694.
Published online 2020 May 8. doi: 10.1177/2045125320921694

How effective are antidepressants for depression over the long term? A critical review of relapse prevention trials and the issue of withdrawal confounding​

Michael P. Hengartner

Abstract​

The aim of this article is to discuss the validity of relapse prevention trials and the issue of withdrawal confounding in these trials. Recommendations for long-term antidepressant treatment are based almost exclusively on discontinuation trials. In these relapse prevention trials, participants with remitted depression are randomised either to have the antidepressant abruptly discontinued and replaced by inert placebo or to continue active treatment. The drug–placebo difference in relapse rates at the end of the maintenance phase is then interpreted as a prophylactic drug effect. These trials consistently produce remarkable benefits for maintenance treatment. However, the internal validity of this trial protocol is compromised, as research has shown that abruptly stopping antidepressants can cause severe withdrawal reactions that lead to (or manifest as) depression relapses. That is, there is substantial withdrawal confounding in discontinuation trials, which renders their findings uninterpretable. It is not clear to what degree the drug–placebo separation in relapse prevention (discontinuation) trials is due to withdrawal reactions, but various estimations suggest that it is presumably the majority. A review of findings based on other methodologies, including real-world long-term effectiveness trials like STAR*D and various naturalistic cohort studies, do not indicate that antidepressants have considerable prophylactic effects. As absence of evidence does not imply evidence of absence, no definitive conclusions can be drawn from the literature. To enable a thorough risk–benefit evaluation, real-world effectiveness trials should not only focus on relapse prevention, but also assess antidepressants’ long-term effects on social functioning and quality of life. Thus far, reliable long-term data on these outcome domains are lacking.

Introduction​

Treatment guidelines like those published by National Institute for Health and Care Excellence (NICE) or the American Psychiatric Association (APA) strongly recommend long-term maintenance treatment in people with (or at risk of) recurrent depression to prevent relapses.1,2 In accordance with these recommendations, the rate and duration of antidepressant use is steadily increasing in the general population,36 but this trend has stirred considerable controversy.7,8 It has been suggested that long-term antidepressant treatment should be revisited,911 and research indicates that many patients in receipt of long-term antidepressant medication do not necessarily require maintenance treatment.1214 Some authors cautioned that long-term antidepressant use may be largely ineffective, or even harmful.10,11,15,16 One possible driver of unnecessary long-term prescriptions could be the propensity of antidepressants to cause dependence and withdrawal reactions.1722 This notion is often met with disbelief, and sometimes it is fiercely dismissed by leading academics as it stands in sharp contrast to the consistently positive findings from dozens of relapse prevention trials.2327 In this article, I will ponder these seemingly contradictory findings and critically discuss major issues that may resolve the conflicting literature on the benefits of long-term antidepressant treatment. To that end, I will focus mostly on antidepressants’ prophylactic effects, as relapse prevention is the main indication for long-term antidepressant use in people with (recurrent) depressive disorders. A critical discussion of potential adverse effects of long-term use is important to consider but beyond the scope of the present article. For tolerability and safety issues, interested readers are referred to the pertinent literature.2830

Relapse prevention trials: too good to be true?​

The scientific evidence in support of long-term maintenance antidepressant treatment is based almost exclusively on relapse prevention trials.1,2,31 These long-term studies are basically discontinuation trials, where antidepressant users in (stable) remission are randomised to either have the antidepressant abruptly stopped and replaced by inert placebo or to continue active treatment. The difference in relapse rates between the antidepressant and the placebo arm at the end of the maintenance phase is then assumed to reflect a prophylactic drug effect. As stated above, the results of these trials are unequivocally positive and consistently show that, after about 12 months, the relapse rate is roughly 40% for those participants who were abruptly switched to placebo and 20% for those maintained on active treatment, which results in a relative risk of 2 and a number needed to treat (NNT) of 5.2527

This, in short, is the scientific evidence on which treatment guidelines largely base their recommendation for long-term antidepressant treatment.1,2,31 At first glance, this evidence base indeed appears impressive, and, without a critical look at the methodology of these trials, which number in dozens, one is understandably tempted to conclude that antidepressants have ‘remarkable’ long-term efficacy.32 Based on evidence from relapse prevention (discontinuation) trials, it was even claimed that antidepressants are ‘one of the most effective of all drugs’.23 However, as I already pointed out in previous articles,10,33 the validity of these trials, and hence the interpretation of their findings, cannot be accepted at face value. As researchers, we should not be seduced into believing that a drug is highly effective simply because a specific trial protocol has consistently produced impressive treatment effects, as these effects could be the result of a flawed trial protocol.34 Such systematic bias in clinical trials is also referred to as ‘hard-wired bias’.35

The persistent superiority of antidepressants over placebo in relapse prevention (discontinuation) trials is a peculiar finding, given that only about 50% of acute treatment trials are positive,36,37 which results in a disappointingly small average treatment effect,38,39 and a NNT of about 9.40,41 This recently led researchers from the Nordic Cochrane Center to state that ‘Taken together, the evidence does not support definitive conclusions regarding the efficacy of antidepressants for depression in adults, including whether they are more efficacious than placebo for depression’ (p. 8).39 Moreover, it is important to note that trial protocols other than discontinuation trials failed to find reliable evidence of remarkable long-term benefits.4244 This prompted SN Ghaemi, a leading psychiatric researcher from Tufts Medical Center in Boston, MA, to conclude that ‘(Antidepressants’) long-term prophylactic effectiveness in recurrent unipolar major depression remains uncertain’ (p. 957).16 In this respect, the evidence from relapse prevention (discontinuation) trials indeed appears too good to be true.34 How could a drug that has very limited efficacy in the acute and long-term treatment of depression symptoms possibly have such impressive prophylactic effects? We therefore need to consider that the strong and consistent effects produced in relapse prevention (discontinuation) trials are possibly a methodological artefact. I will now explain how this impressive drug-placebo separation could come about.

Withdrawal confounding in relapse prevention trials​

Relapse prevention (discontinuation) trials are very popular in psychiatry but have a bad reputation among critics. According to various authors, their validity is poor and findings hence difficult to interpret.34,42,45,46 Issues discussed in the literature include, among others, poor representativity and generalisability of results (findings apply only to a subset of users who responded particularly well to the drugs), inflated effect size estimates (treatment responders are assessed for treatment response, which is tautological) and unblinding effects (participants who have their active treatment abruptly discontinued may notice it). Here, I will focus on one particular issue, that is, withdrawal confounding.46

Various authors have stressed that prolonged antidepressant use can cause neurochemical adaptations (physical dependence) and corresponding withdrawal reactions upon dose reduction or discontinuation comparable with other central nervous system (CNS) drugs like benzodiazepines, stimulants or opioides.18,22,47,48 There is now compelling evidence from clinical trials, observational studies and user surveys that stopping antidepressants can cause severe and persistent withdrawal reactions in a substantial portion of users.49,50 Withdrawal symptoms include, among others, anxiety, panic, irritability, aggression, lethargy, flu-like symptoms, electric-shock sensations (brain zaps), fatigue, dizziness, tremor, dysphoria, bouts of crying, suicidality, insomnia, anorexia and nausea. Many of these symptoms are, therefore, easily misdiagnosed as a depression relapse when relapses are assessed via symptom rating scales such as the Hamilton Depression Rating Scale that cannot differentiate withdrawal from relapse.51,52

Withdrawal reactions can be so severe that they classify as a depression relapse in up to 27% of users within 5–8 days of double-blind placebo-controlled treatment interruption.53 That is, abrupt discontinuation of antidepressants relates to significantly higher rate of new depression episodes.53,54 This increased risk is not necessarily due to misclassification of acute withdrawal symptoms, yet is likely caused by withdrawal reactions, for example, neurochemical adaptations suddenly unopposed.55,56 These types of withdrawal reactions are commonly defined as rebound disorders (rapid return of original symptoms at greater intensity) and persistent (protracted) post-acute withdrawal disorders (return of persistent original symptoms at greater intensity and/or symptoms related to new emerging disorders).50 While rebound disorders usually occur within a few days after drug discontinuation, and resolve spontaneously within up to 6 weeks, persistent post-acute withdrawal disorders may also have a delayed onset and last for several months or, occasionally, even years.47,57,58 Rebound disorders and persistent post-acute withdrawal disorders have also been described with various other CNS drugs, including opioids, benzodiazepines, stimulants, antipsychotics and lithium.48,59

According to two placebo-controlled trials, abrupt discontinuation of antidepressants can lead to a significant decline in social functioning within a few days, with further progression of impairments very likely.60,61 These functional impairments that come along with withdrawal symptoms may cause stress that can trigger or precipitate a depression relapse.62,63 The link between withdrawal-related functional impairments and depression relapse has never been examined directly,60,61 but is indirectly supported by robust epidemiological findings that social functioning deficits, for example, due to job strain,64,65 relate prospectively to increased risk of depression.66 Finally, there is evidence that the more users had previously been exposed to and the longer they had been on antidepressants, the higher the risk of severe withdrawal reactions.17,50,67,68 Thus, as cumulative exposure to antidepressants appears to influence the incidence and severity of withdrawal reactions,50,67 discontinuation trials with a longer pre-randomization (stabilization) phase may thus have more confounded results. Moreover, it is important to note that a majority of participants who enter a relapse prevention (discontinuation) trial had already been on antidepressants and other psychotropic drugs for a long time. In the lead-in (washout) phase, these participants may thus already undergo withdrawal, and then again in the space of a few weeks if randomised to the discontinuation (placebo) arm. For someone who has been on prescribed psychotropics for years, this may cause no small degree of disturbance both psychologically and physiologically.45,62

In sum, abruptly stopping antidepressants can cause various types of withdrawal reactions that meet diagnostic criteria of a new depression episode, including rebound disorders and persistent post-acute withdrawal disorders.47,48,50 Moreover, acute withdrawal symptoms can be misdiagnosed as depression relapse or may trigger a relapse due to withdrawal-related functional impairments.51,52,62 It follows that a significant portion (possibly even a majority) of events recorded as depression relapses in the discontinuation arm of maintenance studies are in fact due to withdrawal reactions.69,70 When we examine the survival curves in relapse prevention (discontinuation) trials, we easily see that the drug–placebo separation occurs almost completely within the first 12 weeks (see for instance the graphs presented in the FDA review25). That is, antidepressants appear to exert a ‘prophylactic’ effect for the first 12 weeks only; thereafter, the drugs do not protect any better against relapse than a placebo pill. This has been noted by various authors and is empirically well established. 10,7072 The findings detailed above hence indeed question the validity of relapse prevention (discontinuation) trials, of which the vast majority, noteworthy, does not attempt to differentiate relapse from withdrawal.46,69 Of course genuine depression relapses also occur in the discontinuation (placebo) arm, but this is not the point. The fundamental issue is that events recorded as relapses could very well be, and in many cases certainly are, the result of withdrawal reactions. Therefore, the internal validity of relapse prevention (discontinuation) trials is compromised.34,46,73 Given that the outcome in these maintenance studies is confounded, we must acknowledge that they are uninterpretable and cannot serve as a valid evidence base for long-term maintenance treatment. The next question hence is whether there is evidence of prophylactic effects from studies with other methodologies that would support long-term antidepressant treatment.

Extension trials and longitudinal observational studies: do they concur with relapse prevention trials?​

Extension trials start as double-blind acute phase trials with a placebo and antidepressant arm. After the acute treatment phase, treatment responders continue on the same treatment they were initially randomised to. The advantage of extension trials over discontinuation trials is thus that they avoid withdrawal confounding, as acute treatment responders continue with the same treatment they were already on (i.e. the placebo arm is not a discontinuation arm). Unfortunately, there are only very few placebo-controlled extension trials. A systematic review and meta-analysis by Zimmerman et al. found only five small trials of 6–12 months duration.74 They report an average relapse rate of 8% for active treatment and 25% for placebo. However, there are flaws in this meta-analysis. For instance, in one trial the reported relapse rate for placebo was not from the extension arm (that is, from participants who were treated with placebo during the acute phase), but from participants re-randomised from antidepressant to placebo (hence a typical discontinuation arm affected by withdrawal confounding).75 In another trial,76 the rates reported by Zimmerman et al. were actually not for relapses (new depression episodes; not reported in the target article), but for loss of response (<30% symptom reduction from baseline),74 which is a different outcome. Due to these flaws, the results reported by Zimmerman et al. must be interpreted with caution.74

The National Institute of Mental Health (NIMH)-sponsored real-world effectiveness trial STAR*D also included a 12-month extension phase for treatment responders, but unfortunately it was not placebo-controlled.77 Nevertheless, the results show that, when prophylactic effects are assessed via long-term follow up of continuously treated acute-phase responders (rather than via abrupt treatment discontinuation after the acute phase), then sustained remission with antidepressants is a rare event.16,43 According to the intent-to-treat re-analysis by Pigott et al.,43 the rate of sustained remission for participants who entered the extension phase in remission was only 6% at the final 12-month assessment. A similarly very low rate of sustained remission (only 11% over 12 months of treatment) was also reported in another NIMH-sponsored real-world effectiveness trial.44 These publicly funded real-world trials based on representative outpatient samples indicate that the long-term benefits of antidepressants appear disappointingly poor once their prophylactic effects are assessed with protocols other than discontinuation trials. These findings are largely confirmed by the meta-analysis of classic long-term trials conducted by Deshauer et al.,42 according to which there is no significant drug–placebo difference in remission rates after 6–8 months of treatment (drug: 45%, placebo: 38%).

I will now turn to a brief discussion of observational studies on relapse prevention. Eli Lilly, manufacturer of fluoxetine, published evidence from observational studies suggesting that short-term antidepressant use, relative to continued use, relates to higher relapse rates.78,79 This was seen as a confirmation that long-term treatment is often necessary and beneficial. However, it was later demonstrated that these studies sponsored by Eli Lilly applied a flawed statistical method that systematically biases the results against short-term use.80 In fact, when the observational data are analysed with an unbiased statistical method, then short-term antidepressant use is associated with lower relapse rates than continued use.8082 Systematic reviews of longitudinal cohort studies likewise do not indicate that antidepressant treatment prevents relapses, chronicity or clinical progression of depression.8385 Noteworthy, in the most recent review of primary care and community studies, the authors stated that antidepressant use typically relates to similar or even worse outcomes than non-use.86 Indeed, many observational studies point to the possibility that (long-term) antidepressant use may increase the risk of recurrent or persistent depression.8789 These findings are also supported by research on the pharmacodynamic mechanisms of tolerance and tachyphylaxis, which suggests that the more and the longer a person has been treated with antidepressants, the larger the risk of non-response, relapse and chronicity;77,90,91 for a comprehensive review, see Fava and Offidani.56

Finally, the average rate of sustained recovery in patients with mood disorders was higher in the pre-treatment era (that is, before the widespread use of antidepressants) than in psychiatry’s modern drug-centred treatment era, despite today’s patients diagnosed with mood disorders being, on average, less severely ill.92,93 Although the aim of this article is not to provide a comprehensive review of observational studies, it can be concluded from previous systematic reviews that antidepressant use does not, on average, relate to less relapses or sustained recovery in people with depression.83,85 If anything, observational studies hint at increased risk of relapses and chronicity with long-term antidepressant use.10,83,86,93 It must be borne in mind that the validity of observational studies is limited due to confounding by indication, so these studies cannot prove that long-term use is ineffective or harmful. However, taken together the findings from observational studies certainly do not indicate that long-term antidepressant use has remarkable benefits.

Summary and conclusion​

Relapse prevention (discontinuation) trials have produced strong and consistent evidence of drug–placebo separation during the first 12 weeks of treatment; thereafter, treatment effects remain constant for at least 12 months.26,27,72 The common interpretation of these findings is that antidepressants have strong prophylactic effects, and that they effectively prevent depression relapses.1,2,23,31 This interpretation is challenged by research on antidepressant withdrawal reactions, which also emerge within days or a few weeks after treatment discontinuation (or dose reduction), and which can be severe and persistent.21,50,94 Clinical trials and observational studies have shown that when antidepressants are abruptly (or rapidly) stopped, patients are at increased risk of relapse.53,54 Severe withdrawal symptoms and related functional impairments may develop within a few days in patients who were in stable remission,53,61 but late onset and slow but persistent progression of symptoms is also possible.47,48,51 Withdrawal reactions comprise not only acute withdrawal symptoms, but also rebound disorders and persistent post-acute withdrawal disorders.47,48,50 This makes the differentiation between withdrawal and relapse even more challenging for an assessor in a clinical trial. For the vivid personal account of a psychiatrist with lived experience, see Stockmann.95 Hundreds of individual case reports are posted on SurvivingAntidepressants.org.

It is difficult to quantify the extent to which events recorded as depression relapse in maintenance studies are related to withdrawal reactions, but different estimations suggest that it is presumably the majority.46,69,70 These findings indicate that there is substantial withdrawal confounding in relapse prevention (discontinuation) trials and that the internal validity of these studies is compromised. It follows that the results of these trials are uninterpretable. Publicly funded real-world long-term effectiveness trials like STAR*D showed that the benefits of continued antidepressant use are disappointingly poor.16,43,77 The results of longitudinal observational studies likewise do not indicate that (long-term) antidepressant use prevents relapses or chronicity.8385 If anything, it appears that long-term antidepressant treatment, compared with short-term use or non-use, relates to worse outcomes.10,15,81 More research is urgently needed to explain how such findings come about, but the pharmacodynamic mechanisms of tolerance and tachyphylaxis are probably a good starting point.56,96

This article concurs with a growing number of physicians and researchers who caution against indiscriminate long-term antidepressant treatment.811,55 Currently, there is no reliable evidence that long-term antidepressant treatment is beneficial and there are legitimate concerns that it may be largely ineffective or even harmful in a substantial portion of users.10,11,16,55,96 It is particularly problematic that we have almost no data on antidepressants’ long-term effects on objective measures of social functioning (e.g. employment and disability rates) and patient-oriented outcomes such as quality of life. A critical reappraisal of current treatment guidelines along these lines is required. However, in keeping with the logical principle of ‘absence of evidence is not evidence of absence’ we must remain mindful that long-term antidepressant use may be useful to some patients.97 It is therefore important to conduct large real-world effectiveness trials that can adequately evaluate antidepressants’ long-term effects on depression symptoms, social functioning and quality of life. Classic long-term parallel-arm placebo-controlled trials are the preferred methodology. Discontinuation trials should be avoided unless they apply very slow and individually tailored tapers and carefully discriminate withdrawal reactions from genuine depression relapses. Finally, it would also be worthwhile to focus more generally on influences of industry-sponsorship and authors’ conflicts of interest,10,98 as these may systematically bias the literature on the risks and benefits of antidepressants.36,99102

 

FunkOdyssey

Well-Known Member
This paper provides further evidence that relapses in antidepressant relapse prevention trials are caused by a pharmacological drug effect and are not indicative of antidepressants' prophylactic power. This one has some cool graphs that @readalot will appreciate -- click the full-text link at the bottom to check those out:

Ther Adv Psychopharmacol. 2021; 11: 20451253211032051.
Published online 2021 Aug 10. doi: 10.1177/20451253211032051

Prophylactic effects or withdrawal reactions? An analysis of time-to-event data from antidepressant relapse prevention trials submitted to the FDA​

Michael P. Hengartner and Martin Plöderl

Abstract​

Background:

Relapse prevention trials build the scientific foundation for recommendation of antidepressant continuation and maintenance therapy. However, the validity of the evidence is disputed and may be biased due to withdrawal confounding.

Methods:

We analysed survival curves from all antidepressant relapse prevention trials submitted to the United States (US) Food and Drug Administration (FDA) between 1987 and 2012 for 13 approved drugs. The main outcome was the percent of the drug effect (placebo-antidepressant difference in relapse events) at any week of the maintenance phase in relation to the total drug effect at the endpoint of the randomised maintenance phase.

Results:

Altogether, 14 studies with a mean observation period of 38.9 weeks (Kaplan–Meier estimators) were analysed. At week 3, a mean of 20.6% [95% confidence interval (CI) = 10.9–30.3%] of the total drug effect was achieved. At weeks 6 and 12, the corresponding figures were 50.3% (37.3–63.3%) and 69.0% (55.1–82.8%). No further antidepressant–placebo separation was observed as of week 24 [101.0% of total drug effect (94.6–107.3%)]. This means that censoring relapse events that occurred in the first 3, 6, 12 and 24 weeks would reduce the total drug effect at study endpoint by 20.6%, 50.3%, 69.0% and 101.0%, respectively. Assuming antidepressants had a constant prophylactic effect over 38.9 weeks, we further showed that, around week 6, the antidepressant–placebo separation was about three times larger than expected.

Conclusion:

The placebo–antidepressant separation was disproportionally large between weeks 3 and 6 of the randomised maintenance phase. The benefits of continuing antidepressants relative to abrupt/rapid discontinuation declined sharply after week 6. This indicates an excess of relapse events in the placebo arms during the early maintenance phase that may be due to withdrawal reactions caused by abrupt/rapid discontinuation of active treatment. If these early relapse events are due to a direct pharmacological effect, then antidepressants’ true prophylactic long-term effects are substantially overestimated.

 

FunkOdyssey

Well-Known Member
This paper comprehensively outlines the various types of harm caused by antidepressants, with a focus on SSRI's, concluding: "The weight of current evidence suggests that, in general, antidepressants are neither safe nor effective; they appear to do more harm than good."

The paper is too large to quote in its entirety, so please check out the full-text link below for an exhaustive review of antidepressant disruption of bodily systems and processes.

Front Psychol. 2012; 3: 117.
Published online 2012 Apr 24. doi: 10.3389/fpsyg.2012.00117

Primum Non Nocere: An Evolutionary Analysis of Whether Antidepressants Do More Harm than Good​

Paul W. Andrews,1,2,* J. Anderson Thomson, Jr.,3,4 Ananda Amstadter,2 and Michael C. Neale2

Abstract​

Antidepressant medications are the first-line treatment for people meeting current diagnostic criteria for major depressive disorder. Most antidepressants are designed to perturb the mechanisms that regulate the neurotransmitter serotonin – an evolutionarily ancient biochemical found in plants, animals, and fungi. Many adaptive processes evolved to be regulated by serotonin, including emotion, development, neuronal growth and death, platelet activation and the clotting process, attention, electrolyte balance, and reproduction. It is a principle of evolutionary medicine that the disruption of evolved adaptations will degrade biological functioning. Because serotonin regulates many adaptive processes, antidepressants could have many adverse health effects. For instance, while antidepressants are modestly effective in reducing depressive symptoms, they increase the brain’s susceptibility to future episodes after they have been discontinued. Contrary to a widely held belief in psychiatry, studies that purport to show that antidepressants promote neurogenesis are flawed because they all use a method that cannot, by itself, distinguish between neurogenesis and neuronal death. In fact, antidepressants cause neuronal damage and mature neurons to revert to an immature state, both of which may explain why antidepressants also cause neurons to undergo apoptosis (programmed death). Antidepressants can also cause developmental problems, they have adverse effects on sexual and romantic life, and they increase the risk of hyponatremia (low sodium in the blood plasma), bleeding, stroke, and death in the elderly. Our review supports the conclusion that antidepressants generally do more harm than good by disrupting a number of adaptive processes regulated by serotonin. However, there may be specific conditions for which their use is warranted (e.g., cancer, recovery from stroke). We conclude that altered informed consent practices and greater caution in the prescription of antidepressants are warranted.

Conclusion​

We have reviewed a great deal of evidence of the effects of antidepressants on serotonergic processes throughout the body. Some of the effects are widely known, but they have been largely ignored in debates about the utility of antidepressants. Indeed, it is widely believed that antidepressant medications are both safe and effective; however, this belief was formed in the absence of adequate scientific verification. The weight of current evidence suggests that, in general, antidepressants are neither safe nor effective; they appear to do more harm than good.

Further research on their effects is clearly needed. We note a few areas of particular importance. First, after antidepressant discontinuation some people report depressive symptoms that are more severe than the initial symptoms that prompted antidepressant treatment. This should be formally tested, and if confirmed it would provide further support for the homeostatic rebound argument we presented above. Second, more research should be conducted on how best to interpret the BrdU signal in the context of antidepressant use. Does it reflect apoptosis, neurogenesis, or both? Particularly helpful would be studies that examine the temporal relationship between the BrdU signal and independent measures of apoptosis and neurogenesis. Third, more studies should examine the morphological changes in neurons that take place with repeated administration of serotonergic antidepressants (Kalia et al., 2000). Fourth, greater research should be devoted to exploring the possibility that the effects of prolonged antidepressant use on neuronal integrity may cause cognitive decline and dementia (Jackson, 2008; Goveas et al., 2011). Finally, greater research should be devoted to the effects of antidepressants on longevity. The quickest experiments could be done on rodents. That such studies were not done decades ago, before antidepressants were approved for widespread use, is troublesome.

Such research will give us a better picture of the effects of antidepressants on overall functioning. Nevertheless, from a legal, ethical, and public health perspective, it now seems prudent, on the basis of existing evidence, for individual practitioners and professional medical organizations to revise informed consent guidelines and reconsider the status of antidepressants in standards of care for many diagnoses and as the immediate front line treatment for depression. Some patients may be more likely to benefit from antidepressants and less likely to suffer adverse effects, but identifying them will require further research and greater understanding of the etiology of depression.

Patients should be informed that current research suggests that unless they have very severe depression, the symptom reducing effects of antidepressants are modest and are not considered clinically significant. Unless there are rapid-onset adverse side effects, antidepressant therapy usually lasts for months. Patients should be advised that prolonged use might cause mild cognitive impairment and interfere with tasks that require highly focused concentration, such as driving, which may increase the risk of accidents. Patients should also be advised that antidepressants might trigger even more severe depressive episodes when they are discontinued. All patients should be advised of the possible bleeding risks, and physicians should exercise particular caution in prescribing these drugs in conjunction with other diuretic or anti-thrombotic medications. The evidence of harm is strongest in the elderly, who should be advised of the risks of falling, hyponatremia, bleeding, stroke, and death.

 

FunkOdyssey

Well-Known Member
This paper from the founder of SurvivingAntidepressants.org highlights the risks that accompany abrupt withdrawal of psychiatric drugs. The author advocates for a careful, protracted withdrawal process, whereby the drug dose is reduced as slowly as 5-10% per month, in order to prevent post-acute withdrawal syndrome (PAWS or PWS):

Ther Adv Psychopharmacol. 2021; 11: 2045125321991274.
Published online 2021 Mar 16. doi: 10.1177/2045125321991274

What I have learnt from helping thousands of people taper off antidepressants and other psychotropic medications​

Adele Framer

Abstract​

Although psychiatric drug withdrawal syndromes have been recognized since the 1950s – recent studies confirm antidepressant withdrawal syndrome incidence upwards of 40% – medical information about how to safely go off the drugs has been lacking. To fill this gap, over the last 25 years, patients have developed a robust Internet-based subculture of peer support for tapering off psychiatric drugs and recovering from withdrawal syndrome. This account from the founder of such an online community covers lessons learned from thousands of patients regarding common experiences with medical providers, identification of adverse drug reactions, risk factors for withdrawal, tapering techniques, withdrawal symptoms, protracted withdrawal syndrome, and strategies to cope with symptoms, in the context of the existing scientific literature.

 

FunkOdyssey

Well-Known Member
Amazing how easily one gets offered and Rx'ed an AD or SSRI in an in network PCP provider's office. They must really work. Never tried one, any recommendations....

Mirtazipine
Lexapro

Throw a little clonazepam in there too?

Serious anxiety and panic now that coincide with exercise intolerance and ectopic during exercise. All doc recommend an AD along with some beta blocker and maybe some benzo in there as well. Twenty years with major depression and never took the plunge down AD lane. Seriously considering it.
Over a similar twenty year period, I've taken fluoxetine, sertraline, escitalopram, bupropion, mirtazapine, selegiline, moclobemide, alprazolam, lorazepam, buspirone, methylphenidate, amphetamine, modafinil, agomelatine, and many more drugs that I'm forgetting. I never found any lasting benefit from any psychiatric drug that outweighed the harms caused by that drug. In other words, I don't think you missed much by staying on the sidelines.

There are so many different angles that you can attack these disorders from and I guarantee there are several you haven't considered or tried yet. I firmly believe non-drug approaches to be most fruitful at this point.
 
Last edited:

TLawyer

Active Member
Over a similar twenty year period, I've taken fluoxetine, sertraline, escitalopram, bupropion, mirtazapine, selegiline, moclobemide, alprazolam, lorazepam, buspirone, methylphenidate, amphetamine, modafinil, agomelatine, and many more drugs that I'm forgetting. I never found any lasting benefit from any psychiatric drug that outweighed the harms caused by that drug. In other words, I don't think you missed much by staying on the sidelines.

There are so many different angles that you can attack these disorders from and I guarantee there are several you haven't considered or tried yet. I firmly believe non-drug approaches to be most fruitful at this point.
I think it would be better to present a balanced argument with studies that both support and run against the use of antidepressants. Your title makes it clear that you’re only looking to present one side of the story and have already come to a conclusion, and some of these “studies” seem to do the same. There are also double-blind studies that show antidepressants can be very effective, particularly when they are part of a treatment protocol (therapy, lifestyle changes, etc.). They certainly can have negative side effects in some that can overcome the benefit, but reading how you’ve gone about presenting this would lead one to believe that they are completely worthless and only harmful. There are many who would contend that antidepressants have saved their lives and have been taking them for years. Not ideal, and I think the hope is that you could wean your way off of them eventually, but I think they do have a place in treatment and should at least be considered as part of a protocol.
 
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