madman
Super Moderator
ABSTRACT
Recent literature connects 5-alpha reductase inhibitors (5-ARIs) with neuropsychiatric adverse effects. Several clinical studies have indicated that former 5-ARIs users had a higher incidence of depressive symptoms and neuropsychiatric side effects than non-users. However, the underlying mechanisms involved in the depression in former 5-ARIs patients, a condition known as “post finasteride syndrome (PFS)”, are not thoroughly understood. This review aims to summarize and discuss the association between 5-ARIs and depression as well as possible mechanisms. We used PubMed search terms including “depression”, “depressive symptoms”, “MDD”, “anxiety”, or “suicidal idea”, and “5-alpha reductase inhibitors”, “finasteride”, “dutasteride”, “5-ARIs”. All relevant articles from in vivo and clinical studies from 2002 to 2021 were carefully reviewed. Any contradictory findings were included and debated. The potential mechanisms that link 5-ARIs and depression include alteration in neuroactive steroids, dopaminergic dysfunction, reduced hippocampal neurogenesis, increased neuroinflammation, alteration of the HPA axis, and epigenetic modifications. From this review, we hope to provide information for future studies based on animal experiments, and potential therapeutic strategies for depressive patients with PFS.
1. Introduction
The prevalence of benign prostatic hyperplasia (BPH) has been found in 50–75% of men aged 50–70 years old, and in 80% of men over 70 years old. The incidence of BPH is 8.5–41 cases/1000 people per year [1]. Androgenetic alopecia (AGA) is the most common disorder of hair loss in both men and women. It usually begins during the teenage years, and the frequency increases with age. The prevalence of androgenic alopecia is 30–50% of men aged 50 years old [2]. In Caucasians, up to 80% of men and 42% of women have signs of androgenic alopecia by age 70 [3]. 5-alpha reductase inhibitors (5-ARIs) are one of the standard forms of medication approved by the Food and Drug Administration (FDA) for BPH [4,5] and AGA [6]. They functionally inhibit 5 alpha-reductase enzymes, resulting in a significant reduction in serum and tissue dihydrotestosterone (DHT) concentrations, in which low levels of DHT induce apoptosis of prostate epithelial cells in BPH [7]. In addition, low levels of DHT are linked to the reduction of cytokines that promote telogen and dermal papilla cell senescence in AGA, such as transforming growth factor-beta 1 and 2 [8]. Since the action of 5-ARIs is to suppress dihydrotestosterone (DHT), they have been used for treating hirsutism in women [9] as well as for hormone therapy in transgender individuals [10]. Two types of 5-ARIs, including finasteride (FIN), a type 2 5-ARI, and dutasteride(DUT), an inhibitor of both type 1 and type 2 5-alpha reductase, are currently available on the market [11]. Both drugs have been widely characterized as well-tolerated and relatively safe drugs, however, this needs to be reconsidered due to several emerging reports about their constellation of adverse effects including sexual, neuropsychiatric, and physical domains [12]. The side effects are continuous from starting treatment until after 5-ARIs suspension [13,14]. The persistent side effects of 5-ARIs have been termed “post finasteride syndrome (PFS)” [12]. Neuropsychiatric adverse effects of 5-ARIs have significantly increased among 5-ARIs users in the last few years, including symptoms including depression, anxiety, mood disturbance, self-harm, suicidal thoughts, and cognitive complaints. Unfortunately, neuropsychiatric adverse effects are acknowledged as having causal relationships with many confounders [15]
While there are many reports of the association between neuropsychiatric adverse events and 5-ARIs users, the underlying mechanisms associated with the brain dysfunction in PFS are still elusive. Therefore, this review aims to comprehensively summarize and discuss the association between 5-ARIs and depression as well as its underlying mechanisms from the evidence reported in vivo and clinical studies. Furthermore, it aims to provide information for future studies based on animal experiments, and potential therapeutic strategies for depressive patients with PFS. All of the evidence in our review focuses on the association between 5-ARIs and the development of depression in different durations of 5ARIs administration, including changes in neuroactive steroids, alterations of CNS receptors, their action on the dopaminergic system, hippocampal neurogenesis, neuroinflammation, alterations of the HPA axis, and epigenetic modification. Any contradictory findings are also included and debated.
2. The association between oral 5-ARIs and depression: Evidence from clinical study
3. The acute effects (<24 h) of finasteride (FIN) on sensorimotor gating behaviors: Evidence from in vivo study
3.1. 5-ARIs- induced the dysfunction of the dopaminergic system
3.2. Alterations of the hypothalamic-pituitary-adrenal (HPA) axis following 5-ARIs
3.3. Epigenetic modifications of 5-ARIs
4. Subacute (24 h to 7 days) and chronic effects (≥ 14 days) of finasteride on sensorimotor gating behaviors and possible underlying mechanisms: Evidence from animal studies
5. The effects of FIN on levels of neuroactive steroids in the withdrawal phase: Evidence from animal studies
6. Association between oral 5-ARIs and depression: Current translational clinical studies
7. Association between changes in neuroactive steroids and other underlying mechanisms: Current translational evidence
8. Conclusion and future perspectives
Until recently, the underlying mechanisms of the neuropsychiatric adverse effects of 5-ARIs therapy have not been fully recognized or well understood. Many clinical data suggested that former FIN users had a higher rate of depressive symptoms and neurological adverse side effects than non-users. However, several studies may suffer from methodological and interpretational flaws. Thus, it is still a controversial topic. Moreover, results from preclinical studies themselves still have inconsistent findings. Potential explanations could be variation of the experimental protocols, specific and genetic history of rodents used, FIN dosage, and duration of FIN administration.
Regarding current evidence, the key possible mechanism of depression in 5-ARIs users could be related to neuroactive steroids. Changes in neuroactive steroids following 5-ARI use can lead to dysfunction of the dopaminergic system, reduction of hippocampal neurogenesis, an increase in neuroinflammation, alterations of the HPA axis, and epigenetic modification. Moreover, the alterations of the neuroactive steroids, especially AP [67,96], are also linked to the alteration of central nervous system receptor functions including dopaminergic receptors [43,47], GABA-A receptors [63,67], estrogen receptors [67], and androgen receptors [67]. Unfortunately, the complete specific effects of 5-ARIs have not yet been fully characterized [67]. All of these findings are illustrated in Fig. 3.
Molecular mechanisms and/or genetic determinants behind 5-ARIs -induced neuropsychiatric effects should be further explored in both preclinical and clinical studies. Other possible links such as obesity [29, 97] and the derivation of neurotrophic factors in the brain of FIN users need examination. Although a causal relationship has not been clearly established, particular care needs to be taken in a patient with an existing psychiatric diagnosis, a patient confirmed as having a first-degree relative with a psychiatric history and adolescents. These groups are more prone to develop depression than other populations [15,19,40]. In all cases, it is paramount that physicians need to carefully assess the risk of depression and other adverse effects, including neuropsychiatric and sexual effects before prescribing 5-ARIs.
Recent literature connects 5-alpha reductase inhibitors (5-ARIs) with neuropsychiatric adverse effects. Several clinical studies have indicated that former 5-ARIs users had a higher incidence of depressive symptoms and neuropsychiatric side effects than non-users. However, the underlying mechanisms involved in the depression in former 5-ARIs patients, a condition known as “post finasteride syndrome (PFS)”, are not thoroughly understood. This review aims to summarize and discuss the association between 5-ARIs and depression as well as possible mechanisms. We used PubMed search terms including “depression”, “depressive symptoms”, “MDD”, “anxiety”, or “suicidal idea”, and “5-alpha reductase inhibitors”, “finasteride”, “dutasteride”, “5-ARIs”. All relevant articles from in vivo and clinical studies from 2002 to 2021 were carefully reviewed. Any contradictory findings were included and debated. The potential mechanisms that link 5-ARIs and depression include alteration in neuroactive steroids, dopaminergic dysfunction, reduced hippocampal neurogenesis, increased neuroinflammation, alteration of the HPA axis, and epigenetic modifications. From this review, we hope to provide information for future studies based on animal experiments, and potential therapeutic strategies for depressive patients with PFS.
1. Introduction
The prevalence of benign prostatic hyperplasia (BPH) has been found in 50–75% of men aged 50–70 years old, and in 80% of men over 70 years old. The incidence of BPH is 8.5–41 cases/1000 people per year [1]. Androgenetic alopecia (AGA) is the most common disorder of hair loss in both men and women. It usually begins during the teenage years, and the frequency increases with age. The prevalence of androgenic alopecia is 30–50% of men aged 50 years old [2]. In Caucasians, up to 80% of men and 42% of women have signs of androgenic alopecia by age 70 [3]. 5-alpha reductase inhibitors (5-ARIs) are one of the standard forms of medication approved by the Food and Drug Administration (FDA) for BPH [4,5] and AGA [6]. They functionally inhibit 5 alpha-reductase enzymes, resulting in a significant reduction in serum and tissue dihydrotestosterone (DHT) concentrations, in which low levels of DHT induce apoptosis of prostate epithelial cells in BPH [7]. In addition, low levels of DHT are linked to the reduction of cytokines that promote telogen and dermal papilla cell senescence in AGA, such as transforming growth factor-beta 1 and 2 [8]. Since the action of 5-ARIs is to suppress dihydrotestosterone (DHT), they have been used for treating hirsutism in women [9] as well as for hormone therapy in transgender individuals [10]. Two types of 5-ARIs, including finasteride (FIN), a type 2 5-ARI, and dutasteride(DUT), an inhibitor of both type 1 and type 2 5-alpha reductase, are currently available on the market [11]. Both drugs have been widely characterized as well-tolerated and relatively safe drugs, however, this needs to be reconsidered due to several emerging reports about their constellation of adverse effects including sexual, neuropsychiatric, and physical domains [12]. The side effects are continuous from starting treatment until after 5-ARIs suspension [13,14]. The persistent side effects of 5-ARIs have been termed “post finasteride syndrome (PFS)” [12]. Neuropsychiatric adverse effects of 5-ARIs have significantly increased among 5-ARIs users in the last few years, including symptoms including depression, anxiety, mood disturbance, self-harm, suicidal thoughts, and cognitive complaints. Unfortunately, neuropsychiatric adverse effects are acknowledged as having causal relationships with many confounders [15]
While there are many reports of the association between neuropsychiatric adverse events and 5-ARIs users, the underlying mechanisms associated with the brain dysfunction in PFS are still elusive. Therefore, this review aims to comprehensively summarize and discuss the association between 5-ARIs and depression as well as its underlying mechanisms from the evidence reported in vivo and clinical studies. Furthermore, it aims to provide information for future studies based on animal experiments, and potential therapeutic strategies for depressive patients with PFS. All of the evidence in our review focuses on the association between 5-ARIs and the development of depression in different durations of 5ARIs administration, including changes in neuroactive steroids, alterations of CNS receptors, their action on the dopaminergic system, hippocampal neurogenesis, neuroinflammation, alterations of the HPA axis, and epigenetic modification. Any contradictory findings are also included and debated.
2. The association between oral 5-ARIs and depression: Evidence from clinical study
3. The acute effects (<24 h) of finasteride (FIN) on sensorimotor gating behaviors: Evidence from in vivo study
3.1. 5-ARIs- induced the dysfunction of the dopaminergic system
3.2. Alterations of the hypothalamic-pituitary-adrenal (HPA) axis following 5-ARIs
3.3. Epigenetic modifications of 5-ARIs
4. Subacute (24 h to 7 days) and chronic effects (≥ 14 days) of finasteride on sensorimotor gating behaviors and possible underlying mechanisms: Evidence from animal studies
5. The effects of FIN on levels of neuroactive steroids in the withdrawal phase: Evidence from animal studies
6. Association between oral 5-ARIs and depression: Current translational clinical studies
7. Association between changes in neuroactive steroids and other underlying mechanisms: Current translational evidence
8. Conclusion and future perspectives
Until recently, the underlying mechanisms of the neuropsychiatric adverse effects of 5-ARIs therapy have not been fully recognized or well understood. Many clinical data suggested that former FIN users had a higher rate of depressive symptoms and neurological adverse side effects than non-users. However, several studies may suffer from methodological and interpretational flaws. Thus, it is still a controversial topic. Moreover, results from preclinical studies themselves still have inconsistent findings. Potential explanations could be variation of the experimental protocols, specific and genetic history of rodents used, FIN dosage, and duration of FIN administration.
Regarding current evidence, the key possible mechanism of depression in 5-ARIs users could be related to neuroactive steroids. Changes in neuroactive steroids following 5-ARI use can lead to dysfunction of the dopaminergic system, reduction of hippocampal neurogenesis, an increase in neuroinflammation, alterations of the HPA axis, and epigenetic modification. Moreover, the alterations of the neuroactive steroids, especially AP [67,96], are also linked to the alteration of central nervous system receptor functions including dopaminergic receptors [43,47], GABA-A receptors [63,67], estrogen receptors [67], and androgen receptors [67]. Unfortunately, the complete specific effects of 5-ARIs have not yet been fully characterized [67]. All of these findings are illustrated in Fig. 3.
Molecular mechanisms and/or genetic determinants behind 5-ARIs -induced neuropsychiatric effects should be further explored in both preclinical and clinical studies. Other possible links such as obesity [29, 97] and the derivation of neurotrophic factors in the brain of FIN users need examination. Although a causal relationship has not been clearly established, particular care needs to be taken in a patient with an existing psychiatric diagnosis, a patient confirmed as having a first-degree relative with a psychiatric history and adolescents. These groups are more prone to develop depression than other populations [15,19,40]. In all cases, it is paramount that physicians need to carefully assess the risk of depression and other adverse effects, including neuropsychiatric and sexual effects before prescribing 5-ARIs.
