Investigating Depression and Post Finasteride Syndrome – Symptoms, Biological Mechanisms, and a Degree of Hope

Introduction  

On paper, the discovery of a drug that can reverse hair loss and restore hair growth would be music to the ears of patients experiencing symptoms of androgenic alopecia. In reality, the discovery of the infamous drug, Finasteride has left males undergoing this treatment feeling somewhat emasculated and confused as they experience the notorious side effects of the drug.  

Post-Finasteride Syndrome (PFS), defined as a series of side effects induced by current/previous Finasteride treatment, has gained an infamous reputation over the past few decades in the medical field (Trüeb et al, 2019). It appears that a lot of researchers and scientific experts shy away from this syndrome and are apprehensive about the idea of investigations to identify a root cause.  

To date, there is no known cause of PFS, and the syndrome is yet to be coined as a medical condition by organizations such as the World Health Organization (WHO) and the International Classification of Diseases (ICD). Given the extremities of Finasteride’s side effects, such as loss of libido, depression, erectile dysfunction, and suicidal thoughts, the sooner this syndrome is recognized and further investigated, the sooner a treatment can be developed to address the symptoms. Although it is estimated that there are only 1,000 PFS cases worldwide, ignorance is not bliss, and a movement is currently underway to legitimize PFS as a recognized condition in an attempt to bridge the gap between Finasteride and symptoms of depression and sexual dysfunction (Trüeb et al, 2019).

What is Finasteride and what is it used for? 

Finasteride is a small molecule therapeutic agent, which is primarily prescribed by medical practitioners for the management of benign prostatic hyperplasia (BPH) and androgenic alopecia (Zito et al, 2024). The drug has diverse applications which go beyond its primary uses as mentioned above (Zito et al, 2024). The drug may also be used in transgender women, where it is combined with estrogen to have anti-androgenic effect (Zito et al, 2024). There have been reports of the drug being used to treat signs of hyperandrogenism, but this was off label and has not been approved for safe and effective use by authorities (Zito et al, 2024).  

The drug was officially approved by the Food & Drug Administration (FDA) in the US for the medical treatment of BPH in 1992, and the treatment of male androgenetic alopecia in 1997 (Periera, 2024). The drug doesn’t stay in the body for very long, with half-life ranges of 4.7 – 7.1 hours (Periera, 2024). It can significantly reduce levels of Dihydrotestosterone (DHT) in sperm, prostate and the scalp, while boosting testosterone (T) levels (Periera, 2024).  

Side Effects of Finasteride Treatment:  

Although Finasteride is renowned for its success in treating BPH and alopecia, there have been various side effects reported which negatively affect both mental and sexual health of patients. Some side effects are reported to such an extent that they may discourage users from undergoing or continuing their Finasteride treatment. 

Various side effects of Finasteride treatment have been reported over the years, with symptoms ranging from mild to severe (NHS, 2024). Nonetheless, the side effects should not outweigh the treatment’s benefits, and if side effects persist and threaten the patient’s health or wellbeing, a GP or medical practitioner should be contacted immediately. A summary of Finasteride’s possible side effects, and their level of severity are outlined in Figure 1 below: 

Figure 1: Summary of common and rare side effects of Finasteride treatment (NHS, 2024), (MedlinePlus, 2024).  

Depression is a widely known mental disorder and is shown in some, but not all PFS patients. It impacts the daily lives of an individual and comprises a series of symptoms. The simple routine of the day, work, family, and relationships in general, as well as the loss of interest in things that once were enjoyable, the combination of mood changes and altered cognition of an individual's way of view and feeling, makes significant impact affecting all aspects of life (World Health Organization, 2023). It is estimated that 5% of adults suffer from depression worldwide, where a significant consequence of untreated conditions may be suicide, of which more than 700,000 people die annually (World Health Organization, 2023). 

The incidence of depression in some Finasteride users highlights the requirement for more research into PFS, alongside its misconceptions. This blog aims to highlight the medical requirement for a PFS treatment, as well as propose a potential root cause. A proposal will be made in a novel attempt at determining the mechanism of action of PFS, which may prove to be a potential target for the development of a treatment method.  

Finasteride’s Mechanism of Action  

The mechanism of action of Finasteride proves to be difficult to grasp, even for those with experience and knowledge in pharmacology. In summary, Finasteride inhibits 5α-reductase, an enzyme responsible for the conversion of the androgen (stimulates the development of male characteristics) T to DHT (Cleveland Clinic, 2024). DHT is a more active form of T and plays a paramount role in the development of sexual organs and characteristics in individuals (Cleveland Clinic, 2024).  

 A visual summary of Finasteride’s mechanism of action can be seen in Figure 2 below.  

Figure 2: Visual summary of the biochemical effect of Finasteride (Zito et al, 2024) (Created using Biorender). 

It is important to note that the 5-alpha-reductase enzyme has two isoforms – type I and type II (Cai, 2023). Finasteride’s mechanism of action targets the type II isoform (Cai, 2023). In the normal physiological state, when T encounters 5-alpha reductase, it will be converted into its more active form, DHT (Cai, 2023). This occurs in a process defined as Competitive Enzyme Inhibition and is depicted in Figure 3 below, which explains Finasteride’s mechanism of action (Cai, 2023). Finasteride molecules are similar in biochemical structure and properties to T, enabling an induced fit where Finasteride binds to the 5-alpha reductase enzyme before T does (Cai, 2023).  This leaves T practically inactive, and unable to be converted to DHT (Cai, 2023).  

Figure 3: Visual representation of Competitive Enzyme Inhibition (Cai, 2023) (Made using Biorender). 

There is an inverse relationship between DHT and T levels in patients undergoing Finasteride treatment. A decrease in DHT levels leads to a minimal to moderate increase in T levels in blood serum (DrugBank, 2024). Given that DHT is the primary androgen responsible for stimulating prostatic growth, a reduction in DHT levels can decrease prostatic volume by 20-30% after 6-24 months of Finasteride therapy (DrugBank, 2022).  Although this is the desired effect in treating benign prostate enlargement, the reduced DHT levels are reported to be a possible reason as to why worrying side effects develop.   

How Finasteride treats Benign Prostatic Hyperplasia and Male Alopecia: 

DHT and hair loss: 

It has been shown by previous studies that those experiencing alopecia (hair loss) will have higher concentrations of DHT in their scalp (Dallob et al, 1994). It has also been proven that men with a predisposed genetic deficiency of type II 5α-reductase will produce little to no DHT and will not develop hair loss to a serious extent (Cai, 2023). Hence, it is fair to conclude that DHT proves to be largely responsible for the onset of hair loss (Cai, 2023). It is for this reason that DHT is the target of Finasteride’s mechanism of action (Cai, 2023).  

The effect of Finasteride on DHT proves to be intense, with studies claiming that a 1mg daily dose of Finasteride can reduce DHT levels of balding men by up to 70% after one month of treatment (Clark et al, 2004). Figure 4 below indicates the positive effects of Finasteride in reversing baldness by targeting DHT. 

Figure 4: Effects of Finasteride treatment in Male Alopecia – reduced hair loss (Made using BioRender).

Benign Prostatic Hyperplasia: 

Benign Prostatic Hyperplasia is the scientific term for an enlarged prostate (Cai, 2023). DHT has a primary role in the development of and growth of the prostate glands, and the cells that make up the prostate glands (Cai, 2023). Finasteride use can relieve symptoms of BPH by lowering the level of DHT present in the prostate (Cai, 2023). Lower levels of DHT will reduce the rate at which prostate gland cells are produced, leading to an overall reduction in prostate size.  

Figure 5: Effect of Finasteride on enlarged prostate (made using BioRender). 

Why do some males develop PFS, while others do not? 

From the limited evidence available regarding PFS, it is apparent that PFS is a real condition with real symptoms that impede the daily lives of past Finasteride users (May, 2024).  On the contrary, the nocebo effect is a factor worth mentioning. The nocebo effect proves to be the opposite of a placebo effect, with Finasteride patients experiencing negative side effects post treatment due to their fear of the medication, or the belief that it is causing harm to their body (May, 2024). Although there is no current explanation as to why some men develop PFS and others don’t some potential reasons that have been suggested are listed below (all based purely on speculation – nothing has been clinically proven): 

• Genetic predisposition to mental health issues/sexual dysfunctions 

• Existing mental health issues/conditions 

• Giving in to the nocebo effect – fear-induced symptoms 

Possible effects of Finasteride on the proteins in the brain: 

The blood brain barrier (BBB) acts as a protective barrier, separating the brain and nervous system from the rest of the body. The brain is well protected by this barrier making it very difficult to study exactly what is happening there without directly analyzing the brain tissue or the fluid surrounding the brain and spinal cord, known as cerebrospinal fluid (CSF) (Redzic, 2011). Finasteride can cross the BBB, meaning it can bind 5α-reductase in the brain affecting the androgen levels there, including T, DHT and the estrogen estradiol (Lephart, 1995).  

The proteins of interest for this blog, namely, the androgen receptor (AR) and 5α-reductase are intracellular proteins, and therefore, may not be secreted into the CSF. This makes analyzing the AR and 5α-reductase levels in the brains of live PFS patients impossible.  

The AR is a transcription factor involved in the regulation of many genes. It is localized in the cytoplasm, and upon binding of its activation ligands, mainly T and DHT, relocates to the nucleus and promotes gene expression or silencing of AR regulated genes. The AR is involved in sexual differentiation and development and is vital for prostate growth (Davey & Grossmann, 2016).  

DHT binds to the AR with a 2x higher affinity than T and dissociates at a much lower rate, making the former a more biologically active and favoured ligand of the AR (Davey & Grossmann, 2016). Figure 7 depicts AR activity in normal cells vs. cells where Finasteride is blocking the conversion of T to DHT via 5α-reductase.  

Figure 7. AR bound to DHT vs. AR bound to T due to Finasteride treatment (made using BioRender). 

AR protein expression levels are regulated by androgens and estrogens in a cell-type dependent manner (Kumar & Thakur, 2004) (Lu et al., 1999). As shown in Table 1, AR downregulation can be caused by increased T but also decreased DHT. In the absence of 5α-reductase, T may be converted to estrogen estradiol, which can also play a role in AR regulation. Given that after Finasteride treatment, 5α-reductase is inhibited and T is not converted to DHT, higher T levels and lower DHT levels are observed in plasma and CSF (Melcangi et al., 2013). This combination may result in lower AR expression in the brain.  

Table 1: The relationship between androgen levels and how they affect AR expression.  

5α-reductase is also regulated by androgens in a cell-dependent manner (Li et al., 2011). Studies have shown that 5α-reductase is downregulated in erectile tissue of rats after Finasteride treatment (Diviccaro et al., 2023). It has also been shown that in PFS patients, T and DHT levels in the CSF do not normalize after discontinuation of Finasteride (Melcangi et al., 2013). A visual of how these disruptions may appear in cells affected by Finasteride vs. normal cells can be seen in Figure 8. Due to this dysregulation of 5α-reductase and androgen levels, it is possible that the AR is also affected. 

Figure 8: Depicts the hypothesis that androgen levels, AR and 5α-reductase are dysregulated in PFS patients (made using BioRender).

If the proposed hypothesis in Figure 7 above is true, downstream effects are anticipated given the ARs importance as a transcription factor, possibly leading to depression as a symptom of PFS, potentially due to disruption of the GABAergic pathway. 

GABA pathway causing depression 

There are many possible side effects and complications of Finasteride treatment, with depression among one of the various negative implications. To understand the development of depression, the disease’s mechanism must be investigated at a molecular level in the brain. Neurotransmitters are chemical messengers that carry chemical signals from one neuron (nerve cell) to a target cell (Cleveland Clinic, 2022). There are two neurotransmitters of importance in the brain; one is the primary excitatory neurotransmitter, glutamate, which is released by the nerve cells in the brain and is involved in learning and memory (Cleveland Clinic, 2022). On the other hand, gamma-amino-butyric acid (GABA) is the predominant inhibitory neurotransmitter, which is the opposite of glutamate and is involved in sleep, relaxation, anxiety regulation, and muscle function (Cleveland Clinic, 2022).  

Now that the most important neurotransmitters linked to mood changes are known, further discussions on the depression development inside the brain can be drawn: 

For a brain to function normally, it is essential to maintain the balance of glutamate (the excitatory neurotransmitter), GABAA (the inhibitory neurotransmitter) and their respective receptors at optimum levels (Wen et al., 2022). If either neurotransmitter is imbalanced, it can contribute to different illnesses. For example, excess glutamate and low levels of GABA can lead to the onset of anxiety disorders, depression, schizophrenia, obsessive-compulsive disorders (OCD), and autism and play a vital role in diseases such as Parkinson's, Alzheimer's, Huntington's disease alongside others (Cleveland Clinic, 2022). 

GABA binds two significant receptors: GABAA, and GABAB which helps essential signaling cascades. However, considering that the role of receptor B in depression is still being studied, the focus will lie on the GABA_A receptors (Korczak et al., 2020; Prévot et al., 2020). Typically, a GABAA receptor, as indicated in Figure 8 below, consists of five subunits comprising a choice of 19 subunits (Fatemi & Folsom, 2014), with the most widely expressed being the α1β2γ2 combination (Cutler et al., 2023). The subunits are involved in various physiological and pathological conditions. For example, the α1 subunit is associated with sedation, and the α2 subunit with anxiety (Wen et al., 2022). Further to this, the high expression of the α2 subunit in the hippocampus and the amygdala suggests the central role of the GABAA α2 receptor in mediating anxiety and depression (Low, 2000). 

Figure 8: Aerial view of the GABA_A receptor, typically embedded in the phospholipid bilayer. Based on findings of (Gomes et al., 2019) and (Ghit et al., 2021) (made using BioRender). 

Studies in support of GABA pathway linked to depression 

In many studies, as per Cutler,et al, (2023) investigations, it was found that elevated levels of glutamate and reduced levels of GABA were commonly present in patients with depression. (Howard et al., 2019; Mondal et al., 2018; Wang et al., 2022; Wang et al., 2020). In addition, studies have linked the dysregulation of the excitatory-inhibitory balance within the brain in depressed individuals (Sarawagi et al., 2021; Fogaça et al., 2019; Lener et al., 2017; Northoff et al., 2014). Another study conducted by Liang et al., (2018) has found that Bisphenol-A (BPA), which is a chemical found in plastics, acted similarly to Finasteride by showing antiandrogenic effects. BPA was found to inhibit the production of DHT by binding to AR, causing depressive-like behaviors in rats, by downregulating AR and GABAA α2 receptor in the hippocampus and amygdala. 

An additional study investigated how Finasteride administration to neonatal rats altered GABA_A receptor in the hippocampus of grown adult rats (Modol et al., 2013). The study indicated that Finasteride could increase the expression of certain GABA_A receptor subunits in the hippocampus, speculating that GABA_A receptor function could be altered. As supported by other studies, these GABAA receptor changes are associated with major depressive disorder (Luscher et al., 2010). Particularly, there is evidence that upregulation in the δ subunit gene of GABA_A receptor causes depression and suicidal thoughts (Luscher et al., 2010). Thus, both studies support the notion that an alteration in the GABA _A receptor is linked to depression. 

Is the possibility of a full recovery attainable? 

Given that there is no standard treatment for PFS to date, patients rely solely on symptom management rather than prevention. Medication such as SSRIs are prescribed to treat depressive symptoms, and lifestyle changes are advised to improve quality of life (Boysan, 2023). This symptom management method is quite inconvenient given the apprehensiveness of most people to succumb to prescribed antidepressants. Additionally, oral medications such as avanafil, sildenafil, tadalafil, and vardenafil, which are PDE5 inhibitors may all be prescribed to treat erectile dysfunction symptoms post-Finasteride treatment (MayoClinic, 2023). These medications are effective in treating the symptoms of Finasteride but are not getting to the root of the problem. The neurological effects of Finasteride need to be addressed, as well as the structural changes to various pathways in the brain that lead to such side effects. Some, but not all individuals will report a gradual reduction in the severity of symptoms over time (Boysan, 2023). Some patients have reported persistent, long-term issues that impede the quality of their daily lives (Boysan, 2023). In-depth research is necessary to investigate this complex syndrome and try and develop an effective treatment method that will help those who experience relentless side effects. 

Hypothesis 

Androgen and estrogen levels play a role in regulating the GABA pathway via the GABA_A receptor (Wang, 2011). Disruption of this pathway is known to lead to depression. So far, it is not known how Finasteride affects the AR and 5α-reductase in the brains of PFS patients. By hypothesizing that Finasteride use causes long-term dysregulation of these androgens (T and DHT) in the brain, and thus, the dysregulation of androgen-associated proteins (AR and 5α-reductase), a link between Finasteride uses and depression in PFS patients can be made. 

Conclusion 

Post Finasteride Syndrome remains a poorly understood and recognized condition, highlighting the lack of evidence supporting its existence whereby the need for further research into its causes is necessary for the development of PFS treatment. While the inhibition of the conversion of Testosterone to DHT is what contributes to the efficacy of Finasteride as a drug, it is suggested that the disruption of the androgens and androgen receptor is the root cause of PFS side effects for some men. While the exact factors contributing to PFS symptom expression is undetermined, external factors may contribute to the severity of the expressed side effects. There appears to be a link between disruption of the androgen receptor, due to a lack of DHT. This suggests that Finasteride may affect the function of the GABAA receptor in the brain, which as a result could contribute to the depressive symptoms experienced by PFS patients. By understanding the dysregulation of the GABA pathway and androgen receptors, targeted therapies could be developed to help mitigate the experienced symptoms of PFS patients, ensuring no tradeoffs for patients upon completion of their prescribed treatment of Finasteride.