Viagra (Sildenafil) as an Adjunct in Treatment‑Resistant Depression

Medically reviewed by John Smith, Jane Doe, Sarah Wilson

Introduction: Beyond Erectile Dysfunction

Treatment-resistant depression (TRD), a medical label applied when at least two adequate antidepressant trials fail, is one of psychiatry’s gravest challenges. Affecting approximately 20–30% of individuals with major depressive disorder, TRD often means persistent suffering, disability, and despair. Patients frequently endure multiple medication switches, augmentation strategies (like lithium or antipsychotics), and off-label trials – sometimes with mild benefit, often with side effects that are difficult to bear. Despite a growing arsenal of antidepressants, augmentation strategies, and even device-based interventions, a significant portion of individuals fail to achieve remission.

Given the biological heterogeneity underlying depression, interest has surged in drug repurposing – finding new psychiatric uses for well-known medications. Examples include ketamine, an anesthetic turned rapid-acting antidepressant, and anti-inflammatory states hinting at roles for celecoxib, minocycline, or NSAIDs. The appeal lies in leveraging existing safety data and market penetration to fast-track new therapies.

One surprising contender is Viagra (the active ingredient of which is sildenafil). Best known as a remedy for combating erectile dysfunction (ED), sildenafil‘s main mechanism of action involves inhibiting phosphodiesterase-5 (PDE-5), increasing cyclic guanosine monophosphate (cGMP), and enhancing nitric oxide mediated vasodilation. However, PDE-5 is also expressed in brain areas like the hippocampus and prefrontal cortex, suggesting potential central nervous system (CNS) effects beyond the cavernous bodies.

In 2024, results from a pivotal double-blind, placebo-controlled trial published in European Journal of Pharmacology [1] showed that TRD patients on imipramine or escitalopram experienced faster remission when low-dose sildenafil was added.² While it wasn’t a cure, time-to-response shortened dramatically — a finding that defies typical SSRI timelines. Combined with encouraging animal data, such as normalized hippocampal BDNF, serotonin, glutathione, and reduced corticosterone, this points to sildenafil’s possible role in modulating neuroplasticity and HPA axis dysfunction.³

This convergence of pharmacological action and unmet clinical need demands both curiosity and caution. But is this evidence enough to consider sildenafil a viable adjunct? Or do we risk a PR-driven flash-in-the-pan, devoid of long-term efficacy or safety? Could the little blue pill, whose image is inextricably linked to virility and masculinity, find a new identity as an adjunctive treatment in psychiatric care? While the enthusiasm is mounting, there are still many questions left unanswered – and some that perhaps psychiatry has been reluctant to ask.

The 2024 Trial: Facts, Figures, and Cautions

The 2024 double-blind randomized controlled trial enrolled patients diagnosed with TRD -defined as non-response to ≥2 prior antidepressants, including either imipramine (a tricyclic) or escitalopram (an SSRI). Subjects were randomized into two groups: (1) antidepressant + placebo, and (2) antidepressant + sildenafil (10-50 mg daily). Primary endpoint: time to clinical remission (HAM-D ≤7).

Key findings:

• Faster response: Median time to remission was ~4 weeks on sildenafil vs. ~7 weeks on placebo (p < 0.05).
• Improved anhedonia and energy: Significant HAM-D subscale improvements at week 2.
• Quality of life: Sildenafil recipients reported better scores on sexual function and daily vitality.

Biomarkers included pre- and post-treatment measures in plasma and hippocampal imaging (in a subset). Reports noted increased BDNF, normalized cortisol, and improved hippocampal synaptic density on MRI.

Caveats include:

• Modest sample size (n ~80)
• Limited follow-up (~8 weeks)
• Potential bias from sexual benefit

Still, the trial is notable as the first human study to directly assess PDE-5 inhibition for TRD independent of ED context.

What makes these findings so compelling is not just the statistical significance, but the consistency with pre-clinical data. The trial included a moderate sample size and employed validated scales such as the Hamilton Depression Rating Scale (HDRS). Participants receiving sildenafil reported both improved affective symptoms and, not surprisingly, enhanced sexual functioning -something that is often compromised in SSRI and tricyclic therapy.

Crucially, the benefits were not limited to male patients. Female participants also experienced improved mood metrics, which undercuts the notion that sildenafil’s psychiatric effects are a mere byproduct of enhanced sexual confidence or function.

Mechanism of Action: Unpacking cGMP → CREB → Plasticity

The rationale stems from perturbed signaling pathways in depression. Classic antidepressants elevate monoamines, which in turn enhance cyclic AMP (cAMP) pathways. Sildenafil boosts cGMP, a parallel messenger capable of activating protein kinase G (PKG) and subsequently CREB -a transcription factor crucial for neuroplasticity.

A 2023 review highlights how PDE inhibitors in the brain enhance both cAMP–PKA–CREB and cGMP–PKG–CREB pathways, reducing neuroinflammation, oxidative stress, and supporting synaptic resilience.⁵ Specifically, PDE-5 inhibition has been linked to:

• Neuroplasticity support (e.g., dendritic spine density)
• Neuroprotection via antioxidant effects
• Anti-inflammatory action, especially in hippocampus and prefrontal cortex

In rat models mimicking TRD through chronic ACTH exposure, sildenafil monotherapy or with antidepressants reduced “behavioral despair” and normalized the levels of hippocampal BDNF, serotonin, norepinephrine, as well as glutathione. These findings align with human biomarker data and the drug’s neurotrophic potential.

Mechanistic complexity also mirrors the systems biology of depression: HPA axis dysregulation, diminished neurotrophic support, oxidative stress, and monoamine imbalance all converge in TRD.

Molecular Mechanism: PDE-5 Inhibition and the Limbic System

From a mechanistic standpoint, the proposed antidepressant effect of sildenafil involves its inhibition of phosphodiesterase type 5 (PDE-5), which leads to increased levels of cyclic guanosine monophosphate (cGMP). Elevated cGMP is thought to restore impaired cGMP–CREB (cyclic AMP response element-binding protein) signaling in limbic brain regions such as the hippocampus and amygdala.

CREB is a transcription factor pivotal to neuroplasticity, long-term potentiation, and memory formation. Several antidepressants are known to increase CREB expression over time, but sildenafil appears to engage this pathway more directly and rapidly. This offers a possible explanation for the accelerated therapeutic effect observed in the 2024 trial.

It’s worth noting that the cGMP–CREB pathway is not unique to depression. It is implicated in cognition, anxiety, and even addiction. The pleiotropic nature of this signaling cascade may position PDE-5 inhibitors as relevant across a broad neuropsychiatric spectrum, though that very pleiotropy also introduces a risk of off-target effects.

A key criticism is that sildenafil may improve mood through improved sexual function rather than CNS action. Depression often coexists with sexual dysfunction, which worsens quality of life and demoralization. SSRIs often exacerbate libido issues, so a drug that restores sexual health could consequently lift mood.

Nevertheless, disentangling sexual from mood benefits demands rigorous study: blinded sexual assessments, delayed-start designs, and specific mood-only outcome measures.

Viagra and the Placebo Effect: Untangling the Psyche

Any discussion of sildenafil in psychiatry must contend with its powerful symbolic and psychosomatic baggage. For many, Viagra is more than a drug; it’s a cultural icon with well-established reputation. The potential placebo effect associated with taking a “confidence-enhancing” medication is nontrivial, especially in populations whose sexual dysfunction contributes to their depressive symptoms.

In clinical practice, depression and sexual dysfunction often exist in a bidirectional, mutually reinforcing loop. A patient who feels sexually inadequate is more likely to experience depressive symptoms, and vice versa. Therefore, even if sildenafil’s mood-enhancing effects were partially psychosomatic, that wouldn’t render them clinically irrelevant.

Yet, this interpretation also invites skepticism: Are we treating brain chemistry or bolstering ego via a chemical crutch? This question matters, but only insofar as the outcome improves the patient’s well-being.

Atypical Use Cases: Beyond Men, Beyond Erectile Dysfunction

One of the striking revelations of recent trials is the apparent efficacy of sildenafil in women with TRD. This directly challenges the assumption that Viagra’s utility in psychiatry is mediated solely through its effects on male erectile function. In fact, women in the trial experienced improvements in anhedonia, energy, and concentration, which are the symptoms often poorly responsive to standard SSRIs.

The application of sildenafil in psychiatric settings is not limited to depression. Preliminary data suggest possible anxiolytic and cognitive-enhancing effects. Animal models have shown sildenafil to reduce learned helplessness and improve exploratory behavior, an indirect marker of reduced anxiety. Whether these results translate meaningfully to human populations remains to be seen.

Moreover, PDE-5 is expressed in the endothelial lining of cerebral vasculature. Improved cerebral blood flow may also contribute to sildenafil’s effects, although this hypothesis remains speculative.

Sildenafil presents an entirely distinct mechanism, with less systemic burden and oral availability. In a multimodal TRD algorithm, after SSRI+TCA failure, sildenafil might be considered alongside safer augmenters (e.g., bupropion).

Celebrity Context & Stigma Reduction

No major celebrity has endorsed sildenafil for depression. However, several, including Tom Jones, Brian Cox, and Michael Douglas, have spoken about its use for ED. Their candor opened the door to acceptance for older adults or those who felt ashamed because of the need to use this medication. Sir Tom Jones on the WTF with Marc Maron podcast claimed: “So far so good … There is always Viagra. A little help here and there is alright.” In his interviews during the early 2000s, Michael Douglas famously praised the innovation of erectile dysfunction drugs: “Some wonderful enhancements have happened in the last few years — Viagra, Cialis — that can make us all feel younger.” Much less advanced in years, the film star Miles Teller admitted in an Elle magazine interview: “I’ve taken it before…I tried Viagra in Las Vegas.”

Though not often discussed in scientific literature, the public perception of a drug can influence both patient openness and adherence. Former US Senator Bob Dole famously discussed his use of Viagra after prostate surgery, normalizing the drug for a generation of men. While this doesn’t directly relate to depression, it underscores the cultural capital sildenafil holds.

If public figures (especially those with mood disorders) later note psychological as well as sexual benefits, sildenafil’s psychiatric potential may gain more public trust. This is an intangible, yet important factor when considering a drug’s real-world impact. Patients may be more inclined to accept an “add-on” like sildenafil than a second antidepressant or a mood stabilizer, simply due to its familiarity and non-stigmatized image.

At the very least, clinicians can use such narratives when counseling patients, reducing shame with verified evidences of influencers and celebrities having the same problems and using the same treatment.

Off-Label Realities and Regulatory Hurdles

Despite promising data, sildenafil is not currently approved for any psychiatric indication. This presents a challenge for clinicians who wish to use it as an adjunctive treatment. Prescribing sildenafil off-label is legal, but reimbursement may be denied, and patients may encounter resistance or confusion. Moreover, the psychiatric use of a drug so closely associated with sexual health may lead to awkward conversations or skepticism. This can be particularly problematic in conservative communities or among older practitioners who remain entrenched in traditional psychopharmacology paradigms.

Still, the history of medicine is replete with examples of repurposing: from minoxidil (a failed antihypertensive turned hair regrowth agent) to bupropion (marketed both as an antidepressant and smoking cessation aid). Sildenafil’s potential repositioning in psychiatry fits well within this narrative, provided the evidence continues to mount.

Challenges and Future Directions

While the preliminary results on sildenafil as an adjunct in treatment-resistant depression (TRD) are promising, they raise as many questions as they answer. At this early stage, the most pressing challenge lies in the limited scale and duration of the existing clinical trials. The 2024 study that reignited interest was relatively small, with fewer than 100 participants, and follow-up lasted only eight weeks. While those early results showed accelerated remission and biochemical improvements, they cannot offer robust conclusions about long-term efficacy, safety, or tolerability in diverse populations. Larger, multicenter randomized controlled trials (RCTs), with broader inclusion criteria and longer-term follow-up, will be necessary to understand how durable and generalizable these effects truly are.

Moreover, the current research landscape lacks clarity regarding optimal dosing strategies. The trial in question used low to moderate doses of sildenafil (10–50 mg daily), but it remains uncertain whether these doses represent a therapeutic ceiling or if titration to higher levels might enhance CNS effects without increasing adverse outcomes. Dose–response relationships for mood outcomes have not been systematically studied. Equally unclear is whether intermittent, as-needed administration (similar to ED protocols) would differ meaningfully from daily regimens in psychiatric use.

Another critical knowledge gap involves the specific mechanisms underlying sildenafil’s putative antidepressant effect. While preclinical models have implicated hippocampal CREB signaling, BDNF enhancement, and antioxidant support, these mechanisms remain hypothetical in humans. Imaging studies, cerebrospinal fluid assays, and real-time molecular biomarkers could help illuminate the pathways involved, offering more than just correlations with symptom scores. This kind of mechanistic insight would not only clarify how sildenafil works but might also point the way toward novel, targeted drug development -perhaps even PDE-5 inhibitors tailored for central rather than peripheral use.

It’s also important to consider gender representation and population diversity in upcoming trials. Much of the ED-related research around sildenafil has skewed male, leaving potential sex-specific responses in TRD underexplored. Female patients, older adults, and individuals with comorbid anxiety or bipolar depression need to be adequately represented, especially given that TRD rarely occurs in isolation.

Finally, there’s a pressing need for ethical and policy frameworks to guide off-label use. With sildenafil widely available over-the-counter in some regions, psychiatric patients might be tempted to self-medicate without clinical supervision. This highlights the responsibility of the medical community to stay ahead of the curve -not only by conducting rigorous studies, but also by developing thoughtful guidelines that balance innovation with patient safety.

Comparison to Other Adjuncts

In the complex landscape of treatment-resistant depression (TRD), sildenafil (Viagra) must be assessed relative to existing augmentation strategies. Unlike traditional options -lithium, atypical antipsychotics, and even ketamine -sildenafil operates through a unique molecular pathway involving phosphodiesterase-5 (PDE-5) inhibition and cGMP–PKG–CREB signaling. While lithium and antipsychotics primarily modulate monoaminergic systems and neuroreceptor pathways, sildenafil taps into intracellular secondary messenger systems that promote neuroplasticity and neuroprotection. It is a mechanism seldom targeted in mainstream psychiatry, and one that aligns well with encouraging preclinical and early clinical trial data.

Yet, the evidence base for sildenafil is currently smaller and more fragmentary. Lithium’s efficacy as an augmenting agent, for instance, is backed by decades of randomized controlled trials and meta-analyses. Meanwhile, aripiprazole and quetiapine, both approved for TRD augmentation, show remission rate improvements of roughly 15–20% above placebo. Ketamine, though not without controversy, offers rapid relief -sometimes within hours -an effect not yet documented for sildenafil. While the 2024 sildenafil-augmentation study demonstrated a statistically significant acceleration in time to remission versus placebo, it lacks large sample size and direct comparative data with these standard adjuncts. It remains unclear whether sildenafil’s effects can match or exceed the benchmarks set by these established treatments.

On the other hand, sildenafil has a relative advantage in convenience and tolerability. Available orally, inexpensive, and familiar to both clinicians and patients, it contrasts sharply with procedures like intravenous ketamine infusions or the metabolic and weight-related side effects commonly associated with antipsychotics. Additionally, sildenafil’s favorable safety profile, widely documented in diverse populations for erectile dysfunction, makes it an appealing alternative for patients who may fear the long-term risks of neuroleptics or lithium, or who lack access to specialized infusion centers.

One must also consider the broader category of phosphodiesterase inhibitors. A recent comprehensive review in Psychopharmacology explored PDE inhibitors across psychiatric domains, including depression, anxiety, schizophrenia, PTSD, and bipolar disorder. This review underscores the broader therapeutic potential and mechanistic rationale for PDE-5 inhibitors like sildenafil in modulating neuroplasticity, inflammation, and oxidative stress -through the activation of both cAMP–PKA–CREB and cGMP–PKG–CREB pathways [2]. The review concludes that while early data are promising, larger and more rigorously designed clinical trials are essential before these agents can be recommended in routine psychiatric practice.

Ultimately, the question becomes one of positioning. Sildenafil is best framed not as a replacement for established augmenters but as a novel mechanism with potential synergistic effects. A clinician might envision sildenafil being offered to patients who have failed multiple lines of monoaminergic augmentation and who have coexisting sexual dysfunction -or perhaps in those who simply wish to avoid the metabolic side effects and monitoring burdens of antipsychotics. In this light, sildenafil becomes a valuable piece of the TRD therapeutic mosaic: a relatively low-cost, low-burden option, ripe for further evaluation in head-to-head or add-on studies with agents like ketamine or aripiprazole.

Conclusions: Curiosity with Caution

The 2024 trial doesn’t validate sildenafil as a first-line TRD agent, but it highlights a mechanistically novel, readily available, and generally well-tolerated candidate. PDE-5 inhibition introduces a fresh molecular axis into the psychopharmacological landscape, distinct from monoamines or glutamate.

While comparisons to rapid-acting agents or brain stimulation aren’t yet feasible, sildenafil wins on cost, familiarity, and ease of use. The sexual function benefit may feel “bonus,” but both stigma and mechanistic realities suggest deeper mood effects.

Unlike FDA-approved augmenters, prescribing sildenafil in TRD remains off-label, and long-term data are absent. Important unknowns include optimal dosing regimens (e.g., daily low-dose versus intermittent), gender-specific responses, and effects in comorbid conditions such as anxiety, bipolar depression, or PTSD. Moreover, the mechanism that makes sildenafil appealing — its peripheral vascular effects and improvement in sexual function — may also confound its psychiatric assessment. Discerning whether mood improvements stem from neurobiological modulation rather than simply restoration of sexual health will require careful study design with hormonal assays, sexual function scales, and imaging correlates.

Clinically, sildenafil represents a rational, empathic intervention, particularly for patients who feel left behind by conventional treatments, or who express frustration over the sexual side effects of antidepressants. Its accessibility means that, with appropriate cardiologic clearance and monitoring, sildenafil could be offered compassionately under careful supervision.