Anti-Depressants: Future Considerations for Clinical Research

Depression is the most common form of mental illness affecting approximately 5% of adults globally. Prescription rates for anti-depressants are at an all-time high having increased 35% in the last 6 years in the UK alone. However, there has been much discourse in the scientific community in recent years about the true efficacy of current anti-depressants in the treatment of clinical depression.

Chemical Imbalance Theory of Depression

In the 1960s the chemical imbalance theory (also known as the monoamine deficiency hypothesis), proposed that depletion in levels of key neurotransmitters in the brain, such as serotonin, was the underlying cause of depression. This was widely supported as medications targeting these neurotransmitters seemingly alleviated depressive symptoms in patients. Following their introduction to the market in the 1980s, selective serotonin reuptake inhibitors (SSRIs) quickly became the gold standard treatment for depression due to their ability to increase serotonin levels in the brain. However, the evidence to support the chemical imbalance theory used to market these drugs has been widely debunked in recent years, calling the widespread usage of current anti-depressants into question.

In July 2022, a systematic review was published analyzing decades of research on the chemical imbalance theory. The review did not find any convincing evidence to support it. For example, studies showed no difference in serotonin levels between healthy patients and those diagnosed with depression. Moreover, the review found that artificially lowering serotonin levels did not induce depression. There was also evidence that long term usage of anti-depressants could cause lower serotonin levels in the long term, contradicting the entire purpose of SSRIs.

However, other experts in the field disagree, arguing that while the theory may not be accurate, anti-depressants are still helpful in the fight against depression – even if we don’t know exactly how they work. New research published in recent weeks suggests that anti-depressants may alleviate depressive symptoms by simply blunting patients' emotions, rather than addressing a chemical imbalance.

Efficacy of Current Anti-Depressant Drugs

Naturally, with the growing body of evidence debunking our understanding of how anti-depressants work, studies are beginning to question the true efficacy of current treatments and their impact on patients’ quality of life.

Despite the increase in anti-depressant prescriptions, suicide rates linked to depression continue to rise with a steady 35% increase in rates observed over the last two decades. One of the main issues with current anti-depressant drugs is that the vast majority of patients fall into the mild-moderate category, on which these drugs tend to be less effective.

Strong evidence has also emerged in recent years to suggest that the efficacy of anti-depressants may largely result from a placebo effect. While it is true that anti-depressants outperform placebos in clinical trials, there is often little statistical difference between them. A recent study reported that current anti-depressants may only be truly effective in 15% of patients. Experts have even suggested that these statistical differences could be because patients’ perception of drug efficacy may be altered if the blind is broken, which it often is.

Quality of life is negatively impacted by side effects and a delay before patients realize any benefit from anti-depressants, which often leads to patients not adhering to the treatment prescribed. Given the strength of the placebo effect, this has caused many researchers to question current prescription practices.

Questions have also been raised about how clinical trials are conducted on anti-depressant drugs. Trials tend to be short in duration, typically lasting 8-12 weeks, which provides little insight into the long-term impact and efficacy of anti-depressants. Moreover, clinical trials generally exclude suicidal patients, the patient population that stands to benefit most from pharmacological intervention. This exclusion stems from concerns that some anti-depressant treatments may put them at increased risk for suicide, as many SSRIs carry a higher risk of suicidal ideation in patients under the age of 25, contradicting a key purpose of anti-depressant prescription.

The purported benefits of current anti-depressants do not appear to outweigh the negatives, suggesting that we need to explore new pharmacological options for the treatment of depression.

A Future Beyond SSRIs

There are a number of new drug targets currently being explored for the treatment of depression that could serve as more effective alternatives to SSRIs.

N-methyl-D-aspartate (NMDA) Receptor Antagonists

Brain imaging studies have shown several structural changes in the regions of the brain that regulate mood in patients with depression. The neurotransmitter glutamate is heavily involved in the regulation of these regions and overproduction may trigger these changes. NMDA receptor antagonist drugs such as Ketamine block the action of glutamate, allowing the brain to produce more brain-derived neurotrophic factor (BDNF), which is often lowered in depression. BDNF is a protein that is involved in the repair and formation of new neurons, so increasing these levels can allow the brain to repair structural changes for rapid relief from symptoms in patients. The nasal spray Esketamine was approved in 2019 and can be effective in managing treatment-resistant depression.

Gamma-Aminobutyric Acid (GABA) Modulators

GABA is a neurotransmitter that plays a prominent role in stress in the brain, with many studies showing deficits in GABA in patients with major depressive disorders. Brexanolone was approved in 2019 for the treatment of postnatal depression. While the mechanism of action is not fully clear, it’s thought that postpartum GABA levels do not recover quickly enough to manage stress, leading to postnatal depression. Brexanolone is a pharmaceutical form of Allopregnanolone, a waste product from the metabolism of progesterone during pregnancy. IV administration stimulates GABA production, allowing the body to better respond to stress and rapidly relieving depressive symptoms.

Psychedelic Drugs

Psilocybin, the active ingredient in magic mushrooms, has gained a lot of attention in recent years as a potential new treatment for depression with a far greater safety profile than SSRIs. A growing number of small-scale clinical trials are showing lasting remission following treatment with this psychoactive. The drug is currently thought to act by remodeling neural circuits in areas of the brain associated with depression, improving cognitive processing of emotions. Fans of the final series of 'The Good Fight' will have seen this type of treatment in action as Christine Baranski’s Diane Lockhart seeks relief from depression and anxiety brought on by the current political landscape. In recent weeks, magic mushrooms have become legal in the state of Oregon in the US, opening the door to large scale clinical trials that can explore these effects further.

Considering the promise of new anti-depressant classes, there is life beyond SSRIs. The scientific evidence is simply not there to support the chemical imbalance theory of depression and the continued over-prescription of these drugs. Clinical research needs to adapt and learn from the past as we pave the way for future treatments. Every debunked theory gets us one step closer to understanding the biological mechanisms of depression, enabling us to develop better treatments that will allow patients to walk from darkness into light.