Why We Are Losing The War on Depression
And how we can possibly win it
Humanity has been familiar with depression since ancient times. In the 5th century BC, a Greek physician Hippocrates described it as “melancholia.” How is it possible that over two millennia later, the problem has only worsened?
The World Health Organisation (WHO) named depression as one of the top health problems globally, and it expects to rank it at number one by 2030 (1). The lifetime possibility of depression is 15–18%, which means that approximately two people out of every ten will experience at least one depressive episode in their lives (2). Given that depression manifests early and affects young and otherwise healthy people, it imposes a yearly economic burden of tens of billions of euros. At worst, the consequences of depression can be devastating, as it increases the risk of suicide. Almost one million people take their own lives every year, which means that every 40 seconds, one person in the world commits suicide.
Specific genes have been associated with the predisposition to depression. However, despite extensive genetic studies and due to high variability, only a small number of genes have been reliably associated with Major Depressive Disorder. Apparently, genetic factors do not play as important a role as they do in other mental diseases. Instead, other factors add heterogeneity to the heritable component of depression.
For example, environment plays an important role. Via epigenetic mechanisms, the environment affects genes’ activity without changing their DNA structure. Adverse and traumatic events, especially during childhood (or even prenatally), significantly increase the odds of becoming depressed or anxious in adulthood (3). The other contributors to depression’s pathophysiology are inflammation, cortisol, sex hormones, microbiome, co-existing illnesses, and lifestyle (4).
Despite a long history of depression studies and the nearly 70-year existence of antidepressant drugs, we are losing the fight against this disease. Why?
Drawbacks in our current approach to depression
Prevention and early detection failed.
Despite being a highly prevalent and disabling disease, depression is generally under-diagnosed according to WHO. Reasons for this problem vary. Firstly, a large percentage of depressed people do not seek professional help. In some cultures, depression is viewed as a weakness and is often stigmatised. As a result, some countries (like South Korea) have a low number of diagnosed depression cases, but their suicide rate is frighteningly high. According to a recent study, the high cost of treatment, fear of medication, and lack of time for treatment or specialist’s visit were named most frequently among reasons for not getting treatment (5).
Secondly, diagnostic criteria are often insufficient to identify depression effectively. Hence, depression symptoms overlap with other mental illnesses or even grief and bereavement (6). Moreover, the Diagnostic and Statistical Manual of Mental Disorders (DSM–5) mixes patients with different degrees of depression severity under the common label, “Major Depressive Disorder.” Consequently, people who have lost a loved one and grieve for a little longer than expected can be diagnosed with MDD, along with people with severe, persistent depression and strong suicidal ideation (7).
The heterogeneity of depression is also often underestimated, even though genetic research, neuroimaging studies, and long-term clinical observations suggest the possibility of a variable form of depression that responds differently to treatment. The shift to a precision medicine approach as in other clinical areas such as cardiology and oncology needs to happen in mental health, keeping in mind that timely intervention can help to decrease negative consequences.
The understanding of depression is uncertain
Unfortunately, an adequate diagnosis does not guarantee a cure, mainly due to the misunderstanding of depression pathophysiology. Depression has been long thought to be a mere biochemical imbalance of monoamines — the neurotransmitters that relay messages between brain cells. This theory emerged from two coincidental events that took place in the early 50s. The first incident happened at Seaview Hospital in New York in 1952. Seriously ill patients treated for tuberculosis with a new drug became energetic, joyful, and “dancing in the hall.”
That new drug, iproniazid, appeared to be a monoamine oxidase inhibitor that prevents the degradation of two important neurotransmitters: serotonin and norepinephrine (8). In the second case, a patient withdrew from his everyday activities and expressed no more interest in the things he used to like after taking the hypertension drug reserpine, which depleted brain monoamines. These two cases gave rise to the idea that neurotransmitters such as serotonin, dopamine, and norepinephrine, when imbalanced, lead to a mood disorder (9). Later, selective serotonin reuptake inhibitors (SSRI) provided further support for the monoamine hypothesis.
Nevertheless, this highly-accepted view comes with important caveats. Conventional antidepressants increase serotonin in the brain very quickly (within hours), but it takes at least two to four weeks for them to reach clinical effect. Moreover, relief of depressive symptoms occurs only in 30% of depressive patients after the first antidepressant trial (10). Besides, monoamine depletion failed to change mood in healthy subjects (11). Apparently, the monoamine hypothesis fails to provide a comprehensive view into depression mechanisms and cannot serve as a solid basis for building treatment strategies.
In fact, over the last two decades, mental illnesses have become increasingly recognised as brain circuit disorders (12). Brain networks involved in emotional processing undergo a substantial change in depressed subjects (13,14). Neuronal activity, interregional connectivity, and grey matter size within these mood-regulating circuits in depressive patients differ from those in healthy volunteers (15,16). The role of neuronal plasticity in depression pathophysiology and antidepressant action also received a lot of attention (17,18,19).
Due to the lack of plasticity, a depressed brain is incapable of escaping a negative thinking pattern. While clinical data confirm impaired plasticity in depressed people, and the basic science demonstrates how antidepressants increase plasticity in the brain, experts so far have reached no consensus, so the serotonin hypothesis still prevails in clinics (20,21).
Current treatment strategies are ineffective.
We base treatment strategies on our understanding of disease mechanisms. Thus, an incomplete picture of disease pathophysiology impedes successful treatment. Indeed, a striking 75% of individuals with depression do not receive adequate treatment, according to WHO. Depression management guidelines suggest that psychological interventions and psychotherapy should precede pharmacotherapy.
Evidence suggests that in mild to moderate depression cases, psychological treatment alone (such as cognitive behavioural therapy, acceptance therapy, interpersonal therapy, or mindfulness therapy) can be sufficient to benefit the patient (22). In reality, however, physicians habitually prescribe antidepressants straight away due to the lack of qualified specialists and the high price of psychological treatment.
As a consequence, psychotherapy is frequently seen as an alternative treatment, and only one-fifth of patients with depression eventually receive it. The vast majority of depression patients receive antidepressants only (23). Sadly, as previously mentioned, antidepressant treatment is not a one — size — fits — all solution despite being useful for some patients.
In the realm of drug therapy for depression, serotonin reuptake inhibitors (SSRIs) like Prozac are king. Being the frontline treatment, they specifically target serotonin transmission in the brain and have less severe side effects than first-generation antidepressants such as tricyclic and monoamine oxidase (MAO) inhibitors. Ironically, the safest SSRIs are the least effective. In general, only one-third of patients can reach remission after the first course of pharmacotherapy.
Tricyclic and MAO inhibitors remain the most effective, but alas, have more severe side effects, are less tolerable, and have the highest drop-off rate (24,25). As a result of low first-intervention efficacy, depressed patients require further treatment. However, the more treatments patients receive, the lower the chances are for a positive outcome (10).
In case of more severe depression, drug treatment is considered necessary in most cases because the severity of the symptoms makes it difficult for patients to participate in psychotherapy (26). Still, a combination of medication with psychotherapy is considered most likely to improve the outcome (27,28). Again, however, most patients obtain medication only (4).
In summary, antidepressants reduce unpleasant symptoms, but they do it too slowly and help too few patients improve. Moreover, antidepressants have serious side effects, and prolonged antidepressant treatment is associated with health risks (24). However, despite being a suboptimal solution for depression treatment, cheap and easily accessible antidepressant pills substitute for other, more effective treatments. Is it any wonder that we cannot manage depression?
How can we improve the situation?
Based on the abovementioned information, insufficient detection, unsatisfactory diagnostics, poor understanding of the mechanism, and ineffective treatment strategies are the main contributors to our dishonorable defeat by depression. But is there hope that in the near future the situation can change for the common good?
Use technologies for detection.
Living in a smartphone era gives us unprecedented opportunities for the early detection of depression. Socializing, working, and entertainment via phone navigation have become routine. Early detection of various health conditions using these devices should be the next step, and the instruments are already in place. Nowadays, smartphones can detect early signs of depression by analyzing movement, sleep patterns, phone usage, speech, and other indicators.
Research shows that depressed people decrease their everyday activities and the number of places they visit, but they increase their phone usage and spend more time online (29,30,31). Moreover, speech recognition can show some early signs of depression based on the voice tone or word patterns a person uses (32). Most importantly, this way of depression detection is based on passive data collection and does not rely on whether a potentially depressed person answers a questionnaire.
Make psychological therapy available.
Psychotherapy has proven to be effective for treating depression, with little difference between various approaches (33,34). Moreover, patients seem to prefer psychological therapy versus medicines, and their unwillingness to take drugs, in some cases, is an avoidable obstacle to starting treatment (35). How can we make psychological interventions more accessible? Again, this area is where technology can step in.
Firstly, remote professional support via internet services and smartphone applications can make psychotherapy more available in terms of time and cost. Secondly, nowadays, behavioral therapy is possible even without interacting with a therapist. Self-guided, internet-based cognitive behavioral therapy significantly reduces costs and increases availability (36). At the same time, innovative technologies bring this method to a new level of autonomy, such as using chatbots powered by artificial intelligence.
Although therapies with human-to-human contact are understandably more valuable, even simple communication with a chatbot has proven effective, and some people even prefer talking to machines (37).
Use existing antidepressants smarter.
Additionally, preclinical research confirms a theoretical framework suggesting that enhanced brain plasticity increases susceptibility to the environment (38,39). Perhaps antidepressant drugs do not change mood per se, but rather they provide a substrate for this change by making the brain more plastic. And when the brain is plastic enough to rewire itself, the second step is needed — the behavioral change. Psychological retraining, or simply a supportive environment, can promote this behavioral change and bring a patient to recovery. The opposite could be true as well: when the environment remains detrimental, antidepressants could be harmful, as they increase sensitivity (39).
If we assume that this two-component model for depression treatment (plasticity boost + behavioral change) is relevant to the human brain, it should affect our use of conventional antidepressants. Based on this model, antidepressants possibly should not be prescribed without concurrent behavioral intervention.
Put effort into investigating new drugs and treatment strategies.
During the last decade, a few new treatments for depression have emerged. For instance, ketamine — an old anesthetic drug — appears to be useful in quickly and effectively alleviating depression symptoms. In contrast to conventional antidepressants that require weeks to take full effect, ketamine relieved depressive symptoms (and, more importantly, stopped suicidal ideation) within mere hours after infusion (40,41).
However, ketamine has prominent side effects such as sedation, difficulties with concentration, dissociative effects, and potential for addiction, making it impractical for general application. Ketamine metabolites, essentially lacking these undesirable side effects, have demonstrated their efficacy in animal models of depression, but to date, the human population has not undergone any ketamine metabolite trials (42,43,44).
The use of psychedelics for depression is the second significant breakthrough (45,46). For many years, these medicines were under stigma, but they have currently undergone a renaissance after proving to be safe and efficacious in treating a number of mental conditions. Although centers for psychedelic research have recently opened in the US and UK, this area’s progress is not yet at full speed. Funding for psychedelic research still comes mostly from private sources, and psychedelics remain scheduled as dangerous drugs with high abuse potential in most countries, contrary to scientific and clinical evidence. This belief system halts their progress (47,48).
Brain stimulation — magnetic or electric — has demonstrated its efficacy in treating depression for many decades. Benefits from brain stimulation are associated with mood and emotional regulation. While early stimulation methods were quite harsh, modern techniques are more precise and far better tolerated.
Among the most significant drawbacks to brain stimulation are the prohibitive cost, the necessity of visiting a clinical institution for regular sessions, and the high probability of relapse. Inexpensive portable devices could resolve all of these problems and allow patients to control their depression independently on their own schedule. Such self-sufficiency is a highly desirable feature for effective depression treatment, especially for those patients living with a social stigma about their condition or lacking available treatment resources.
Despite the fact that these alternative treatment methods exist, they are usually offered only in cases of so-called “treatment-resistant” depression after several pharmacological therapy trials have failed to help. It is essential to explore these new treatment classes’ possibilities further and reconsider the sequence in which clinical guidelines recommend treatment steps. Obviously, for patients with suicidal ideation, for example, a rapid-acting antidepressant similar to ketamine — rather than slow and possibly ineffective SSRIs — could be lifesaving.
Conclusion
Is it possible that human beings will ever overcome depression? Yes, it is. Despite the bleak worldwide situation with depression, plentiful opportunities have presented themselves for new treatment strategies that differ from our current legacy of pharmacological servitude.
Why don’t we join the efforts to facilitate a better dialogue between basic science and clinicians and create new pathophysiology models whereby we can adjust conventional treatment strategies and legal regulations? It is equally important to raise public awareness, reduce negative attitudes towards mental health issues, and encourage new business models such as psychedelic therapy centers, medical devices for home use, and remote or automated psychotherapy that can replace antidepressant pills. When we successfully accomplish these changes, we will enter a new, happier era.
