"Depression is a side effect of dying."
- John Green
Ten years ago I undertook a medical placement in India during which I had the privilege to be supervised by one of the most notable physicians in that vast country. He taught me a lot, and in the midst of our chaotic outpatient clinics one day he gave me the best single piece of advice regarding clinical medicine that I have ever received. He said only this, that "Every patient should leave the clinic with a smile." I initially scoffed at this notion, but in the years ahead I came to understand what he meant - that even if a condition has no effective treatment, a doctor can still help that patient in some other significant way be it giving them a diagnosis, talking about some of their other concerns, or even just letting them vent their frustrations. I have never forgotten what that wise old doctor said, and have endeavoured to put it into practice as much as possible. Unfortunately, there is one condition that continues to elude my best efforts to fulfill his advice, one condition where I often fail to help the patient leave the clinic with a smile. That condition is depression.
Since it is complex and its origins not well understood, depression is difficult to define. The official rendering is a bit long-winded and fuzzy but essentially defines depression as one or more major depressive episodes which are indicated by the presence of five or more of the following symptoms over a minimum two-week period - low mood, loss of interest or pleasure, significant changes in weight or appetite, insomnia or hypersomnia, restlessness or lethargy that is noticeable by others, loss of energy, feelings of worthlessness, reduced ability to concentrate or make decisions, and suicidal ideation (1). So depression is not just about having a really, really low mood for an extended period of time, it's much more than that, and since low mood may not even necessarily be present, depression can be easily missed. Depression is complicated further by the many depression "mimics" such as dysthymia (persistent mild depressive symptoms lasting two years or more), grief (depressive symptoms following the loss of a loved one that are usually tolerable and self-limited), drugs that produce depressive symptoms (particularly alcohol, beta blockers, calcium channel blockers, digitalis, benzodiazepines, corticosteroids, interferons, and many antibiotics), and medical conditions that produce depressive symptoms (such as sleep apnea, thyroid disorders, and cortisol disorders, to name just a few). This list is by no means exhaustive.
Many people - some doctors included - trivialize depression for some bizarre reason, yet let us consider what a diagnosis of depression means for the brain, the body, and behaviour. Let's start with the brain. It has been consistently shown by dozens of studies that the brains of people with depression are atrophied, with significant volume reductions in the basal nuclei, hippocampus, and frontal lobes compared to normal subjects (2,3,4). Depressed brains also have more MRI lesions, particularly in the basal nuclei and frontal lobes (4). Furthermore, the frontal lobes of depressed brains have reduced numbers of glial cells, non-neuronal cells that support and protect neurons in all sorts of ways (5). Next, the body. Depression is strongly associated with a multitude of chronic medical conditions such as diabetes, cardiovascular disease, Alzheimer's dementia, and Parkinson's disease (6,7,8,9). It is also associated with a worse outcome for any co-existing chronic medical conditions (10). Finally, behaviour. Depression is associated with social role disruption in the form of low marital quality, work performance, and earnings (10). Sleep disturbance is a key feature (11). Furthermore, depressed people have a relatively high suicide risk (12). The cumulative effect of all of these negative associations makes it easy to see how depression is the leading source of disability worldwide (13).
Depression really is a global scourge - the numbers vary depending on the particular country, but about 10% of people across the planet experience it at some point in their lives (14). Depression afflicts all socioeconomic groups in all countries, although it is more prevalent in lower socioeconomic groups and in richer countries (10,14). Depression can strike at any age, from childhood to late life, and although it is diagnosed in a 5:2 ratio in females compared to males (15), its prevalence in men is rather underestimated since the successful suicide rate is several times higher in males compared to females (16).
Right then, that's enough - we know that depression is complex, it's bad, and it's far too common. So now let's talk about where it comes from, and what can be done about it.
Origin of Depression
Despite many attempts, a unified theory of depression remains elusive (17). Theories with the most evidence behind them include the genetic susceptibility theory (that depression results from genetic factors), the stress hormone theory (it results from a dysregulated hypothalamic-pituitary-adrenal hormonal axis), the monoamine deficiency theory (it results from depleted levels of the neurotransmitters serotonin, noradrenaline, or dopamine), the neurotrophic theory (it results from low levels of factors such as brain-derived neutrophilic factor or BDNF, a protein that supports the growth of neurons), the GABAergic theory (it results from reduced activity of the neurotransmitter gamma-aminobutyric acid or GABA), the impaired circadian rhythms theory (it results from sleep-wake dysregulation), and the vitamin D deficiency theory (it results from low vitamin D levels) (17,18). There are others. Each of them is strong in its own way, but they are all missing something.
Basically while each of these theories offers a proximate physiological explanation for depression, not one of them provides an ultimate evolutionary explanation for depression. It's like trying to understand the nature of a painting - on a proximate level this is best achieved by describing the stylistic aspects of the painting, but on an ultimate level it is best achieved by trying to understand how the painting came to be in the first place. Depression lacks an ultimate evolutionary explanation, and without that - without understanding the reason it exists - it will continue to appear etiologically complex.
To discover this ultimate evolutionary explanation, animal models provide a starting point. It has been shown that when an animal perceives they are losing a social hierarchy struggle they temporarily display depressive-like symptoms such as agitation, lethargy, loss of interest, and altered sleep patterns (19,20). It is thought that the temporary perception of defeat lets the losing animal momentarily withdraw from the struggle, protecting them from any further attack and allowing them to focus their cognitive resources on planning a way out of it (21). However, when an animal repeatedly loses in a social hierarchy struggle they display long-lasting social withdrawal behaviour (19). This lasting perception of defeat also lets the animal withdraw from the struggle but the reduced sociability of the animal persists; they are changed (19).
It is not unreasonable to extrapolate these studies to humans. In humans, a losing situation often produces a temporary perception of defeat followed by a state of subthreshold depression, which we will define as a depressive episode that meets some but not enough of the criteria to diagnose depression, into which that person withdraws internally, protecting themselves from further harm and allowing them to plan at how to succeed at the situation the next time around. Subthreshold depression occurs at multiple points throughout most people's lives; I am sure most of the people reading this are personally acquainted with it. It is temporary and limited to a particular situation, so it lasts for a while and then resolves. However, certain factors in a person's life can produce a more lasting perception of defeat followed by a state of depression in which that person also withdraws internally in the interests of safety and planning, but they remain withdrawn and eventually display the lasting alterations in the brain, body, and behaviour that characterize depression. In essence, a temporary perception of defeat regarding a limited situation leads to subthreshold depression whereas a lasting perception of defeat regarding all of life leads to depression. The former is normal; the latter is not.
There are many factors that can accumulate to transform the normal, adaptive evolutionary mechanism that is subthreshold depression into the abnormal, maladaptive disability that is depression. They all contribute to the perception of defeat.
(1) General risk factors for depression.
Some of the commonest general risk factors include a family history of depression, adverse events in childhood, chronic stress, lower socioeconomic status, and living in a richer country. It has been argued that a family history of depression represents a strong genetic influence (22). Adverse events in childhood, particularly childhood sexual abuse, can be extremely traumatic and nearly 100% association between severe childhood sexual abuse and depression in later life has been reported (23). Most studies show an excess of stressful, undesirable events prior to the onset of depression (15). There is compelling evidence that low socioeconomic status contributes to depression (24) and yet it is more prevalent in richer countries (10,14), two facts which might appear to contradict each other, but since richer countries have greater income inequality than low or middle income countries (17), belonging to a lower socioeconomic group in a richer country means that it is that much harder to climb the socioeconomic ladder. Childhood sexual abuse, chronic stress, lower socioeconomic status, and living in a richer country - all of these factors contribute to the perception of defeat.
(2) Age-related risk factors for depression.
The circumstances in which depression arises in young and old people are usually different. In youths and young adults, depression often occurs in the context of an excess of life events with negative outcomes on top of a background of a non-supportive home or school environment (25, 26, 27). As a result, young people with depression often feel depressed and worthless (28). In contrast, it is well established that late life depression occurs in the context of a serious or chronic medical condition such as diabetes, cardiovascular disease, Alzheimer's dementia, or Parkinson's disease (9,29). Instead of feeling depressed or worthless, old people with depression often complain of feeling unwell in a nonspecific way, or they may complain of a physical symptom (30). Too many life events with negative outcomes in young people and chronic disease in old people - both contribute to the perception of defeat.
(3) Gender-related risk factors for depression.
The circumstances in which depression arises in women and men differ. In women, depression is more likely to occur after a negative outcome in their social network such as difficulty getting along with a particular individual or a serious illness in a family member or friend (31). This is supported by the fact that women show greater cortisol stress responses to social rejection challenges than men (32). In contrast, depression in men is more likely to occur after a negative outcome following an attempted achievement such as work difficulties, divorce, or separation (31). Men show greater cortisol stress responses to achievement challenges than women (32). Too many negative social outcomes in women and too many negative achievement outcomes in men - both contribute to the perception of defeat.
In summary, it is normal to have a temporary perception of defeat in a limited situation, leading to a state of subthreshold depression. Most people experience subthreshold depression at multiple points throughout their lives; it is an adaptive evolutionary mechanism that lets a person withdraw from a losing situation so as to remove themselves from further harm and plan on how to succeed at it the next time around. However, it is not normal or adaptive to experience a lasting perception of defeat that overshadows all situations. Depression is an adaptive evolutionary mechanism on overdrive, where the ability to deal with losing in a particular situation in life is twisted into a perception that it is not possible to win at anything in life. This happens in the context of a myriad of factors. General factors such as family history, adverse childhood events, chronic stress, lower socioeconomic status, and living in a richer country increase the likelihood of depression in everyone, but young women are additionally at risk after an excess of negative social outcomes, young men are additionally at risk after an excess of negative achievement outcomes, and older women and men are additionally at risk in the setting of chronic disease. These factors are all united by the simple fact that they contribute to the perception of defeat and, given enough exposure and time, transform a normal, adaptive evolutionary adaptation into the monstrous "side effect of dying" that is depression.
Treatment of Depression
It is a sad fact that most people with depression do not receive treatment, and of those who do the treatment quality is unacceptably poor (10). There are quite a few treatment strategies out there but we will restrict our discussion to those with the highest impact potential - lifestyle therapies, psychological therapies, and antidepressant medications. There is supportive evidence behind several lifestyle therapies, all of which are under-utilized (33). The evidence behind many of the psychological therapies is compelling, with an enduring treatment effect even after they are stopped (34,35) and yet these therapies are oftentimes neglected. While the evidence behind antidepressant medications is solid, they lack an enduring treatment effect once they are discontinued (34). However, antidepressant medications are prescribed so routinely that they must be mentioned. We won't talk about more specialized treatment strategies such as electroconvulsive therapy, vagus nerve stimulation, bright light therapy, transcranial magnetic stimulation, or deep brain stimulation; these treatments are best guided by a psychiatrist.
Before proceeding I would like to say one thing - that if anyone reading this is suffering from depression, give The Power of Now by Eckhart Tolle a read (36). In this book, Tolle speaks from his own personal experience with depression as he repeatedly emphasizes the importance of living in the present over the past or future. Since the abnormal perception of defeat often results from negative events in the past, Tolle's book provides an excellent therapeutic starting point.
(1) Lifestyle therapies.
Modernity has come at a cost. In general, people in the west are now more distracted, sedentary, socially isolated, and sleep-deprived compared to previous generations (33). These things all take away from the ability to relax and focus on important, non-urgent situations; they remain unresolved, reinforcing the perception of defeat. There are numerous lifestyle therapies that can be tried but the following have the best evidence to date (33).
First, try mindfulness-based training - this focuses on mindfulness, which can be defined as paying attention in a particular way, on purpose, in the present moment, and non-judgmentally (37). This can be instituted with 8-10 weeks of basic training, after which it can be done on an individual basis. Evidence for mindfulness-based training is growing, with a review and meta-analysis of 39 studies showing that it is effective in improving mood in depression and variety of other conditions (38).
Second, exercise at regular intervals - several studies, including a meta-analysis involving 37 randomized-controlled trials, have demonstrated that exercise is an effective mood elevator (39,40, 41). It also increases enhances a person's body image, self-esteem, and social engagement (33).
Third, listen to more music - a systematic review of 17 studies found that listening to music over a period of time reduced depressive symptoms in adults (42). No specific type of music was found to be superior, so personal preference was recommended.
Fourth, seek positive social interaction - positive, supportive, intimate relationships have been established to have a beneficial effect on general health, particularly psychological health (43). Negative exchanges with family and friends are associated with a greater occurrence of depression (44).
Fifth, limit alcohol to two drinks a day - in alcoholics, it has been shown that depression is considerably alleviated a short time after abstaining from alcohol, within a few weeks (45). Alcohol should be limited to no more than two standard drinks per day.
Sixth, obtain sufficient sleep - sleep deprivation and insomnia are strongly linked to depression (46). However, the association appears to be bidirectional.
(2) Psychological therapies.
Psychological therapies are too often neglected in the treatment of depression (47). They are just as effective as antidepressant medications and multiple placebo-controlled trials have additionally demonstrated an enduring treatment effect that persists long after therapy is discontinued (34,35). The reason for this is that psychological therapies dismantle the abnormal perception of defeat that lies at the heart of depression. Three of them warrant mentioning.
Interpersonal therapy is based on two major principles - first, that depression is a medical illness rather than the patient's fault or personal defect, which helps to define the problem and excuse the patient from symptomatic self-blame, and second, that depression arises in the setting of negative interactions with others (48,49). During 12-16 weeks of structured interviews the focus is on solving any focal interpersonal problems that triggered or followed the onset of depression (48,49). Interpersonal therapy has a very strong empirical support base in treating depression, with a greater breadth of effect than antidepressant medications regardless of the duration and severity of a patient's depression (50).
Cognitive therapy, a subset of the cognitive behavioural therapies, is based on the premise that depression arises from inaccurate beliefs and maladaptive thinking regarding situational outcomes resulting in a bias towards negative information processing (34). The focus is on correcting these negative biases. Cognitive therapy has a strong empirical support base in treating depression (50).
Behavioural activation, a subset of the behavioural therapies, is based on the premise that depression arises from the avoidance of valued activities (51). The focus is on structuring the day according to these activities so as to reduce the cognitive processes that initiate the avoidant behaviour (51). Behavioural activation has a strong empirical support base in treating depression (50).
(3) Antidepressant medications.
Antidepressant medications are often prescribed without proper consideration of the alternatives (47). Thousands of placebo-controlled trials prove that they work (34) but if discontinued there is an elevated risk of depression recurrence (52). The reason for this is that antidepressant medications suppress the symptoms of depression but appear to do nothing to alter its course (53). This makes sense, as antidepressant medications do nothing to address the abnormal perception of defeat that lies at the heart of depression. They just cover it up. There are also potential side-effects to consider.
The oldest antidepressant medications are the tricyclic antidepressants (TCAs) such as amitriptyline and nortriptyline, drugs that block the transporters for serotonin, noradrenaline, and a few other compounds in the brain, and the monoamine oxidase inhibitors (MAOIs) such as selegiline, drugs that prevent the degradation of serotonin and noradrenaline. The first prescribed TCA improves symptoms in about half of depressed patients (54). Common TCA side-effects include dry mouth, blurred vision, drowsiness, and hypotension (15). MAOIs can induce potentially lethal hypertension when combined with the compound tyramine found in foods such as aged cheese and alcoholic beverages, although the severity of this reaction is over-stated (55).
The most common newer antidepressant medications are the selective serotonin reuptake inhibitors (SSRIs) such as citalopram, sertraline, fluoxetine, escitalopram, and paroxetine, drugs that block serotonin transporters in the brain, and the serotonin-noradrenaline reuptake inhibitors (SNRIs) such as duloxetine and desvenlafaxine, drugs that block serotonin and noradrenaline reuptake in the brain. The first prescribed SSRI improves symptoms in a third of depressed patients (54), not quite as good as the TCAs, but there are fewer side-effects (15). The most common SSRI and SNRI side-effects are nausea, sexual dysfunction, sleepiness, and weight changes (weight gain for SSRIs, weight loss for SNRIs) (56,57).
There are also atypical antidepressants such as vilazodone, trazodone, and bupropion, drugs with various and different pharmacological properties to the classes listed above. Since they do not produce sexual dysfunction, many patients prefer the atypicals.
In depression, the ability to deal with losing in a particular situation in life is twisted into an abnormal perception of defeat, a warped outlook that subverts a person's soul and whispers to them over and over that they cannot win at anything in life. Subthreshold depression is normal, but depression is abnormal and if it does not kill quickly, it kills slowly. Despite its seriousness, there are many treatments for depression. Here is a summary.
(1) Try mindfulness-based training.
(1) Interpersonal therapy (removal of negative interactions with others).
(1) TCAs (amitriptyline, nortriptyline).