Introduction to Antidepressants

Antidepressants are a class of medications used primarily in the treatment of mood disorders (e.g. - major depressive disorder) and anxiety disorders. Its use has expanded to neurodegenerative and neuropsychiatric disorders in recent years.

• The development and history of antidepressants began in the 1950s, with the clinical use of two antidepressant drugs: iproniazid (a monoamine-oxidase inhibitor, or MAOI) and imipramine (a tricyclic antidepressant, or TCA).^[1]
• Iproniazid was used to treat tuberculosis at the time, but it was noticed that it also significantly improved the mood of patients, beyond just treating the medical illness. Imipramine, on the other hand, was discovered through a series of trials and errors by experimentation by Swiss psychiatrist Roland Kuhn.^[2][3]
• These two discoveries heralded the first step towards psychopharmacology, as the only other major treatment that was available at the time was electroconvulsive therapy. The efficacy of these medications led to various theories on why the medications worked, including the monoamine hypothesis.
• TCAs and MAOIs remained the mainstay of antidepressant treatment until the introduction of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), in the late 1980s.^[4]

• The introduction of the SSRIs revolutionized the treatment of depression and other psychiatric disorders, as these medications had a wider therapeutic index, and were more well tolerated with less side effects.
• However, there has been criticism that this increased ease of prescribing has led to overdiagnosis and overtreatment,^[5] especially in primary care settings, where there is very limited time for a detailed psychiatric history.^[6][7]

• Given the wide range of classes of antidepressants, each of them have their own specific mechanism of action. The key mechanism of action of most modern antidepressants is some modulation of serotonin reuptake, while others have more dopaminergic/noradrenergic effects (e.g - bupropion).
• Older antidepressants such as TCAs and MAOIs also work by other mechanisms. For example, MAOIs work by inhibiting monoamine oxidase, which slows the breakdown of norepinephrine, serotonin and dopamine in the brain.

• Despite many decades of research, there is no single proven theory that supports the monoamine hypothesis.
• The monoamine hypothesis is too reductionistic and simplistic to explain complex a phenomenon such as depression.
• Although the specific mechanism of how antidepressants improve mood, ahedonia, and neurovegetative symptoms is not well understood, the use of these medications remains indicated for treatment of psychiatric disorders.
• Drawing parallels from other areas of medicine, general anesthesia has been used for over 160 years, yet there is still no formal understanding of the exact mechanism of how it works and why patients fall asleep.^[8][9] There are also rare, but significant risks with use, such as memory impairment and death.^[10] Despite this, general anesthesia remains in widespread use because of its benefits.

• It is important to educate patients about how medications work, and how side effects occur. It is important to remind patients that side effects start early in treatment, and the benefits of the medications come later (“Think of this as an investment in the future!”).
• There is huge variability in the side effect profiles that patients experience, despite our understandings of the psychopharmacology of these medications. What might work for one patient may not work for another.

• In the treatment of mood and anxiety disorders, some may experience benefits in the first six weeks of a treatment strategy, but full benefits may not be realized until 10 or 12 weeks have passed. During this time, doctors should work with their patients to adjust dosages so as to find an optimal level, and avoid stopping treatment prematurely.
• For a first episode of depression, the general recommended treatment timeline is 1 year. For a second episode, 2 years of treatment is recommended. For any third and subsequent episodes, lifetime treatment is recommended, as the risk of relapse is close to 100% off treatment.^[16]

• Patients should be carefully monitored every 1 to 2 weeks when first starting medications, as this is the period of greatest risk, including side effects. Treatment should be monitored with the routine use of validated outcome scales.

• Bridging the Gap Between Research and Real World

• When a patient stops an antidepressant abruptly, antidepressant withdrawal (discontinuation syndrome) is a very clinically important phenomenon to monitor for.
• Different antidepressants will have different discontinuation side effects.^[17]
• Psychiatric symptoms of discontinuation such as anxiety and agitation, crying spells, or irritability are also sometimes misdiagnosed as a depressive relapse. Antidepressants should thus be tapered slowly and on a schedule.

• Common side effects include nausea, headaches, and gastrointestinal issues including nausea or diarrhea.
• Most of these side effects will self-resolve 1 to 2 weeks into treatment. Some may experience sexual dysfunction or loss of libido and it is important to screen and monitor for this in patients.

• Excessive sweating can be common in patients on SSRIs and SNRIs.^[18]
  • The mechanism not understood but likely related to 5-HT receptors or NE reuptake inhibition
  • Severe cases have been reported (especially in summer months)
  • Benztropine, clonidine or terazosin may be helpful, or switching to another SSRI may be helpful (sweating may be most likely to occur with paroxetine and least likely with escitalopram)

In the elderly, falls can also be common with the use of SNRIs, TCAs, but less commonly in SSRIs.^[19]

• The incidence of hyponatremia caused by SSRIs varies widely, from 0.5% to 32%. In the majority of cases, hyponatremia occurs within the first few weeks of the onset of therapy. The hyponatremia typically resolves 2 weeks after discontinuation of the SSRI.^[20]
• Routine monitoring of sodium levels is important in elderly.

• Almost all antidepressants decrease sleep efficiency, increase REM latency, suppress REM, delay REM onset, increase number of awakenings, worsen PLMS and RLS, can worsen parasomnias, and increase Stage 1 sleep.^[21]
• The exceptions to this are trazodone and bupropion. SSRIs can have idiosyncratic effects on sleep, and they may cause insomnia or agitation in any individual patient.
• SSRIs have been associated with non-REM eye movements, colloquially referred to as “Prozac Eyes.”^[22][23] The presence of NREM movements are not been associated with any specific symptomatology.

• In recent years, a popular and controversial theory has emerged through the media and the literature suggesting that modern antidepressants (SSRIs and beyond), do not exert any actual antidepressant effect (but is instead all driven by a placebo response).^[24][25] Decades of research into the effects and mechanisms of antidepressants suggests that there are significant physiological mechanisms at work.^[26]
• Prior to the development of SSRIs, tricyclic antidepressants and monoamine oxidase inhibitors were the dominant classes of antidepressants, and the efficacy of these medications were very well documented at the time.^[27] The decades of research, latest large scale meta-analyses, and clinical evidence pushes against the theory that antidepressants are a pure placebo^[28][29][30] The largest known study on antidepressant efficacy to date supports the efficacy and use for the acute treatment of adults with major depressive disorder (but this meta-analysis had its own limitations^[31]).^[32] More recent re-evaluation of placebo studies have shown that the placebo response rate has in fact has not increased over time.^[33]
• Despite the evidence of efficacy in short-term use, it is important to recognize there is a definite and strong placebo response to antidepressants. Most studies show a placebo response of anywhere from 30-40% in major depressive disorder.^[34][35] However, it should also be noted this phenomenon is not just limited to psychiatry. The placebo effect is pervasive and apparently increasing throughout all areas of medicine. This includes sham surgeries in benign prostatic hyperplasia,^[36] sham percutaneous coronary intervention in stable angina,^[37] arthroscopy for osteoarthritis,^[38] antiepileptic treatment of migraines,^[39] bronchodilators for asthma,^[40] and many others.^[41][42]
• Just like with antidepressants, it does not mean that these treatments do not work, but that medicine is both an art and a science, and that every treatment decision requires clinical judgement and judicious use. The placebo response is poorly understood, and likely involves a complex interaction between neurobiologic mechanisms and the therapeutic doctor-patient interaction.^[43]

• The role of antidepressants, specifically SSRIs, in causing aggression/violence has been debated since their introduction in the 1980s, especially in the popular media.^[44] Studying aggression is complicated, as human behaviour is complex and multifactorial. There are multiple confounding factors and variables that research cannot necessarily capture. A controversial paper was published in 2016 by Bielefeldt et al suggested that SSRIs doubled the risk of suicide/violence.^[45] However, the paper was a meta-analysis that reviewed original papers. Importantly, there were no actual reported violent events or suicides, but adverse events (such as increased anxiety) were extrapolated to include the possibility that it could lead to violence/suicides.^[46]
• Some have also hypothesized the role of akathisia in violence/agitation.^[47]
• A comprehensive review of the literature so far reveals limited evidence to support the hypothesis that modern antidepressants increase suicidality or aggression in adults.^[48]

• Recent controversy has come up regarding concerns about the incidence of mental illness (autism, mood disorders, somatoform disorders, and behavioural disorders) in offspring of mothers taking SSRIs.
• Although animal studies of the neurobehavioral outcomes of fetal antidepressant exposure suggest mechanisms for such effects, most human studies indicate that maternal psychiatric illness account for much (but not all) of this risk.
• The fraction of cases attributable to antidepressant use (0.5%) is substantially lower than what would be attributable to parental psychiatric illness.
• Thus, current treatment guidelines advise that antidepressants be used for severely ill mothers and advocate for discontinuation only in those with minimal illness/symptoms.^[51][52]
• Antidepressant use late in pregnancy and has been associated with a risk of persistent pulmonary hypertension of the newborn.^[53]

• Ongoing research and clinicians have brought on concerns about antidepressants being generally harmful, because they may disrupt ancient neurotransmitters such as serotonin, which plays a role in not just neurotransmission, but also other important bodily functions.^[54] There are concerns that alterations to these ancient processes could potentially increase mortality.
• Therefore, questions have been raised not necessarily about their short-term use, but the long-term health effects.^[55]
• It is also important to recognize that antidepressants also have anticlotting properties that can be efficacious in treating cardiovascular disease and stroke. Various studies have in fact reinforced the importance of early treatment with antidepressants in post-stroke as it improves recovery.^[56]