What is the Management of Depression?

Introduction

Depression is a symptom of some physical diseases; a side effect of some drugs and medical treatments; and a symptom of some mood disorders such as major depressive disorder or dysthymia. Physical causes are ruled out with a clinical assessment of depression that measures vitamins, minerals, electrolytes, and hormones. Management of depression may involve a number of different therapies: medications, behaviour therapy, psychotherapy, and medical devices.

Though psychiatric medication is the most frequently prescribed therapy for major depression, psychotherapy may be effective, either alone or in combination with medication. Combining psychotherapy and antidepressants may provide a “slight advantage”, but antidepressants alone or psychotherapy alone are not significantly different from other treatments, or “active intervention controls”. Given an accurate diagnosis of major depressive disorder, in general the type of treatment (psychotherapy and/or antidepressants, alternate or other treatments, or active intervention) is “less important than getting depressed patients involved in an active therapeutic program.”

Psychotherapy is the treatment of choice in those under the age of 18, with medication offered only in conjunction with the former and generally not as a first line agent. The possibility of depression, substance misuse or other mental health problems in the parents should be considered and, if present and if it may help the child, the parent should be treated in parallel with the child.

Psychotherapy and Behaviour Therapy

There are a number of different psychotherapies for depression which are provided to individuals or groups by psychotherapists, psychiatrists, psychologists, clinical social workers, counsellors or psychiatric nurses. With more chronic forms of depression, the most effective treatment is often considered to be a combination of medication and psychotherapy. Psychotherapy is the treatment of choice in people under 18. A meta-analysis examined the effectiveness of psychotherapy for depression across ages from younger than 13 years to older than 75 years. It summarizes results from 366 trials included 36,702 patients. It found that the best results were for young adults, with an average effect size of g=.98 (95% CI, 0.79-1.16). The effects were smallest for young children (<13 years), g = .35 (95% CI, 0.15-0.55), and second largest in the oldest group, g = .97 (95% CI, 0.42-1.52). The study was not able to compare the different types of therapy to each other. Most of the studies with children used therapies originally developed with adults, which may have reduced the effectiveness. The greater benefits with young adults might be due to a large number of studies including college students, who might have an easier time learning therapy skills and techniques. Most of the studies in children were done in the USA, whereas in older age groups, more balanced numbers of studies came from Europe and other parts of the world as well.

As the most studied form of psychotherapy for depression, cognitive behavioural therapy (CBT) is thought to work by teaching clients to learn a set of cognitive and behavioural skills, which they can employ on their own. Earlier research suggested that cognitive behavioural therapy was not as effective as antidepressant medication in the treatment of depression; however, more recent research suggests that it can perform as well as antidepressants in treating patients with moderate to severe depression. Beck’s treatment manual, Cognitive therapy of depression, has undergone the most research and accumulated the most evidence for its use. However, a number of other CBT manuals also have evidence to support their effectiveness with depression.

The effect of psychotherapy on patient and clinician rated improvement as well as on revision rates have declined steadily from the 1970s.

A systematic review of data comparing low-intensity CBT (such as guided self-help by means of written materials and limited professional support, and website-based interventions) with usual care found that patients who initially had more severe depression benefited from low-intensity interventions at least as much as less-depressed patients.

For the treatment of adolescent depression, one published study found that CBT without medication performed no better than a placebo, and significantly worse than the antidepressant fluoxetine. However, the same article reported that CBT and fluoxetine outperformed treatment with only fluoxetine. Combining fluoxetine with CBT appeared to bring no additional benefit in two different studies or, at the most, only marginal benefit, in a fourth study.

Behaviour therapy for depression is sometimes referred to as behavioural activation. Studies exist showing behavioural activation to be superior to CBT. In addition, behavioural activation appears to take less time and lead to longer lasting change. Two well-researched treatment manuals include Social skills training for depression and Behavioural activation treatment for depression.

Emotionally focused therapy, founded by Sue Johnson and Les Greenberg in 1985, treats depression by identifying and processing underlying emotions. The treatment manual, Facilitating emotional change, outlines treatment techniques.

Acceptance and commitment therapy (ACT), a mindfulness form of CBT, which has its roots in behaviour analysis, also demonstrates that it is effective in treating depression, and can be more helpful than traditional CBT, especially where depression is accompanied by anxiety and where it is resistant to traditional CBT.

A review of four studies on the effectiveness of mindfulness-based cognitive therapy (MBCT), a recently developed class-based program designed to prevent relapse, suggests that MBCT may have an additive effect when provided with the usual care in patients who have had three or more depressive episodes, although the usual care did not include antidepressant treatment or any psychotherapy, and the improvement observed may have reflected non-specific or placebo effects. Of note, although Mindfulness-based cognitive therapy for depression prevented relapse of future depressive episodes, there is no research on whether it can cause the remission of a current depressive episode.

Interpersonal psychotherapy (IPT) focuses on the social and interpersonal triggers that may cause depression. There is evidence that it is an effective treatment for depression. Here, the therapy takes a fairly structured course (often 12 sessions, as in the original research versions) as in the case with CBT; however, the focus is on relationships with others. Unlike family therapy, IPT is an individual format, so it is possible to work on interpersonal themes even if other family members do not come to the session. Therapy can be used to help a person develop or improve interpersonal skills in order to allow him or her to communicate more effectively and reduce stress. In a meta-analysis of 16 studies and 4,356 patients, the average improvement in depressive symptoms was an effect size of d = 0.63 (95% CI, 0.36 to 0.90). IPT combined with pharmacotherapy was more effective in preventing relapse than pharmacotherapy alone, number needed to treat = 7.63.

Psychoanalysis, a school of thought founded by Sigmund Freud that emphasizes the resolution of unconscious mental conflicts, is used by its practitioners to treat clients presenting with major depression. A more widely practiced technique, called psychodynamic psychotherapy, is loosely based on psychoanalysis and has an additional social and interpersonal focus. In a meta-analysis of three controlled trials, psychodynamic psychotherapy was found to be as effective as medication for mild to moderate depression.

Shared Care

Shared decision making is an approach whereby patients and clinicians freely share important evidence when tasked with decision making and where patients are guided to consider the best available options to make an informed decision. The principles are well documented, but there is a gap in that it’s hard to apply them in routine clinical practice. The steps have been simplified into five steps. The first step is seeking patient participation in that the health practitioner is tasked with communicating existing choices and therefore inviting them to the decision making process. The next step involves assisting the patient to explore and compare the treatment options by a critical analysis of the risks and benefits. The third step involves the assessment of the patient’s values and what they prefer taking to account what is of paramount urgency to the patient. Step 4 involves decision making where the patient and the practitioner make a conclusive decision on the best option and arrange for subsequent follow up meetings. Finally, the fifth step involves the analysis of the patient’s decision’. Five steps for you and your patients to work together to make the best possible health care decisions. The step involves monitoring of the degree of implementation, overcoming of barriers of decision implantation consequently the decisions need to be revisited and optimised thus ensuring the decision has a positive impact on health outcomes its success relies on the ability of the health practitioner to create a good interpersonal relationship with the patient.

Depression still remains a major problem in the US whereby statistics have it that 16 million people were affected in the year 2017. The depression is multifactorial and has been on the increase due to societal pressure, genetic association and increase in use of drugs. incorporation of nursing in management of depression may seem important in that nursing holds a pivotal role in health care delivery where they are the health practitioners that have been trained to be versatile from clinical to psychological care. Their incorporation in shared decision making in treating depression may be important as nurses are known to have the best interpersonal relationship with the patients thus a better collaborative model can be achieved due to this fact. With this in mind, the nurses may serve to administer drugs in management, prepare and maintain the patient’s records, interaction with other care staff to achieve optimum care, and organising therapy sessions. In a study another study concerning shared decision-making interventions for people with mental health conditions there were no overt benefits that were discovered and the called for further research in this area. Another study found that it is important to begin the dissemination and implementation of SDM as they proved that it has benefits in healthcare especially in mental health care and has received social and government support and however transitioning to SDM has proven to be an uphill task. It has been suggested that SDM is of importance in demonstrating patient preferences in decision making when there is no clear approach to treatment. In addition, numerous tools can be used to make the decision making the process easier these include the Controlled Preferences Scale that informs clinicians on how to actively involve patients

Commentators suggest that providers need to embrace shared decision making by making sure that patients participate actively in their management thus enabling the success of the model.

Medication

To find the most effective pharmaceutical drug treatment, the dosages of medications must often be adjusted, different combinations of antidepressants tried, or antidepressants changed. Norepinephrine reuptake inhibitor (NRIs) can be used as antidepressants. Selective serotonin reuptake inhibitors (SSRIs), such as sertraline (Zoloft, Lustral), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac), paroxetine (Seroxat), and citalopram, are the primary medications considered, due to their relatively mild side effects and broad effect on the symptoms of depression and anxiety, as well as reduced risk in overdose, compared to their older tricyclic alternatives. Those who do not respond to the first SSRI tried can be switched to another. If sexual dysfunction is present prior to the onset of depression, SSRIs should be avoided. Another popular option is to switch to the atypical antidepressant bupropion (Wellbutrin) or to add bupropion to the existing therapy; this strategy is possibly more effective. It is not uncommon for SSRIs to cause or worsen insomnia; the sedating noradrenergic and specific serotonergic antidepressant (NaSSA) antidepressant mirtazapine (Zispin, Remeron) can be used in such cases. CBT for Insomnia can also help to alleviate the insomnia without additional medication. Venlafaxine (Effexor) from the SNRI class may be moderately more effective than SSRIs; however, it is not recommended as a first-line treatment because of the higher rate of side effects, and its use is specifically discouraged in children and adolescents. Fluoxetine is the only antidepressant recommended for people under the age of 18, though, if a child or adolescent patient is intolerant to fluoxetine, another SSRI may be considered. Evidence of effectiveness of SSRIs in those with depression complicated by dementia is lacking.

Tricyclic antidepressants (TCAs) have more side effects than SSRIs (but less sexual dysfunctions) and are usually reserved for the treatment of inpatients, for whom the tricyclic antidepressant amitriptyline, in particular, appears to be more effective. A different class of antidepressants, the monoamine oxidase inhibitors, have historically been plagued by questionable efficacy (although early studies used dosages now considered too low) and life-threatening adverse effects. They are still used only rarely, although newer agents of this class (RIMA), with a better side effect profile, have been developed.

In older patients TCAs and SSRIs are of the same efficacy. However, there are differences between TCA related antidepressants and classical TCAs in terms of side effect profiles and withdrawal when compared to SSRIs.

There is evidence a prominent side-effect of antidepressants, emotional blunting, is confused with a symptom of depression itself. The cited study, according to Professor Linda Gask was: ‘funded by a pharmaceutical company (Servier) and two of its authors are employees of that company’, which may bias the results. The study authors’ note: “emotional blunting is reported by nearly half of depressed patients on antidepressants and that it appears to be common to all monoaminergic antidepressants not only SSRIs”. Additionally, they note: “The OQuESA scores are highly correlated with the HAD depression score; emotional blunting cannot be described simply as a side-effect of antidepressant, but also as a symptom of depression…More emotional blunting is associated with a poorer quality of remission…”

Acetyl-l-Carnitine

Acetylcarnitine levels were lower in depressed patients than controls and in rats it causes rapid antidepressant effects through epigenetic mechanisms. A systematic review and meta-analysis of 12 randomised controlled trials found “supplementation significantly decreases depressive symptoms compared with placebo/no intervention, while offering a comparable effect with that of established antidepressant agents with fewer adverse effects.”

Zinc

A 2012 cross-sectional study found an association between zinc deficiency and depressive symptoms among women, but not men, and a 2013 meta-analysis of 17 observational studies found that blood zinc concentrations were lower in depressed subjects than in control subjects. A 2012 meta-analysis found that zinc supplementation as an adjunct to antidepressant drug treatment significantly lowered depressive symptom scores of depressed patients. The potential mechanisms underlying the association between low serum zinc and depression remain unclear, but may involve the regulation of neurotransmitter, endocrine and neurogenesis pathways. Zinc supplementation has been reported to improve symptoms of ADHD and depression. A 2013 review found that zinc supplementation may be an effective treatment in major depression.

Magnesium

Many studies have found an association between magnesium intake and depression. Magnesium was lower in serum of depressed patients than controls. One trial found magnesium chloride to be effective for depression in seniors with type 2 diabetes while another trial found magnesium citrate decreased depression in patients with fibromyalgia. One negative trial used magnesium oxide, which is poorly absorbed. A randomised, open-label study found that consumption of magnesium chloride for 6 weeks resulted in a clinically significant net improvement in depression, and that effects were observed within 2 weeks.

Augmentation

Physicians often add a medication with a different mode of action to bolster the effect of an antidepressant in cases of treatment resistance; a 2002 large community study of 244,859 depressed Veterans Administration patients found that 22% had received a second agent, most commonly a second antidepressant. Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone. Furthermore, lithium dramatically decreases the suicide risk in recurrent depression. Addition of atypical antipsychotics when the patient has not responded to an antidepressant is also known to increase the effectiveness of antidepressant drugs, albeit at the cost of more frequent and potentially serious side effects. There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function. Stephen M. Stahl, renowned academician in psychopharmacology, has stated resorting to a dynamic psychostimulant, in particular, d-amphetamine is the “classical augmentation strategy for treatment-refractory depression”. However, the use of stimulants in cases of treatment-resistant depression is relatively controversial.

Efficacy of Medication and Psychotherapy

Antidepressants are statistically superior to placebo but their overall effect is low-to-moderate. In that respect they often did not exceed the National Institute for Health and Clinical Excellence (NICE) criteria for a “clinically significant” effect. In particular, the effect size was very small for moderate depression but increased with severity, reaching “clinical significance” for very severe depression. These results were consistent with the earlier clinical studies in which only patients with severe depression benefited from either psychotherapy or treatment with an antidepressant, imipramine, more than from the placebo treatment. Despite obtaining similar results, the authors argued about their interpretation. One author concluded that there “seems little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed to provide benefit.” The other author agreed that “antidepressant ‘glass’ is far from full” but disagreed “that it is completely empty”. He pointed out that the first-line alternative to medication is psychotherapy, which does not have superior efficacy.

Antidepressants in general are as effective as psychotherapy for major depression, and this conclusion holds true for both severe and mild forms of MDD. In contrast, medication gives better results for dysthymia. The subgroup of SSRIs may be slightly more efficacious than psychotherapy. On the other hand, significantly more patients drop off from the antidepressant treatment than from psychotherapy, likely because of the side effects of antidepressants. Successful psychotherapy appears to prevent the recurrence of depression even after it has been terminated or replaced by occasional “booster” sessions. The same degree of prevention can be achieved by continuing antidepressant treatment.

Two studies suggest that the combination of psychotherapy and medication is the most effective way to treat depression in adolescents. Both TADS (Treatment of Adolescents with Depression Study) and TORDIA (Treatment of Resistant Depression in Adolescents) showed very similar results. TADS resulted in 71% of their teen subjects having “much” or “very much” improvement in mood over the 61% with medication alone and 43% with CBT alone. Similarly, TORDIA showed a 55% improvement with CBT and drugs versus a 41% with drug therapy alone. However, a more recent meta-analysis of 34 trials of 14 drugs used with children and adolescents found that only fluoxetine produced significant benefit compared to placebo, with a medium sized effect (standardize mean difference = .5).

Treatment Resistance

The risk factors for treatment resistant depression are: the duration of the episode of depression, severity of the episode, if bipolar, lack of improvement in symptoms within the first couple of treatment weeks, anxious or avoidant and borderline comorbidity and old age. Treatment resistant depression is best handled with a combination of conventional antidepressant together with atypical antipsychotics. Another approach is to try different antidepressants. It is inconclusive which approach is superior. Treatment resistant depression can be misdiagnosed if subtherapeutic doses of antidepressants is the case, patient nonadherence, intolerable adverse effects or their thyroid disease or other conditions is misdiagnosed as depression.

Experimental Treatments

Chromium

Clinical and experimental studies have reported antidepressant activity of chromium particularly in atypical depression, characterised by increased appetite and carbohydrate craving.

Essential Fatty Acids

A 2015 Cochrane Collaboration review found insufficient evidence with which to determine if omega-3 fatty acid has any effect on depression. A 2016 review found that if trials with formulations containing mostly eicosapentaenoic acid (EPA) are separated from trials using formulations containing docosahexaenoic acid (DHA), it appeared that EPA may have an effect while DHA may not, but there was insufficient evidence to be sure.

Creatine

The amino acid creatine, commonly used as a supplement to improve the performance of bodybuilders, has been studied for its potential antidepressant properties. A double-blinded, placebo-controlled trial focusing on women with major depressive disorder found that daily creatine supplementation adjunctive to escitalopram was more effective than escitalopram alone. Studies on mice have found that the antidepressant effects of creatine can be blocked by drugs that act against dopamine receptors, suggesting that the drug acts on dopamine pathways.

Dopamine Receptor Agonist

Some research suggests dopamine receptor agonist may be effective in treating depression, however studies are few and results are preliminary.

Inositol

Inositol, an alcohol sugar found in fruits, beans grains and nuts may have antidepressant effects in high doses. Inositol may exert its effects by altering intracellular signalling.

Ketamine

Research on the antidepressant effects of ketamine infusions at subanaesthetic doses has consistently shown rapid (4 to 72 hours) responses from single doses, with substantial improvement in mood in the majority of patients and remission in some. However, these effects are often short-lived, and attempts to prolong the antidepressant effect with repeated doses and extended (“maintenance”) treatment have resulted in only modest success.

N-Acetylcysteine

A systematic review and meta-analysis of 5 studies found that N-Acetylcysteine reduces depressive symptoms more than placebo and has good tolerability. N-Acetylecysteine may exert benefits as a precursor to the antioxidant glutathione, thus modulating glutamatergic, neurotropic, and inflammatory pathways.

St John’s Wort

A 2008 Cochrane Collaboration meta-analysis concluded that:

“The available evidence suggests that the hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; c) and have fewer side effects than standard antidepressants. The association of country of origin and precision with effects sizes complicates the interpretation.”

The United States National Centre for Complementary and Integrative Health advice is that “St. John’s wort may help some types of depression, similar to treatment with standard prescription antidepressants, but the evidence is not definitive.” and warns that “Combining St. John’s wort with certain antidepressants can lead to a potentially life-threatening increase of serotonin, a brain chemical targeted by antidepressants. St. John’s wort can also limit the effectiveness of many prescription medicines.”

Rhodiola Rosea

A 2011 review reported Rhodiola rosea “is an adaptogen plant that can be especially helpful in treating asthenic or lethargic depression, and may be combined with conventional antidepressants to alleviate some of their common side effects.” A 6 week double-blind, placebo-controlled, randomised study with 89 patients with mild to moderate depression found that R. rosea statistically significantly reduced depression symptoms, and no side effects were reported.

Saffron

A 2013 meta-analysis found that saffron supplementation significantly reduced depression symptoms compared to placebo, and both saffron supplementation and the antidepressant groups were similarly effective in reducing depression symptoms. A 2015 meta-analysis supported the “efficacy of saffron as compared to placebo in improving the following conditions: depressive symptoms (compared to anti-depressants and placebo), premenstrual symptoms, and sexual dysfunction. In addition, saffron use was also effective in reducing excessive snacking behavior.” The antidepressant effect of saffron stigma extracts may be mediated via its components safranal and crocin: “crocin may act via the uptake inhibition of dopamine and norepinephrine, and safranal via serotonin.” Therapeutic doses of saffron exhibits no significant toxicity in both clinical and experimental investigations.

SAMe

S-Adenosyl methionine (SAMe) is available as a prescription antidepressant in Europe and an over-the-counter dietary supplement in the US. Evidence from 16 clinical trials with a small number of subjects, reviewed in 1994 and 1996 suggested it to be more effective than placebo and as effective as standard antidepressant medication for the treatment of major depression.

Tryptophan and 5-HTP

The amino acid tryptophan is converted into 5-hydroxytryptophan (5-HTP) which is subsequently converted into the neurotransmitter serotonin. Since serotonin deficiency has been recognized as a possible cause of depression, it has been suggested that consumption of tryptophan or 5-HTP may therefore improve depression symptoms by increasing the level of serotonin in the brain. 5-HTP and tryptophan are sold over the counter in North America, but requires a prescription in Europe. The use of 5-HTP instead of tryptophan bypasses the conversion of tryptophan into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin, and 5-HTP easily crosses the blood–brain barrier unlike tryptophan, which requires a transporter.

Small studies have been performed using 5-HTP and tryptophan as adjunctive therapy in addition to standard treatment for depression. While some studies had positive results, they were criticised for having methodological flaws, and a more recent study did not find sustained benefit from their use. The safety of these medications has not been well studied. Due to the lack of high quality studies, preliminary nature of studies showing effectiveness, the lack of adequate study on their safety, and reports of Eosinophilia-myalgia syndrome from contaminated tryptophan in 1989 and 1990, the use of tryptophan and 5-HTP is not highly recommended or thought to be clinically useful.

Medical Devices

A variety of medical devices are in use or under consideration for treatment of depression including devices that offer electroconvulsive therapy, vagus nerve stimulation, repetitive transcranial magnetic stimulation, and cranial electrotherapy stimulation. The use of such devices in the United States requires approval by the US Food and Drug Administration (FDA) after field trials. In 2010 an FDA advisory panel considered the question of how such field trials should be managed. Factors considered were whether drugs had been effective, how many different drugs had been tried, and what tolerance for suicides should be in field trials.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is a standard psychiatric treatment in which seizures are electrically induced in patients to provide relief from psychiatric illnesses. ECT is used with informed consent as a last line of intervention for major depressive disorder. Among the elderly, who often experience depression, the efficacy of ECT is difficult to determine due to the lack of trials comparing ECT to other treatments.

A round of ECT is effective for about 50% of people with treatment-resistant major depressive disorder, whether it is unipolar or bipolar. Follow-up treatment is still poorly studied, but about half of people who respond, relapse with twelve months.

Aside from effects in the brain, the general physical risks of ECT are similar to those of brief general anaesthesia. Immediately following treatment, the most common adverse effects are confusion and memory loss. ECT is considered one of the least harmful treatment options available for severely depressed pregnant women.

A usual course of ECT involves multiple administrations, typically given two or three times per week until the patient is no longer suffering symptoms ECT is administered under anaesthetic with a muscle relaxant. Electroconvulsive therapy can differ in its application in three ways: electrode placement, frequency of treatments, and the electrical waveform of the stimulus. These three forms of application have significant differences in both adverse side effects and symptom remission. After treatment, drug therapy is usually continued, and some patients receive maintenance ECT.

ECT appears to work in the short term via an anticonvulsant effect mostly in the frontal lobes, and longer term via neurotrophic effects primarily in the medial temporal lobe.

Deep Brain Stimulation

The support for the use of deep brain stimulation in treatment-resistant depression comes from a handful of case studies, and this treatment is still in a very early investigational stage. In this technique electrodes are implanted in a specific region of the brain, which is then continuously stimulated. A March 2010 systematic review found that “about half the patients did show dramatic improvement” and that adverse events were “generally trivial” given the younger psychiatric patient population than with movements disorders. Deep brain stimulation is available on an experimental basis only in the United States; no systems are approved by the FDA for this use. It is available in Australia.

Repetitive Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) or deep transcranial magnetic stimulation is a non-invasive method used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator, or “coil” is placed near the head of the person receiving the treatment. The coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. The coil is connected to a pulse generator, or stimulator, that delivers electric current to the coil.

TMS was approved by the FDA for treatment-resistant major depressive disorder in 2008 and as of 2014 clinical evidence supports this use. The American Psychiatric Association, the Canadian Network for Mood and Anxiety Disorders, and the Royal Australia and New Zealand College of Psychiatrists have endorsed rTMS for trMDD.

Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) uses an implanted electrode and generator to deliver electrical pulses to the vagus nerve, one of the primary nerves emanating from the brain. It is an approved therapy for treatment-resistant depression in the EU and US and is sometimes used as an adjunct to existing antidepressant treatment. The support for this method comes mainly from open-label trials, which indicate that several months may be required to see a benefit. The only large double-blind trial conducted lasted only 10 weeks and yielded inconclusive results; VNS failed to show superiority over a sham treatment on the primary efficacy outcome, but the results were more favourable for one of the secondary outcomes. The authors concluded “This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.”

Cranial Electrotherapy Stimulation

A 2014 Cochrane review found insufficient evidence to determine whether or not Cranial electrotherapy stimulation with alternating current is safe and effective for treating depression.

Transcranial Direct Current Stimulation

A 2016 meta-analysis of transcranial direct current stimulation (tDCS) reported some efficacy of tDCS in the treatment of acute depressive disorder with moderate effect size, and low efficacy in treatment-resistant depression, and that use of 2 mA current strength over 20 minutes per day over a short time span can be considered safe.

Other Treatments

Bright Light Therapy

A meta-analysis of bright light therapy commissioned by the American Psychiatric Association found a significant reduction in depression symptom severity associated with bright light treatment. Benefit was found for both seasonal affective disorder and for non-seasonal depression, with effect sizes similar to those for conventional antidepressants. For non-seasonal depression, adding light therapy to the standard antidepressant treatment was not effective. A meta-analysis of light therapy for non-seasonal depression conducted by Cochrane Collaboration, studied a different set of trials, where light was used mostly in combination with antidepressants or wake therapy. A moderate statistically significant effect of light therapy was found, with response significantly better than control treatment in high-quality studies, in studies that applied morning light treatment, and with patients who respond to total or partial sleep deprivation. Both analyses noted poor quality of most studies and their small size, and urged caution in the interpretation of their results. The short 1-2 weeks duration of most trials makes it unclear whether the effect of light therapy could be sustained in the longer term.

Exercise

The 2013 Cochrane Collaboration review on physical exercise for depression noted that, based upon limited evidence, it is moderately more effective than a control intervention and comparable to psychological or antidepressant drug therapies. Smaller effects were seen in more methodologically rigorous studies. Three subsequent 2014 systematic reviews that included the Cochrane review in their analysis concluded with similar findings: one indicated that physical exercise is effective as an adjunct treatment with antidepressant medication; the other two indicated that physical exercise has marked antidepressant effects and recommended the inclusion of physical activity as an adjunct treatment for mild-moderate depression and mental illness in general. These studies also found smaller effect sizes in more methodologically rigorous studies. All four systematic reviews called for more research in order to determine the efficacy or optimal exercise intensity, duration, and modality. The evidence for brain-derived neurotrophic factor (BDNF) in mediating some of the neurobiological effects of physical exercise was noted in one review which hypothesized that increased BDNF signalling is responsible for the antidepressant effect.

Meditation

Mindfulness meditation programs may help improve symptoms of depression, but they are no better than active treatments such as medication, exercise, and other behavioural therapies.

Music Therapy

A 2009 review found that 3 to 10 sessions of music therapy resulted in a noticeable improvement in depressive symptoms, with still greater improvement after 16 to 51 sessions.

Sleep

Depression is sometimes associated with insomnia – (difficulty in falling asleep, early waking, or waking in the middle of the night). The combination of these two results, depression and insomnia, will only worsen the situation. Hence, good sleep hygiene is important to help break this vicious circle. It would include measures such as regular sleep routines, avoidance of stimulants such as caffeine and management of sleeping disorders such as sleep apnoea.

Smoking Cessation

Quitting smoking cigarettes is associated with reduced depression and anxiety, with the effect “equal or larger than” those of antidepressant treatments.

Total/Partial Sleep Deprivation

Sleep deprivation (skipping a night’s sleep) has been found to improve symptoms of depression in 40-60% of patients. Partial sleep deprivation in the second half of the night may be as effective as an all night sleep deprivation session. Improvement may last for weeks, though the majority (50-80%) relapse after recovery sleep. Shifting or reduction of sleep time, light therapy, antidepressant drugs, and lithium have been found to potentially stabilise sleep deprivation treatment effects.

Shared Care

Shared care, when primary and specialty physicians have joint management of an individual’s health care, has been shown to alleviate depression outcomes.

What are Tricyclic Antidepressants?

Introduction

Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

Although TCAs are sometimes prescribed for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as

  • Selective serotonin reuptake inhibitors (SSRIs);
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs); and
  • Norepinephrine reuptake inhibitors (NRIs).

Adverse effects have been found to be of a similar level between TCAs and SSRIs.

Brief History

The TCAs were developed amid the “explosive birth” of psychopharmacology in the early 1950s. The story begins with the synthesis of chlorpromazine in December 1950 by Rhône-Poulenc’s chief chemist, Paul Charpentier, from synthetic antihistamines developed by Rhône-Poulenc in the 1940s. Its psychiatric effects were first noticed at a hospital in Paris in 1952. The first widely used psychiatric drug, by 1955 it was already generating significant revenue as an antipsychotic. Research chemists quickly began to explore other derivatives of chlorpromazine.

The first TCA reported for the treatment of depression was imipramine, a dibenzazepine analogue of chlorpromazine code-named G22355. It was not originally targeted for the treatment of depression. The drug’s tendency to induce manic effects was “later described as ‘in some patients, quite disastrous'”. The paradoxical observation of a sedative inducing mania led to testing with depressed patients. The first trial of imipramine took place in 1955 and the first report of antidepressant effects was published by Swiss psychiatrist Roland Kuhn in 1957. Some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz. Geigy later became Ciba-Geigy and eventually Novartis.

Dibenzazepine derivatives are described in US patent 3,074,931 issued 1963-01-22 by assignment to Smith Kline & French Laboratories. The compounds described share a tricyclic backbone different from the backbone of the TCA amitriptyline.

Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961. This compound has a different three-ring structure than imipramine.

Medical Uses

The TCAs are used primarily in the clinical treatment of mood disorders such as major depressive disorder (MDD), dysthymia, and treatment-resistant variants. They are also used in the treatment of a number of other medical disorders, including anxiety disorders such as:

Clinical Depression

For many years the TCAs were the first choice for pharmacological treatment of clinical depression. Although they are still considered to be highly effective, they have been increasingly replaced by antidepressants with an improved safety and side effect profile, such as the SSRIs and other newer antidepressants such as the novel reversible MAOI (monoamine oxidase inhibitors) moclobemide. However, tricyclic antidepressants are possibly more effective in treating melancholic depression than other antidepressant drug classes. Newer antidepressants are thought to have fewer and less severe side effects and are also thought to be less likely to result in injury or death if used in a suicide attempt, as the doses required for clinical treatment and potentially lethal overdose are far wider in comparison.

Nonetheless, the TCAs are commonly prescribed for treatment-resistant depression that has failed to respond to therapy with newer antidepressants, they also tend to have fewer emotional blunting and sexual side effects than SSRI antidepressants. They are not considered addictive and are somewhat preferable to the MAOIs. The side effects of the TCAs usually come to prominence before the therapeutic benefits against depression and/or anxiety do, and for this reason, they may potentially be somewhat dangerous, as volition can be increased, possibly giving the patient a greater desire to attempt or commit suicide.

ADHD

The TCAs were used in the past in the clinical treatment of ADHD, though they are not typically used anymore, having been replaced by more effective agents with fewer side effects such as atomoxetine (Strattera, Tomoxetin) and stimulants like methylphenidate (Ritalin, Focalin, Concerta), and amphetamine (Adderall, Attentin, Dexedrine, Vyvanse). ADHD is thought to be caused by an insufficiency of dopamine and norepinephrine activity in the prefrontal cortex of the brain. Most of the TCAs inhibit the reuptake of norepinephrine, though not dopamine, and as a result, they show some efficacy in remedying the disorder. Notably, the TCAs are more effective in treating the behavioural aspects of ADHD than the cognitive deficits, as they help limit hyperactivity and impulsivity, but have little to no benefits on attention.

Chronic Pain

The TCAs show efficacy in the clinical treatment of a number of different types of chronic pain, notably neuralgia or neuropathic pain and fibromyalgia. The precise mechanism of action in explanation of their analgesic efficacy is unclear, but it is thought that they indirectly modulate the opioid system in the brain downstream via serotonergic and noradrenergic neuromodulation, among other properties. They are also effective in migraine prophylaxis, though not in the instant relief of an acute migraine attack. They may also be effective to prevent chronic tension headaches.

Side Effects

Many side effects may be related to the antimuscarinic properties of the TCAs. Such side effects are relatively common and may include dry mouth, dry nose, blurry vision, lowered gastrointestinal motility or constipation, urinary retention, cognitive and/or memory impairment, and increased body temperature.

Other side effects may include drowsiness, anxiety, emotional blunting (apathy/anhedonia), confusion, restlessness, dizziness, akathisia, hypersensitivity, changes in appetite and weight, sweating, muscle twitches, weakness, nausea and vomiting, hypotension, tachycardia, and rarely, irregular heart rhythms. Twitching, hallucinations, delirium and coma are also some of the toxic effects caused by overdose. Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.

Tolerance to these adverse effects of these drugs often develops if treatment is continued. Side effects may also be less troublesome if treatment is initiated with low doses and then gradually increased, although this may also delay the beneficial effects.

TCAs can behave like class 1A antiarrhythmics, as such, they can theoretically terminate ventricular fibrillation, decrease cardiac contractility and increase collateral blood circulation to ischemic heart muscle. Naturally, in overdose, they can be cardiotoxic, prolonging heart rhythms and increasing myocardial irritability.

New research has also revealed compelling evidence of a link between long-term use of anticholinergic medications like TCAs and dementia. Although many studies have investigated this link, this was the first study to use a long-term approach (over seven years) to find that dementias associated with anticholinergics may not be reversible even years after drug use stops. Anticholinergic drugs block the action of acetylcholine, which transmits messages in the nervous system. In the brain, acetylcholine is involved in learning and memory.

Discontinuation

Antidepressants in general may produce withdrawal. However, since the term “withdrawal” has been linked to addiction to recreational drugs like opioids, the medical profession and pharmaceutical public relations prefer that a different term be used, hence “discontinuation syndrome.” Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms. In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance.

Overdose

Refer to Tricyclic Antidepressant Overdose.

TCA overdose is a significant cause of fatal drug poisoning. The severe morbidity and mortality associated with these drugs is well documented due to their cardiovascular and neurological toxicity. Additionally, it is a serious problem in the paediatric population due to their inherent toxicity and the availability of these in the home when prescribed for bed-wetting and depression. In the event of a known or suspected overdose, medical assistance should be sought immediately.

A number of treatments are effective in a TCA overdose.

An overdose on TCA is especially fatal as it is rapidly absorbed from the GI tract in the alkaline conditions of the small intestines. As a result, toxicity often becomes apparent in the first hour after an overdose. However, symptoms may take several hours to appear if a mixed overdose has caused delayed gastric emptying.

Many of the initial signs are those associated to the anticholinergic effects of TCAs such as dry mouth, blurred vision, urinary retention, constipation, dizziness, and emesis (or vomiting). Due to the location of norepinephrine receptors all over the body, many physical signs are also associated with a TCA overdose:

  • Anticholinergic effects: Altered mental status (e.g., agitation, confusion, lethargy, etc.), resting sinus tachycardia, dry mouth, mydriasis (pupil dilation), and fever.
  • Cardiac effects: Hypertension (early and transient, should not be treated), tachycardia, orthostasis and hypotension, arrhythmias (including ventricular tachycardia and ventricular fibrillation, most serious consequence) / ECG changes (prolonged QRS, QT, and PR intervals).
  • CNS effects: Syncope, seizure, coma, myoclonus, hyperreflexia.
  • Pulmonary effects: Hypoventilation resulting from CNS depression.
  • Gastrointestinal effects: Decreased or absent bowel sounds.

Treatment of TCA overdose depends on severity of symptoms:

Initially, gastric decontamination of the patient is achieved by administering, either orally or via a nasogastric tube, activated charcoal pre-mixed with water, which adsorbs the drug in the gastrointestinal tract (most useful if given within 2 hours of drug ingestion). Other decontamination methods such as stomach pumps, gastric lavage, whole bowel irrigation, or (ipecac induced) emesis, are not recommended in TCA poisoning.

If there is metabolic acidosis, intravenous infusion of sodium bicarbonate is recommended by Toxbase.org, the UK and Ireland poisons advice database (TCAs are protein bound and become less bound in more acidic conditions, so by reversing the acidosis, protein binding increases and bioavailability thus decreases – the sodium load may also help to reverse the Na+ channel blocking effects of the TCA).

Interactions

The TCAs are highly metabolised by the cytochrome P450 (CYP) hepatic enzymes. Drugs that inhibit cytochrome P450 (for example cimetidine, methylphenidate, fluoxetine, antipsychotics, and calcium channel blockers) may produce decreases in the TCAs’ metabolism, leading to increases in their blood concentrations and accompanying toxicity. The major factor that distinguishes SSRI’s amongst one another is the inhibition of select CYP enzymes. Drugs that prolong the QT interval including antiarrhythmics such as quinidine, the antihistamines astemizole and terfenadine, and some antipsychotics may increase the chance of ventricular dysrhythmias. TCAs may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. Side effects may also be enhanced by other drugs that have antimuscarinic properties.

Pharmacology

The majority of the TCAs act primarily as SNRIs by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission. Notably, with the sole exception of amineptine, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs). Both serotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders.

In addition to their reuptake inhibition, many TCAs also have high affinity as antagonists at the 5-HT2 (5-HT2A and 5-HT2C), 5-HT6, 5-HT7, α1-adrenergic, and NMDA receptors, and as agonists at the sigma receptors (σ1 and σ2), some of which may contribute to their therapeutic efficacy, as well as their side effects. The TCAs also have varying but typically high affinity for antagonising the H1 and H2 histamine receptors, as well as the muscarinic acetylcholine receptors. As a result, they also act as potent antihistamines and anticholinergics. These properties are often beneficial in antidepressants, especially with comorbid anxiety, as it provides a sedative effect.

Most, if not all, of the TCAs also potently inhibit sodium channels and L-type calcium channels, and therefore act as sodium channel blockers and calcium channel blockers, respectively. The former property is responsible for the high mortality rate upon overdose seen with the TCAs via cardiotoxicity. It may also be involved in their efficacy as analgesics, however.

In summary, tricyclic antidepressants can act through NMDA antagonism, opioidergic effects, sodium, potassium and calcium channel blocking, through interfering with the reuptake of serotonin and acting as antagonists to SHAM (serotonin, histamine, alpha, muscarinic) receptors. Thus their dangerous side effect profile limits their use in daily practice.

Chemistry

There are two major groups of TCAs in terms of chemical structure, which most, but not all, TCAs fall into. The groupings are based on the tricyclic ring system. They are the dibenzazepines (imipramine, desipramine, clomipramine, trimipramine, lofepramine) and the dibenzocycloheptadienes (amitriptyline, nortriptyline, protriptyline, butriptyline). Minor TCA groups based on ring system include the dibenzoxepins (doxepin), the dibenzothiepines (dosulepin), and the dibenzoxazepines (amoxapine). In addition to classification based on the ring system, TCAs can also be usefully grouped based on the number of substitutions of the side chain amine. These groups include the tertiary amines (imipramine, clomipramine, trimipramine, amitriptyline, butriptyline, doxepin, dosulepin) and the secondary amines (desipramine, nortriptyline, protriptyline). Lofepramine is technically a tertiary amine, but acts largely as a prodrug of desipramine, a secondary amine, and hence is more similar in profile to the secondary amines than to the tertiary amines. Amoxapine does not have the TCA side chain and hence is neither a tertiary nor secondary amine, although it is often grouped with the secondary amines due to sharing more in common with them.

Society and Culture

Recreational Use

A very small number of cases involving non-medical use of antidepressants have been reported over the past 30 years. According to the US government classification of psychiatric medications, TCAs are “non-abusable” and generally have low abuse potential. Nonetheless due to their atypical MOA, amineptine and tianeptine (dopamine reuptake inhibition and μ-opioid receptor agonism, respectively) are the two TCAs with the highest addiction and abuse potential. Despite tianeptine’s recreational value, many people use it as a nootropic and follow other countries’ usage guidelines, such as France, as a way to treat their depression if other antidepressants do not work. Their prescription guidelines are 12.5 mg three times a day, and not to exceed 50 mg in one day. Tianeptine has no recreational value when taken at that dosage and kept under 50 mg a day. Many people report that tianeptine has treated their depression when SSRI’s or SNRI’s have not. Several cases of the misuse of amitriptyline alone or together with methadone or in other drug dependent patients and of dosulepin with alcohol or in methadone patients have been reported.

List of TCAs

Those that preferentially inhibit the reuptake of serotonin (by at least 10-fold over norepinephrine) include:

  • Butriptyline† (Evadyne) (relatively weak serotonin reuptake inhibitor).
  • Clomipramine (Anafranil).
  • Imipramine (Tofranil, Janimine, Praminil).
  • Trimipramine (Surmontil) (relatively weak serotonin reuptake inhibitor).

Those that preferentially inhibit the reuptake of norepinephrine (by at least 10-fold over serotonin) include:

  • Desipramine (Norpramin, Pertofrane).
  • Dibenzepin‡ (Noveril, Victoril).
  • Lofepramine§ (Lomont, Gamanil).
  • Maprotiline (Ludiomil) – can be classed with the TCAs though more frequently classed with the TeCAs.
  • Nortriptyline (Pamelor, Aventyl, Norpress).
  • Protriptyline (Vivactil).

Whereas either fairly balanced reuptake inhibitors of serotonin and norepinephrine or unspecified inhibitors include:

  • Amitriptyline (Elavil, Endep).
  • Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin).
  • Amoxapine (Asendin) – can be classed with the TeCAs but more frequently classed with the TCAs.
  • Demexiptiline† (Deparon, Tinoran).
  • Dimetacrine† (Istonil, Istonyl, Miroistonil).
  • Dosulepin§ (Prothiaden).
  • Doxepin (Adapin, Sinequan).
  • Fluacizine† (Phtorazisin).
  • Imipraminoxide† (Imiprex, Elepsin).
  • Melitracen§ (Deanxit, Dixeran, Melixeran, Trausabun).
  • Metapramine† (Timaxel).
  • Nitroxazepine‡ (Sintamil).
  • Noxiptiline‡ (Agedal, Elronon, Nogedal).
  • Pipofezine‡ (Azafen/Azaphen).
  • Propizepine† (Depressin, Vagran).
  • Quinupramine† (Kevopril, Kinupril, Adeprim, Quinuprine).

And the following are TCAs that act via main mechanisms other than serotonin or norepinephrine reuptake inhibition:

  • Amineptine‡ (Survector, Maneon, Directim) – norepinephrine–dopamine reuptake inhibitor.
  • Iprindole† (Prondol, Galatur, Tetran) – 5-HT2 receptor antagonist.
  • Opipramol‡ (Insidon, Pramolan, Ensidon, Oprimol) – σ receptor agonist.
  • Tianeptine § (Stablon, Coaxil, Tatinol) – atypical μ-opioid receptor agonist.

Legend:

  • † indicates products which have been withdrawn from the market worldwide.
  • ‡ indicates products which are not available in any country in which English is an official language.
  • § indicates products which are not available in the United States, but are available in other English-speaking countries such as Australia, Canada, United Kingdom, etc.
  • Bolded names indicates products which are available in at least three countries in which English is an official language.

What are Tetracyclic Antidepressants?

Introduction

Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced in the 1970s.

They are named after their tetracyclic chemical structure, containing four rings of atoms, and are closely related to the tricyclic antidepressants (TCAs), which contain three rings of atoms.

List of TeCAs

Marketed

  • Maprotiline (Ludiomil): can also be classified as a TCA and grouped with the secondary amines
  • Mianserin (Tolvon).
  • Mirtazapine (Remeron).
  • Setiptiline (Tecipul).
  • Drugs that contain four rings not all fused together but are sometimes still classified as TeCAs include:
    • Amoxapine (Asendin):– often classified as a TCA and grouped with the secondary amines.
  • Miscellaneous:
    • Benzoctamine (Tacitin): a tetracyclic compound and is closely related to maprotiline, with the two compounds differing only in the length of their side chain, but benzoctamine is not used as an antidepressant and is instead used as an anxiolytic.
    • Loxapine (Adasuve, Loxitane): a typical antipsychotic that produces amoxapine as a major metabolite and is said to have antidepressant effects, but it is not usually regarded as a TeCA.
  • Drugs that contain four rings not all fused together but could still be classified as tetracyclic include:
    • Mazindol (Mazanor, Sanorex): a monoamine reuptake inhibitor used as an appetite suppressant and with potential antidepressant effects, but not classified as a TeCA.

Never Marketed

  • Aptazapine (CGS-7525A): a close analogue of mirtazapine.
  • Esmirtazapine (ORG-50,081): the (S)-(+) enantiomer of mirtazapine.
  • Oxaprotiline (C 49-802 BDA): a close analogue of maprotiline.
  • Drugs that contain four rings not all fused together but could still be classified as tetracyclic include:
    • Ciclazindol (WY-23,409): a close analogue of mazindol.

Pharmacology

TeCAs have diverse pharmacology and differ from TCAs in a number of ways. With the exception of amoxapine, TeCAs do not inhibit the reuptake of serotonin. However, aside from mirtazapine, they do inhibit the reuptake of norepinephrine. TeCAs block the serotonin 5-HT2 receptors similarly to TCAs. Besides mirtazapine, they also block the α1-adrenergic receptor. Conversely, whereas TCAs have relatively low affinity for the α2-adrenergic receptor, mianserin and mirtazapine potently antagonise this receptor, and this action is thought to be involved in their antidepressant effects. TeCAs block the histamine H1 receptor similarly to the TCAs, but tend to be even stronger antihistamines than TCAs. On the other hand, in contrast to almost all TCAs, TeCAs have only low affinity for the muscarinic acetylcholine receptors, and for this reason, are associated with few or no anticholinergic side effects. Mianserin and mirtazapine are far less toxic than TCAs in overdose.

Binding Profiles

The binding profiles of various TeCAs in terms of their affinities (Ki, nM) for various receptors and transporters are as follows:

CompoundSERTNETDAT5-HT1A5-HT2A5-HT2B5-HT2C5-HT35-HT65-HT7α1α2D2H1H2mACh
Amoxapine58164,310ND0.5ND2.0ND6.0-5041502,6003.6-1607.9-25ND1,000
Maprotiline5,80011-121,000ND51ND122NDND50909,400350-6650.79-2.0776570
Mianserin4,000719,400400-2,6001.6-201.6-550.63-6.55.8-30055-8148-56343.8-73≥2,100.30-1.7437820
Mirtazapine>10,000≥4,600>10,000≥3,3306.3-692008.9-397.9ND265316-1,81518-88>5,4540.14-1.6>10,000670
Setiptiline>10,000220>10,000NDNDNDNDNDNDNDND24NDNDNDND

Notes:

  • Values are Ki (nM).
    • The smaller the value, the more strongly the drug binds to the site.
    • For assay species and references, see the individual drug articles.
    • Most but not all values are for human proteins.
  • The TeCAs act as antagonists or inverse agonists of the receptors and as inhibitors of the transporters.

What is an Antidepressant?

Introduction

Antidepressants are medications used to treat major depressive disorder, some anxiety disorders, some chronic pain conditions, and to help manage some addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, headaches, sexual dysfunction, and emotional blunting. Most types of antidepressants are typically safe to take, but may cause increased thoughts of suicide when taken by children, adolescents, and young adults. A discontinuation syndrome can occur after stopping any antidepressant which resembles recurrent depression.

Some reviews of antidepressants for depression in adults find benefit while others do not. Evidence of benefit in children and adolescents is unclear. There is debate in the medical community about how much of the observed effects of antidepressants can be attributed to the placebo effect. Most research on whether antidepressant drugs work is done on people with very severe symptoms, so the results cannot be extrapolated to the general population.

There are methods for managing depression which do not involve medications or may be used in conjunction with medications.

Refer to Tricyclic Antidepressants (TCAs) and Tetracyclic Antidepressants (TeCAs).

Medical Uses

Antidepressants are used to treat major depressive disorder and of other conditions, including some anxiety disorders, some chronic pain conditions, and to help manage some addictions. Antidepressants are often used in combinations with one another. The proponents of the monoamine hypothesis of depression recommend choosing the antidepressant with the mechanism of action impacting the most prominent symptoms – for example, they advocate that people with major depressive disorder (MDD) who are also anxious or irritable should be treated with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), and the ones with the loss of energy and enjoyment of life – with norepinephrine and dopamine enhancing drugs.

Major Depressive Disorder

The UK National Institute for Health and Care Excellence (NICE) 2009 guidelines indicated that antidepressants should not be routinely used for the initial treatment of mild depression, because the risk-benefit ratio is poor. The guidelines recommended that antidepressant treatment be considered for:

  • People with a history of moderate or severe depression;
  • Those with mild depression that has been present for a long period;
  • As a second-line treatment for mild depression that persists after other interventions; and
  • As a first-line treatment for moderate or severe depression.

The guidelines further note that antidepressant treatment should be used in combination with psychosocial interventions in most cases, should be continued for at least six months to reduce the risk of relapse, and that SSRIs are typically better tolerated than other antidepressants.

American Psychiatric Association treatment guidelines recommend that initial treatment should be individually tailored based on factors that include severity of symptoms, co-existing disorders, prior treatment experience, and the person’s preference. Options may include pharmacotherapy, psychotherapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) or light therapy. They recommended antidepressant medication as an initial treatment choice in people with mild, moderate, or severe major depression, that should be given to all people with severe depression unless ECT is planned.

Some reviews of antidepressants in adults with depression find benefits while others do not.

Anxiety Disorders

Generalised Anxiety Disorder

Antidepressants are recommended by NICE for the treatment of generalised anxiety disorder (GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD is a common disorder of which the central feature is excessive worry about a number of different events. Key symptoms include excessive anxiety about multiple events and issues, and difficulty controlling worrisome thoughts that persists for at least 6 months.

Antidepressants provide a modest-to-moderate reduction in anxiety in GAD. The efficacy of different antidepressants is similar.

Social Anxiety Disorder

Some antidepressants are used as a treatment for social anxiety disorder (SAD), but their efficacy is not entirely convincing, as only a small proportion of antidepressants showed some efficacy for this condition. Paroxetine was the first drug to be Food and Drug Administration (FDA)-approved for this disorder. Its efficacy is considered beneficial, although not everyone responds favourably to the drug. Sertraline and fluvoxamine extended release were later approved for it as well, while escitalopram is used off-label with acceptable efficacy. However, there is not enough evidence to support citalopram for treating social phobia, and fluoxetine was no better than placebo in clinical trials. SSRIs are used as a first-line treatment for social anxiety, but they do not work for everyone. One alternative would be venlafaxine, which is a SNRI. It showed benefits for social phobia in five clinical trials against placebo, while the other SNRIs are not considered particularly useful for this disorder as many of them didn’t undergo testing for it. As of now, it is unclear if duloxetine and desvenlafaxine can provide benefits for social anxiety sufferers. However, another class of antidepressants called MAOIs (monoamine oxidase inhibitors) are considered effective for social anxiety, but they come with many unwanted side effects and are rarely used. Phenelzine was shown to be a good treatment option, but its use is limited by dietary restrictions. Moclobemide is a RIMA (reversible inhibitors of monoamine oxidase-A) and showed mixed results but still got approval in some European countries for social anxiety disorder. TCA antidepressants (tricyclic antidepressants), such as clomipramine and imipramine, are not considered effective for this anxiety disorder in particular. This leaves out SSRIs such as paroxetine, sertraline and fluvoxamine CR as acceptable and tolerated treatment options for this disorder.

Obsessive Compulsive Disorder

SSRIs are a second-line treatment of adult obsessive compulsive disorder (OCD) with mild functional impairment and as first-line treatment for those with moderate or severe impairment. In children, SSRIs are considered as a second-line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects. SSRIs appear useful for OCD, at least in the short term. Efficacy has been demonstrated both in short-term treatment trials of 6 to 24 weeks and in discontinuation trials of 28 to 52 weeks duration. Clomipramine, a TCA drug, is considered effective and useful for OCD, however it is used as a second line treatment because it is less well tolerated than the SSRIs. Despite this, it has not shown superiority to fluvoxamine in trials. All SSRIs can be used effectively for OCD, and in some cases, SNRIs can also be tried even though none of them is approved specifically for OCD. However, even with all these treatment options, many people remain symptomatic after initiating the medication, and less than half of them do achieve remission.

Post Traumatic Stress Disorder

Antidepressants are one of the treatment options for post traumatic stress disorder (PTSD), however their efficacy is not well established. Two antidepressants are FDA approved for it, paroxetine and sertraline, they belong to the serotonin reuptake inhibitors class. Paroxetine has slightly higher response and remission rates than sertraline for this condition, however both drugs are not considered very helpful for every person that takes them. Fluoxetine and venlafaxine are used off label, with fluoxetine producing unsatisfactory mixed results and venlafaxine, while having a response rates of 78%, which is significantly higher than what paroxetine and sertraline achieved, but it did not address all the symptoms of PTSD like the two drugs did, which is in part due to the fact the venlafaxine is an SNRI, this class of drugs inhibit the reuptake of norepinephrine too, this could cause some anxiety in some people. Fluvoxamine, escitalopram and citalopram were not well tested in this disorder. MAOIs, while some of them may be helpful, are not used much because of their unwanted side effects. This leaves paroxetine and sertraline as acceptable treatment options for some people, although more effective antidepressants are needed.

Panic Disorder

Panic disorder is relatively treated well with medications compared with other disorders, several classes of antidepressants have shown efficacy for this disorder, however SSRIs and SNRIs are used first-line. Paroxetine, sertraline, fluoxetine are FDA approved for panic disorder, although fluvoxamine, escitalopram and citalopram are considered effective for it. The SNRI venlafaxine is also approved for this condition. Unlike with social anxiety and PTSD, some TCAs antidepressants, like clomipramine and imipramine, have shown efficacy for panic disorder. Moreover, the MAOI phenelzine is considered useful too. Panic disorder has many drugs for its treatment, however, the starting dose must be lower than the one used for MDD because people, in the initiation of treatment, have reported an increase in anxiety as a result of starting the medication. In conclusion, while panic disorder’s treatment options seem acceptable and useful for this condition, many people are still symptomatic after treatment with residual symptoms.

Eating Disorders

Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa. SSRIs (fluoxetine in particular) are preferred over other antidepressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterised. Bupropion is not recommended for the treatment of eating disorders due to an increased risk of seizure.

Similar recommendations apply to binge eating disorder. SSRIs provide short-term reductions in binge eating behaviour, but have not been associated with significant weight loss.

Clinical trials have generated mostly negative results for the use of SSRIs in the treatment of anorexia nervosa. Treatment guidelines from NICE recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association note that SSRIs confer no advantage regarding weight gain, but that they may be used for the treatment of co-existing depressive, anxiety, or OCD.

Pain

Fibromyalgia

A 2012 meta-analysis concluded that antidepressants treatment favourably affects pain, health-related quality of life, depression, and sleep in fibromyalgia syndrome. Tricyclics appear to be the most effective class, with moderate effects on pain and sleep and small effects on fatigue and health-related quality of life. The fraction of people experiencing a 30% pain reduction on tricyclics was 48% versus 28% for placebo. For SSRIs and SNRIs the fraction of people experiencing a 30% pain reduction was 36% (20% in the placebo comparator arms) and 42% (32% in the corresponding placebo comparator arms). Discontinuation of treatment due to side effects was common. Antidepressants including amitriptyline, fluoxetine, duloxetine, milnacipran, moclobemide, and pirlindole are recommended by the European League Against Rheumatism (EULAR) for the treatment of fibromyalgia based on “limited evidence”.

Neuropathic Pain

A 2014 meta-analysis from the Cochrane Collaboration found the antidepressant duloxetine to be effective for the treatment of pain resulting from diabetic neuropathy. The same group reviewed data for amitriptyline in the treatment of neuropathic pain and found limited useful randomised clinical trial data. They concluded that the long history of successful use in the community for the treatment of fibromyalgia and neuropathic pain justified its continued use. The group was concerned about the potential for overestimating the amount of pain relief provided by amitriptyline, and highlighted that only a small number of people will experience significant pain relief by taking this medication.

Other

Antidepressants may be modestly helpful for treating people who both have depression and alcohol dependence, however the evidence supporting this association is of low quality. Buproprion is used to help people stop smoking. Antidepressants are also used to control some symptoms of narcolepsy. Antidepressants may be used to relieve pain in people with active rheumatoid arthritis however, further research is required. Antidepressants have been shown to be superior to placebo in treating depression in individuals with physical illness, although reporting bias may have exaggerated this finding.

Limitations and Strategies

Between 30% and 50% of individuals treated with a given antidepressant do not show a response. Approximately one-third of people achieve a full remission, one-third experience a response and one-third are non-responders. Partial remission is characterised by the presence of poorly defined residual symptoms. These symptoms typically include depressed mood, anxiety, sleep disturbance, fatigue and diminished interest or pleasure. It is currently unclear which factors predict partial remission. However, it is clear that residual symptoms are powerful predictors of relapse, with relapse rates 3-6 times higher in people with residual symptoms than in those who experience full remission. In addition, antidepressant drugs tend to lose efficacy over the course of treatment. According to data from the Centres for Disease Control and Prevention, less than one-third of Americans taking one antidepressant medication have seen a mental health professional in the previous year. A number of strategies are used in clinical practice to try to overcome these limits and variations. They include switching medication, augmentation, and combination.

Switching Antidepressants

The American Psychiatric Association 2000 Practice Guideline advises that where no response is achieved following six to eight weeks of treatment with an antidepressant, to switch to an antidepressant in the same class, then to a different class of antidepressant. A 2006 meta-analysis review found wide variation in the findings of prior studies; for people who had failed to respond to an SSRI antidepressant, between 12% and 86% showed a response to a new drug. However, the more antidepressants an individual had already tried, the less likely they were to benefit from a new antidepressant trial. However, a later meta-analysis found no difference between switching to a new drug and staying on the old medication; although 34% of treatment resistant people responded when switched to the new drug, 40% responded without being switched.

Augmentation and Combination

For a partial response, the American Psychiatric Association guidelines suggest augmentation, or adding a drug from a different class. These include lithium and thyroid augmentation, dopamine agonists, sex steroids, NRIs, glucocorticoid-specific agents, or the newer anticonvulsants.

A combination strategy involves adding another antidepressant, usually from a different class so as to have effect on other mechanisms. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy. Other tests conducted include the use of psychostimulants as an augmentation therapy. Several studies have shown the efficacy of combining modafinil for treatment-resistant people. It has been used to help combat SSRI-associated fatigue.

Long-Term Use

The effects of antidepressants typically do not continue once the course of medication ends. This results in a high rate of relapse. A 2003 meta-analysis found that 18% of people who had responded to an antidepressant relapsed while still taking it, compared to 41% whose antidepressant was switched for a placebo.

A gradual loss of therapeutic benefit occurs in a minority of people during the course of treatment. A strategy involving the use of pharmacotherapy in the treatment of the acute episode, followed by psychotherapy in its residual phase, has been suggested by some studies.

Adverse Effects

Difficulty tolerating adverse effects is the most common reason for antidepressant discontinuation.

Almost any medication involved with serotonin regulation has the potential to cause serotonin toxicity (also known as serotonin syndrome) – an excess of serotonin that can induce mania, restlessness, agitation, emotional lability, insomnia and confusion as its primary symptoms. Although the condition is serious, it is not particularly common, generally only appearing at high doses or while on other medications. Assuming proper medical intervention has been taken (within about 24 hours) it is rarely fatal. Antidepressants appear to increase the risk of diabetes by about 1.3 fold.

MAOIs tend to have pronounced (sometimes fatal) interactions with a wide variety of medications and over-the-counter drugs. If taken with foods that contain very high levels of tyramine (e.g. mature cheese, cured meats, or yeast extracts), they may cause a potentially lethal hypertensive crisis. At lower doses, the person may only experience a headache due to an increase in blood pressure.

In response to these adverse effects, a different type of MAOI has been developed: the reversible inhibitor of monoamine oxidase A (RIMA) class of drugs. Their primary advantage is that they do not require the person to follow a special diet, while being purportedly effective as SSRIs and tricyclics in treating depressive disorders.

Tricyclics and SSRI can cause the so-called drug-induced QT prolongation, especially in older adults; this condition can degenerate into a specific type of abnormal heart rhythm called torsades de points which can potentially lead to sudden cardiac arrest.

Pregnancy

SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflects a causative relationship has been difficult in some cases. In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear.

SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold, and is associated with preterm birth and low birth weight.

A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies. A study of fluoxetine-exposed pregnancies found a 12% increase in the risk of major malformations that just missed statistical significance. Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting the possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants. Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies. The FDA advises for the risk of birth defects with the use of paroxetine and the MAOI should be avoided.

A 2013 systematic review and meta-analysis found that antidepressant use during pregnancy was statistically significantly associated with some pregnancy outcomes, such as gestational age and preterm birth, but not with other outcomes. The same review cautioned that because differences between the exposed and unexposed groups were small, it was doubtful whether they were clinically significant.

A neonate (infant less than 28 days old) may experience a withdrawal syndrome from abrupt discontinuation of the antidepressant at birth. Antidepressants have been shown to be present in varying amounts in breast milk, but their effects on infants are currently unknown.

Moreover, SSRIs inhibit nitric oxide synthesis, which plays an important role in setting vascular tone. Several studies have pointed to an increased risk of prematurity associated with SSRI use, and this association may be due to an increase risk of pre-eclampsia of pregnancy.

Antidepressant-Induced Mania

Another possible problem with antidepressants is the chance of antidepressant-induced mania or hypomania in people with or without a diagnosis of bipolar disorder. Many cases of bipolar depression are very similar to those of unipolar depression. Therefore, the person can be misdiagnosed with unipolar depression and be given antidepressants. Studies have shown that antidepressant-induced mania can occur in 20-40% of people with bipolar disorder. For bipolar depression, antidepressants (most frequently SSRIs) can exacerbate or trigger symptoms of hypomania and mania.

Suicide

Studies have shown that the use of antidepressants is correlated with an increased risk of suicidal behaviour and thinking (suicidality) in those aged under 25. This problem has been serious enough to warrant government intervention by the FDA to warn of the increased risk of suicidality during antidepressant treatment. According to the FDA, the heightened risk of suicidality occurs within the first one to two months of treatment. NICE places the excess risk in the “early stages of treatment”. A meta-analysis suggests that the relationship between antidepressant use and suicidal behaviour or thoughts is age-dependent. Compared with placebo, the use of antidepressants is associated with an increase in suicidal behaviour or thoughts among those 25 or younger (OR=1.62). There is no effect or possibly a mild protective effect among those aged 25 to 64 (OR=0.79). Antidepressant treatment has a protective effect against suicidality among those aged 65 and over (OR=0.37).

Sexual

Sexual side effects are also common with SSRIs, such as loss of sexual drive, failure to reach orgasm, and erectile dysfunction. Although usually reversible, these sexual side-effects can, in rare cases, continue after the drug has been completely withdrawn.

In a study of 1,022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1% with SSRI values between 57% and 73%, mirtazapine 24%, nefazodone 8%, amineptine 7% and moclobemide 4%. Moclobemide, a selective reversible MAO-A inhibitor, does not cause sexual dysfunction, and can actually lead to an improvement in all aspects of sexual function.

Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5-HT2 and 5-HT3 receptors; decreased dopamine; decreased norepinephrine; blockade of cholinergic and α1adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels. Mirtazapine is reported to have fewer sexual side effects, most likely because it antagonizes 5-HT2 and 5-HT3 receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs by the same mechanism.

Bupropion, a weak NDRI and nicotinic antagonist, may be useful in treating reduced libido as a result of SSRI treatment.

Changes in Weight

Changes in appetite or weight are common among antidepressants, but are largely drug-dependent and related to which neurotransmitters they affect. Mirtazapine and paroxetine, for example, may be associated with weight gain and/or increased appetite, while others (such as bupropion and venlafaxine) achieve the opposite effect.

The antihistaminic properties of certain TCA- and TeCA-class antidepressants have been shown to contribute to the common side effects of increased appetite and weight gain associated with these classes of medication.

Discontinuation Syndrome

Antidepressant discontinuation syndrome, also called antidepressant withdrawal syndrome, is a condition that can occur following the interruption, reduction, or discontinuation of antidepressant medication. The symptoms may include flu-like symptoms, trouble sleeping, nausea, poor balance, sensory changes, and anxiety. The problem usually begins within three days and may last for several months. Rarely psychosis may occur.

A discontinuation syndrome can occur after stopping any antidepressant including SSRIs, SNRIs, and TCAs. The risk is greater among those who have taken the medication for longer and when the medication in question has a short half-life. The underlying reason for its occurrence is unclear. The diagnosis is based on the symptoms.

Methods of prevention include gradually decreasing the dose among those who wish to stop, though it is possible for symptoms to occur with tapering. Treatment may include restarting the medication and slowly decreasing the dose. People may also be switched to the long acting antidepressant fluoxetine which can then be gradually decreased.

Approximately 20-50% of people who suddenly stop an antidepressant develop an antidepressant discontinuation syndrome. The condition is generally not serious. Though about half of people with symptoms describe them as severe. Some restart antidepressants due to the severity of the symptoms.

Emotional Blunting

SSRIs appear to cause emotional blunting, or numbness in some people who take them. This is a reduction in extremes of emotion, both positive and negative. While the person may feel less depressed, they may also feel less happiness or empathy. This may be cause for a dose reduction or medication change. The mechanism is unknown.

Pharmacology

The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis (which can be traced back to the 1950s), which states that depression is due to an imbalance (most often a deficiency) of the monoamine neurotransmitters (namely serotonin, norepinephrine and dopamine).

It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters. All currently marketed antidepressants have the monoamine hypothesis as their theoretical basis, with the possible exception of agomelatine which acts on a dual melatonergic-serotonergic pathway.

Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants. A number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses.

Types of Antidepressant

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are believed to increase the extracellular level of the neurotransmitter serotonin by limiting its reabsorption into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having only weak affinity for the norepinephrine and dopamine transporters.

SSRIs are the most widely prescribed antidepressants in many countries. The efficacy of SSRIs in mild or moderate cases of depression has been disputed.

Serotonin-Norepinephrine Reuptake Inhibitors

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are potent inhibitors of the reuptake of serotonin and norepinephrine. These neurotransmitters are known to play an important role in mood. SNRIs can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which act mostly upon serotonin alone.

The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane proteins that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of monoamine reuptake can possibly offer advantages over other antidepressants drugs by treating a wider range of symptoms.

SNRIs are sometimes also used to treat anxiety disorders, obsessive–compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), chronic neuropathic pain, and fibromyalgia syndrome (FMS), and for the relief of menopausal symptoms.

Serotonin Modulators and Stimulators

Serotonin modulator and stimulators (SMSs), sometimes referred to more simply as “serotonin modulators”, are a type of drug with a multimodal action specific to the serotonin neurotransmitter system. To be precise, SMSs simultaneously modulate one or more serotonin receptors and inhibit the reuptake of serotonin. The term was coined in reference to the mechanism of action of the serotonergic antidepressant vortioxetine, which acts as a serotonin reuptake inhibitor (SRI), partial agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors. However, it can also technically be applied to vilazodone, which is an antidepressant as well and acts as an SRI and 5-HT1A receptor partial agonist.

An alternative term is serotonin partial agonist/reuptake inhibitor (SPARI), which can be applied only to vilazodone.

Serotonin Antagonists and Reuptake Inhibitors

Serotonin antagonist and reuptake inhibitors (SARIs) while mainly used as antidepressants, are also anxiolytics and hypnotics. They act by antagonising serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also act as α1-adrenergic receptor antagonists. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds. They include trazodone and nefazodone.

Norepinephrine Reuptake Inhibitors

Norepinephrine reuptake inhibitors (NRIs or NERIs) are a type of drug that acts as a reuptake inhibitor for the neurotransmitter norepinephrine (noradrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine.

NRIs are commonly used in the treatment of conditions like ADHD and narcolepsy due to their psychostimulant effects and in obesity due to their appetite suppressant effects. They are also frequently used as antidepressants for the treatment of major depressive disorder, anxiety and panic disorder. Additionally, many drugs of abuse such as cocaine and methylphenidate possess NRI activity, though it is important to mention that NRIs without combined dopamine reuptake inhibitor (DRI) properties are not significantly rewarding and hence are considered to have a negligible abuse potential. However, norepinephrine has been implicated as acting synergistically with dopamine when actions on the two neurotransmitters are combined (e.g. in the case of NDRIs) to produce rewarding effects in psychostimulant drugs of abuse.

Norepinephrine-Dopamine Reuptake Inhibitors

The only drug used of this class for depression is bupropion.

Tricyclic Antidepressants

The majority of the tricyclic antidepressants (TCAs) act primarily as SNRIs by blocking the SERT and the NET, respectively, which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission. Notably, with the sole exception of amineptine, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs).

Although TCAs are sometimes prescribed for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as SSRIs, SNRIs and NRIs. Adverse effects have been found to be of a similar level between TCAs and SSRIs.

Tetracyclic Antidepressants

Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their chemical structure, which contains four rings of atoms, and are closely related to the TCAs, which contain three rings of atoms.

Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) are chemicals which inhibit the activity of the monoamine oxidase enzyme family. They have a long history of use as medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression. They are also used in the treatment of Parkinson’s disease and several other disorders.

Because of potentially lethal dietary and drug interactions, monoamine oxidase inhibitors have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example SSRIs and TCAs) have failed.

MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety and depression, bulimia, and PTSD, as well as borderline personality disorder. MAOIs appear to be particularly effective in the management of bipolar depression according to a retrospective-analysis. There are reports of MAOI efficacy in OCD, trichotillomania, dysmorphophobia, and avoidant personality disorder, but these reports are from uncontrolled case reports.

MAOIs can also be used in the treatment of Parkinson’s disease by targeting MAO-B in particular (therefore affecting dopaminergic neurons), as well as providing an alternative for migraine prophylaxis. Inhibition of both MAO-A and MAO-B is used in the treatment of clinical depression and anxiety disorders.

NMDA Receptor Antagonists

NMDA receptor antagonists like ketamine and esketamine are rapid-acting antidepressants and seem to work via blockade of the ionotropic glutamate NMDA receptor.

Others

See the list of antidepressants and management of depression for other drugs that are not specifically characterised.

Adjuncts

Adjunct medications are an umbrella category of substances that increase the potency or “enhance” antidepressants. They work by affecting variables very close to the antidepressant, sometimes affecting a completely different mechanism of action. This may be attempted when depression treatments have not been successful in the past.

Common types of adjunct medication techniques generally fall into the following categories:

  • Two or more antidepressants taken together.
  • From the same class (affecting the same area of the brain, often at a much higher level).
  • From different classes (affecting multiple parts of the brain not covered simultaneously by either drug alone).
  • An antipsychotic combined with an antidepressant, particularly atypical antipsychotics such as aripiprazole (Abilify), quetiapine (Seroquel), olanzapine (Zyprexa), and risperidone (Risperdal).

It is unknown if undergoing psychological therapy at the same time as taking anti-depressants enhances the anti-depressive effect of the medication.

Less Common Adjuncts

Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone. Furthermore, lithium dramatically decreases the suicide risk in recurrent depression. There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function.

Psychopharmacologists have also tried adding a stimulant, in particular, d-amphetamine. However, the use of stimulants in cases of treatment-resistant depression is relatively controversial. A review article published in 2007 found psychostimulants may be effective in treatment-resistant depression with concomitant antidepressant therapy, but a more certain conclusion could not be drawn due to substantial deficiencies in the studies available for consideration, and the somewhat contradictory nature of their results.

Brief History

Before the 1950s, opioids and amphetamines were commonly used as antidepressants. Their use was later restricted due to their addictive nature and side effects. Extracts from the herb St John’s wort have been used as a “nerve tonic” to alleviate depression.

Isoniazid, Iproniazid, and Imipramine

In 1951, Irving Selikoff and Edward H. Robitzek, working out of Sea View Hospital on Staten Island, began clinical trials on two new anti-tuberculosis agents developed by Hoffman-LaRoche, isoniazid and iproniazid. Only patients with a poor prognosis were initially treated; nevertheless, their condition improved dramatically. Selikoff and Robitzek noted “a subtle general stimulation … the patients exhibited renewed vigour and indeed this occasionally served to introduce disciplinary problems.” The promise of a cure for tuberculosis in the Sea View Hospital trials was excitedly discussed in the mainstream press.

In 1952, learning of the stimulating side effects of isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and Harry Salzer reported that isoniazid improved depression in two-thirds of their patients and coined the term antidepressant to refer to its action. A similar incident took place in Paris, where Jean Delay, head of psychiatry at Sainte-Anne Hospital, heard of this effect from his pulmonology colleagues at Cochin Hospital. In 1952 (before Lurie and Salzer), Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients. The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of diamine oxidase, coupled with a weak inhibition of monoamine oxidase A.

Selikoff and Robitzek also experimented with another anti-tuberculosis drug, iproniazid; it showed a greater psychostimulant effect, but more pronounced toxicity. Later, Jackson Smith, Gordon Kamman, George E. Crane, and Frank Ayd, described the psychiatric applications of iproniazid. Ernst Zeller found iproniazid to be a potent monoamine oxidase inhibitor. Nevertheless, iproniazid remained relatively obscure until Nathan S. Kline, the influential head of research at Rockland State Hospital, began to popularize it in the medical and popular press as a “psychic energiser”. Roche put a significant marketing effort behind iproniazid. Its sales grew until it was recalled in 1961, due to reports of lethal hepatotoxicity.

The antidepressant effect of a tricyclic, a three ringed compound, was first discovered in 1957 by Roland Kuhn in a Swiss psychiatric hospital. Antihistamine derivatives were used to treat surgical shock and later as neuroleptics. Although in 1955 reserpine was shown to be more effective than placebo in alleviating anxious depression, neuroleptics were being developed as sedatives and antipsychotics.

Attempting to improve the effectiveness of chlorpromazine, Kuhn – in conjunction with the Geigy Pharmaceutical Company – discovered the compound “G 22355”, later renamed imipramine. Imipramine had a beneficial effect in patients with depression who showed mental and motor retardation. Kuhn described his new compound as a “thymoleptic” “taking hold of the emotions,” in contrast with neuroleptics, “taking hold of the nerves” in 1955-1956. These gradually became established, resulting in the patent and manufacture in the US in 1951 by Häfliger and SchinderA.

Second Generation Antidepressants

Antidepressants became prescription drugs in the 1950s. It was estimated that no more than 50 to 100 individuals per million suffered from the kind of depression that these new drugs would treat, and pharmaceutical companies were not enthusiastic in marketing for this small market. Sales through the 1960s remained poor compared to the sales of tranquilizers, which were being marketed for different uses. Imipramine remained in common use and numerous successors were introduced. The use of monoamine oxidase inhibitors (MAOI) increased after the development and introduction of “reversible” forms affecting only the MAO-A subtype of inhibitors, making this drug safer to use.

By the 1960s, it was thought that the mode of action of tricyclics was to inhibit norepinephrine reuptake. However, norepinephrine reuptake became associated with stimulating effects. Later tricyclics were thought to affect serotonin as proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug.

Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented was zimelidine in 1971, while the first released clinically was indalpine. Fluoxetine was approved for commercial use by the FDA in 1988, becoming the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly and Company in the early 1970s by Bryan Molloy, Klaus Schmiegel, David T. Wong and others. SSRIs became known as “novel antidepressants” along with other newer drugs such as SNRIs and NRIs with various selective effects.

St John’s wort fell out of favour in most countries through the 19th and 20th centuries, except in Germany, where Hypericum extracts were eventually licensed, packaged and prescribed. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis. It remains an over-the-counter drug (OTC) supplement in most countries. Of concern are lead contaminant; on average, lead levels in women in the United States taking St. John’s wort are elevated about 20%. Research continues to investigate its active component hyperforin, and to further understand its mode of action.

Rapid-Acting Antidepressants

Esketamine (brand name Spravato), the first rapid-acting antidepressant to be approved for clinical treatment of depression, was introduced for this indication in March 2019 in the United States.

Research

A 2016 placebo randomised controlled trial evaluated the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression with positive outcome. In 2018 the FDA granted Breakthrough Therapy Designation for psilocybin-assisted therapy for treatment-resistant depression and in 2019, the FDA granted Breakthrough Therapy Designation for psilocybin therapy treating major depressive disorder.

Society and Culture

Prescription Trends

In the United States, antidepressants were the most commonly prescribed medication in 2013. Of the estimated 16 million “long term” (over 24 months) users, roughly 70% are female. As of 2017, about 16.5% of white people in the United States took antidepressants compared with 5.6% of black people in the United States.

In the UK, figures reported in 2010 indicated that the number of antidepressants prescribed by the National Health Service (NHS) almost doubled over a decade. Further analysis published in 2014 showed that number of antidepressants dispensed annually in the community went up by 25 million in the 14 years between 1998 and 2012, rising from 15 million to 40 million. Nearly 50% of this rise occurred in the four years after the 2008 banking crash, during which time the annual increase in prescriptions rose from 6.7% to 8.5%. These sources also suggest that aside from the recession, other factors that may influence changes in prescribing rates may include: improvements in diagnosis, a reduction of the stigma surrounding mental health, broader prescribing trends, GP characteristics, geographical location and housing status. Another factor that may contribute to increasing consumption of antidepressants is the fact that these medications now are used for other conditions including social anxiety and PTSD.

Adherence

As of 2003, worldwide, 30 to 60% of people did not follow their practitioner’s instructions about taking their antidepressants, and as of 2013 in the US, it appeared that around 50% of people did not take their antidepressants as directed by their practitioner.

When people fail to take their antidepressants, there is a greater risk that the drug will not help, that symptoms get worse, that they miss work or are less productive at work, and that the person may be hospitalised. This also increases costs for caring for them.

Social Science Perspective

Some academics have highlighted the need to examine the use of antidepressants and other medical treatments in cross-cultural terms, due to the fact that various cultures prescribe and observe different manifestations, symptoms, meanings and associations of depression and other medical conditions within their populations. These cross-cultural discrepancies, it has been argued, then have implications on the perceived efficacy and use of antidepressants and other strategies in the treatment of depression in these different cultures. In India, antidepressants are largely seen as tools to combat marginality, promising the individual the ability to reintegrate into society through their use – a view and association not observed in the West.

Environmental Impacts

Because most antidepressants function by inhibiting the reuptake of neurotransmitters serotonin, dopamine, and norepinepherine these drugs can interfere with natural neurotransmitter levels in other organisms impacted by indirect exposure. Antidepressants fluoxetine and sertraline have been detected in aquatic organisms residing in effluent dominated streams. The presence of antidepressants in surface waters and aquatic organisms has caused concern because ecotoxicological effects to aquatic organisms due to fluoxetine exposure have been demonstrated.

Coral reef fish have been demonstrated to modulate aggressive behaviour through serotonin. Artificially increasing serotonin levels in crustaceans can temporarily reverse social status and turn subordinates into aggressive and territorial dominant males.

Exposure to fluoxetine has been demonstrated to increase serotonergic activity in fish, subsequently reducing aggressive behaviour. Perinatal exposure to fluoxetine at relevant environmental concentrations has been shown to lead to significant modifications of memory processing in 1-month-old cuttlefish. This impairment may disadvantage cuttlefish and decrease their survival. Somewhat less than 10% of orally administered fluoxetine is excreted from humans unchanged or as glucuronide.