What is a Selective Serotonin Reuptake Inhibitor?

Introduction

Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.

SSRIs increase the extracellular level of the neurotransmitter serotonin by limiting its reabsorption (reuptake) into the presynaptic cell. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having strong affinity for the serotonin transporter and 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 and may be outweighed by side effects, especially in adolescent populations.

Refer to Serotonin-Norepinephrine Reuptake Inhibitor (SNRI).

Brief History

Refer to Development and discovery of SSRI Drugs.

Fluoxetine was introduced in 1987 and was the first major SSRI to be marketed.

Medical Uses

The main indication for SSRIs is major depressive disorder (MDD); however, they are frequently prescribed for anxiety disorders, such as social anxiety disorder, generalised anxiety disorder (GAD), panic disorder, obsessive-compulsive disorder (OCD), eating disorders, chronic pain, and, in some cases, for posttraumatic stress disorder (PTSD). They are also frequently used to treat depersonalisation disorder, although with varying results.

Depression

Antidepressants are recommended by the UK National Institute for Health and Care Excellence (NICE) as a first-line treatment of severe depression and for the treatment of mild-to-moderate depression that persists after conservative measures such as cognitive therapy. They recommend against their routine use in those who have chronic health problems and mild depression.

There has been controversy regarding the efficacy of SSRIs in treating depression depending on its severity and duration.

  • Two meta-analyses published in 2008 (Kirsch) and 2010 (Fournier) found that in mild and moderate depression, the effect of SSRIs is small or none compared to placebo, while in very severe depression the effect of SSRIs is between “relatively small” and “substantial”. The 2008 meta-analysis combined 35 clinical trials submitted to the Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine and fluoxetine, the non-SSRI antidepressant nefazodone, and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine). The authors attributed the relationship between severity and efficacy to a reduction of the placebo effect in severely depressed patients, rather than an increase in the effect of the medication. Some researchers have questioned the statistical basis of this study suggesting that it underestimates the effect size of antidepressants.
  • A 2012 meta-analysis of fluoxetine and venlafaxine concluded that statistically and clinically significant treatment effects were observed for each drug relative to placebo irrespective of baseline depression severity; some of the authors however disclosed substantial relationships with pharmaceutical industries.
  • A 2017 systematic review stated that “SSRIs versus placebo seem to have statistically significant effects on depressive symptoms, but the clinical significance of these effects seems questionable and all trials were at high risk of bias. Furthermore, SSRIs versus placebo significantly increase the risk of both serious and non-serious adverse events. Our results show that the harmful effects of SSRIs versus placebo for major depressive disorder seem to outweigh any potentially small beneficial effects”. Fredrik Hieronymus et al. criticised the review as inaccurate and misleading, but they also disclosed multiple ties to pharmaceutical industries.

In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed escitalopram to be one of the most effective.

In children, there are concerns around the quality of the evidence on the meaningfulness of benefits seen. If a medication is used, fluoxetine appears to be first line.

Social Anxiety Disorder

Some SSRIs are effective for social anxiety disorder, although their effects on symptoms is not always robust and their use is sometimes rejected in favour of psychological therapies. Paroxetine was the first drug to be approved for social anxiety disorder and it is considered effective for this disorder, sertraline and fluvoxamine were later approved for it, too, escitalopram and citalopram are used off label with acceptable efficacy, while fluoxetine is not considered to be effective for this disorder.

Post-Traumatic Stress Disorder

PTSD is relatively hard to treat and generally treatment is not highly effective; SSRIs are no exception. They are not very effective for this disorder and only two SSRI are US Food and Drug Administration (FDA) approved for this condition, paroxetine and sertraline. Paroxetine has slightly higher response and remission rates for PTSD than sertraline, but both are not fully effective for many patients. Fluoxetine is used off label, but with mixed results, venlafaxine, an SNRI, is considered somewhat effective, although used off label, too. Fluvoxamine, escitalopram and citalopram are not well tested in this disorder. Paroxetine remains the most suitable drug for PTSD as of now, but with limited benefits.

Generalised Anxiety Disorder

SSRIs are recommended by NICE for the treatment of 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, and are superior to placebo in treating GAD. The efficacy of different antidepressants is similar.

Obsessive-Compulsive Disorder

In Canada, SSRIs are a first-line treatment of adult OCD. In the UK, they are first-line treatment only with moderate to severe functional impairment and as second line treatment for those with mild impairment, though, as of early 2019, this recommendation is being reviewed. In children, SSRIs can be considered a second line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects. SSRIs, especially fluvoxamine, which is the first one to be FDA approved for OCD, are efficacious in its treatment; patients treated with SSRIs are about twice as likely to respond to treatment as those treated with placebo. 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.

Panic Disorder

Paroxetine CR was superior to placebo on the primary outcome measure. In a 10-wk randomised controlled, double-blind trial escitalopram was more effective than placebo. Fluvoxamine has shown positive results. However, evidence for their effectiveness and acceptability is unclear.

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 anti-depressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterised.

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 the National Institute of Health and Clinical Excellence 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.

Stroke Recovery

SSRIs have been used off-label in the treatment of stroke patients, including those with and without symptoms of depression. A 2019 meta-analysis of randomised, controlled clinical trials found a statistically significant effect of SSRIs on dependence, neurological deficit, depression, and anxiety but the studies had a high risk of bias. No reliable evidence points to their routine use to promote recovery following stroke. Thrombosis risk is reduced because SSRIs limit serotonin availability to platelets, so benefits, such as stroke recovery, of reduced clotting go up, with SSRIs.

Premature Ejaculation

SSRIs are effective for the treatment of premature ejaculation. Taking SSRIs on a chronic, daily basis is more effective than taking them prior to sexual activity. The increased efficacy of treatment when taking SSRIs on a daily basis is consistent with clinical observations that the therapeutic effects of SSRIs generally take several weeks to emerge. Sexual dysfunction ranging from decreased libido to anorgasmia is usually considered to be a significantly distressing side effect which may lead to noncompliance in patients receiving SSRIs. However, for those suffering from premature ejaculation, this very same side effect becomes the desired effect.

Other Uses

SSRIs such as sertraline have been found to be effective in decreasing anger.

Side Effects

Side effects vary among the individual drugs of this class and may include:

  • Increased risk of bone fractures.
  • Akathisia.
  • Suicidal ideation (thoughts of suicide) and other risks (see below).

Sexual Dysfunction

SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, diminished libido, genital numbness, and sexual anhedonia (pleasureless orgasm). Sexual problems are common with SSRIs. While initial trials showed side effects in 5-15% of users (based on spontaneous reporting by users), later studies (based on asking patients directly) have shown side effect rates from 36% to 98%. Poor sexual function is also one of the most common reasons people stop the medication.

In some cases, symptoms of sexual dysfunction may persist after discontinuation of SSRIs. This combination of symptoms is sometimes referred to as Post-SSRI Sexual Dysfunction (PSSD). On the 11 June 2019 the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency concluded that a possible relationship exists between SSRI use and persistent sexual dysfunction after cessation of use. The committee concluded that a warning should be added to the label of SSRIs and SNRIs regarding this possible risk.

The mechanism by which SSRIs may cause sexual side effects is not well understood as of 2021. The range of possible mechanisms includes:

  • Nonspecific neurological effects (e.g. sedation) that globally impair behaviour including sexual function;
  • Specific effects on brain systems mediating sexual function;
  • Specific effects on peripheral tissues and organs, such as the penis, that mediate sexual function; and
  • Direct or indirect effects on hormones mediating sexual function.

Management strategies include: for erectile dysfunction the addition of a PDE5 inhibitor such as sildenafil; for decreased libido, possibly adding or switching to bupropion; and for overall sexual dysfunction, switching to nefazodone.

A number of non-SSRI drugs are not associated with sexual side effects (such as bupropion, mirtazapine, tianeptine, agomelatine and moclobemide).

Several studies have suggested that SSRIs may adversely affect semen quality.

While trazodone (an antidepressant with alpha adrenergic receptor blockade) is a notorious cause of priapism, cases of priapism have also been reported with certain SSRIs (e.g. fluoxetine, citalopram).

Violence

Researcher David Healy and others have reviewed available data, concluding that SSRIs increase violent acts, in adults and children, both on therapy and during withdrawal. This view is also shared by some patient activist groups.

Vision

Acute narrow-angle glaucoma is the most common and important ocular side effect of SSRIs, and often goes misdiagnosed.

Cardiac

SSRIs do not appear to affect the risk of coronary heart disease (CHD) in those without a previous diagnosis of CHD. A large cohort study suggested no substantial increase in the risk of cardiac malformations attributable to SSRI usage during the first trimester of pregnancy. A number of large studies of people without known pre-existing heart disease have reported no EKG changes related to SSRI use. The recommended maximum daily dose of citalopram and escitalopram was reduced due to concerns with QT prolongation. In overdose, fluoxetine has been reported to cause sinus tachycardia, myocardial infarction, junctional rhythms and trigeminy. Some authors have suggested electrocardiographic monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRIs.

Bleeding

SSRIs directly increase the risk of abnormal bleeding by lowering platelet serotonin levels, which are essential to platelet-driven haemostasis. SSRIs interact with anticoagulants, like warfarin, and antiplatelet drugs, like aspirin. This includes an increased risk of GI bleeding, and post operative bleeding. The relative risk of intracranial bleeding is increased, but the absolute risk is very low. SSRIs are known to cause platelet dysfunction. This risk is greater in those who are also on anticoagulants, antiplatelet agents and NSAIDs (nonsteroidal anti-inflammatory drugs), as well as with the co-existence of underlying diseases such as cirrhosis of the liver or liver failure.

Fracture Risk

Evidence from longitudinal, cross-sectional, and prospective cohort studies suggests an association between SSRI usage at therapeutic doses and a decrease in bone mineral density, as well as increased fracture risk, a relationship that appears to persist even with adjuvant bisphosphonate therapy. However, because the relationship between SSRIs and fractures is based on observational data as opposed to prospective trials, the phenomenon is not definitively causal. There also appears to be an increase in fracture-inducing falls with SSRI use, suggesting the need for increased attention to fall risk in elderly patients using the medication. The loss of bone density does not appear to occur in younger patients taking SSRIs.

Bruxism

SSRI and SNRI antidepressants may cause jaw pain/jaw spasm reversible syndrome (although it is not common). Buspirone appears to be successful in treating bruxism on SSRI/SNRI induced jaw clenching.

Discontinuation Syndrome

Refer to (SSRI) Antidepressant Discontinuation Syndrome.

Serotonin reuptake inhibitors should not be abruptly discontinued after extended therapy, and whenever possible, should be tapered over several weeks to minimise discontinuation-related symptoms which may include nausea, headache, dizziness, chills, body aches, paraesthesia’s, insomnia, and brain zaps. Paroxetine may produce discontinuation-related symptoms at a greater rate than other SSRIs, though qualitatively similar effects have been reported for all SSRIs. Discontinuation effects appear to be less for fluoxetine, perhaps owing to its long half-life and the natural tapering effect associated with its slow clearance from the body. One strategy for minimizing SSRI discontinuation symptoms is to switch the patient to fluoxetine and then taper and discontinue the fluoxetine.

Serotonin Syndrome

Refer to Serotonin Syndrome.

Serotonin syndrome is typically caused by the use of two or more serotonergic drugs, including SSRIs. Serotonin syndrome is a condition that can range from mild (most common) to deadly. Mild symptoms may consist of increased heart rate, shivering, sweating, dilated pupils, myoclonus (intermittent jerking or twitching), as well as overresponsive reflexes. Concomitant use of an SSRI or selective norepinephrine reuptake inhibitor for depression with a triptan for migraine does not appear to heighten the risk of the serotonin syndrome. The prognosis in a hospital setting is generally good if correctly diagnosed. Treatment consists of discontinuing any serotonergic drugs as well as supportive care to manage agitation and hyperthermia, usually with benzodiazepines.

Suicide Risk

Children and Adolescents

Meta analyses of short duration randomized clinical trials have found that SSRI use is related to a higher risk of suicidal behaviour in children and adolescents. For instance, a 2004 FDA analysis of clinical trials on children with major depressive disorder found statistically significant increases of the risks of “possible suicidal ideation and suicidal behavior” by about 80%, and of agitation and hostility by about 130%. According to the FDA, the heightened risk of suicidality is within the first one to two months of treatments. NICE places the excess risk in the “early stages of treatment”. The European Psychiatric Association places the excess risk in the first two weeks of treatment and, based on a combination of epidemiological, prospective cohort, medical claims, and randomized clinical trial data, concludes that a protective effect dominates after this early period. A 2014 Cochrane review found that at six to nine months, suicidal ideation remained higher in children treated with antidepressants compared to those treated with psychological therapy.

A recent comparison of aggression and hostility occurring during treatment with fluoxetine to placebo in children and adolescents found that no significant difference between the fluoxetine group and a placebo group. There is also evidence that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, though since the evidence is correlational, the true nature of the relationship is unclear.

In 2004, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom judged fluoxetine (Prozac) to be the only antidepressant that offered a favourable risk-benefit ratio in children with depression, though it was also associated with a slight increase in the risk of self-harm and suicidal ideation. Only two SSRIs are licensed for use with children in the UK, sertraline (Zoloft) and fluvoxamine (Luvox), and only for the treatment of OCD. Fluoxetine is not licensed for this use.

Adults

It is unclear whether SSRIs affect the risk of suicidal behaviour in adults.

  • A 2005 meta-analysis of drug company data found no evidence that SSRIs increased the risk of suicide; however, important protective or hazardous effects could not be excluded.
  • A 2005 review observed that suicide attempts are increased in those who use SSRIs as compared to placebo and compared to therapeutic interventions other than tricyclic antidepressants. No difference risk of suicide attempts was detected between SSRIs versus tricyclic antidepressants.
  • On the other hand, a 2006 review suggests that the widespread use of antidepressants in the new “SSRI-era” appears to have led to a highly significant decline in suicide rates in most countries with traditionally high baseline suicide rates. The decline is particularly striking for women who, compared with men, seek more help for depression. Recent clinical data on large samples in the US too have revealed a protective effect of antidepressant against suicide.
  • A 2006 meta-analysis of random controlled trials suggests that SSRIs increase suicide ideation compared with placebo. However, the observational studies suggest that SSRIs did not increase suicide risk more than older antidepressants. The researchers stated that if SSRIs increase suicide risk in some patients, the number of additional deaths is very small because ecological studies have generally found that suicide mortality has declined (or at least not increased) as SSRI use has increased.
  • An additional meta-analysis by the FDA in 2006 found an age-related effect of SSRI’s. Among adults younger than 25 years, results indicated that there was a higher risk for suicidal behaviour. For adults between 25 and 64, the effect appears neutral on suicidal behaviour but possibly protective for suicidal behaviour for adults between the ages of 25 and 64. For adults older than 64, SSRI’s seem to reduce the risk of both suicidal behaviour.
  • In 2016 a study criticised the effects of the FDA Black Box suicide warning inclusion in the prescription. The authors discussed the suicide rates might increase also as a consequence of the warning.

Pregnancy and Breastfeeding

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. Use is also associated preterm birth.

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. 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 issued a statement on 19 July 2006 stating nursing mothers on SSRIs must discuss treatment with their physicians. However, the medical literature on the safety of SSRIs has determined that some SSRIs like Sertraline and Paroxetine are considered safe for breastfeeding.

Neonatal Abstinence Syndrome

Several studies have documented neonatal abstinence syndrome, a syndrome of neurological, gastrointestinal, autonomic, endocrine and/or respiratory symptoms among a large minority of infants with intrauterine exposure. These syndromes are short-lived, but insufficient long-term data is available to determine whether there are long-term effects.

Persistent Pulmonary Hypertension

Persistent pulmonary hypertension (PPHN) is a serious and life-threatening, but very rare, lung condition that occurs soon after birth of the newborn. Newborn babies with PPHN have high pressure in their lung blood vessels and are not able to get enough oxygen into their bloodstream. About 1 to 2 babies per 1000 babies born in the US develop PPHN shortly after birth, and often they need intensive medical care. It is associated with about a 25% risk of significant long-term neurological deficits. A 2014 meta analysis found no increased risk of persistent pulmonary hypertension associated with exposure to SSRI’s in early pregnancy and a slight increase in risk associates with exposure late in pregnancy; “an estimated 286 to 351 women would need to be treated with an SSRI in late pregnancy to result in an average of one additional case of persistent pulmonary hypertension of the newborn.”. A review published in 2012 reached conclusions very similar to those of the 2014 study.

Neuropsychiatric Effects in Offspring

According to a 2015 review available data found that “some signal exists suggesting that antenatal exposure to SSRIs may increase the risk of ASDs (autism spectrum disorders)” even though a large cohort study published in 2013 and a cohort study using data from Finland’s national register between the years 1996 and 2010 and published in 2016 found no significant association between SSRI use and autism in offspring. The 2016 Finland study also found no association with ADHD, but did find an association with increased rates of depression diagnoses in early adolescence.

Overdose

Refer to Serotonin Syndrome.

SSRIs appear safer in overdose when compared with traditional antidepressants, such as the tricyclic antidepressants. This relative safety is supported both by case series and studies of deaths per numbers of prescriptions. However, case reports of SSRI poisoning have indicated that severe toxicity can occur and deaths have been reported following massive single ingestions, although this is exceedingly uncommon when compared to the tricyclic antidepressants.

Because of the wide therapeutic index of the SSRIs, most patients will have mild or no symptoms following moderate overdoses. The most commonly reported severe effect following SSRI overdose is serotonin syndrome; serotonin toxicity is usually associated with very high overdoses or multiple drug ingestion. Other reported significant effects include coma, seizures, and cardiac toxicity.

Bipolar Switch

In adults and children suffering from bipolar disorder, SSRIs may cause a bipolar switch from depression into hypomania/mania. When taken with mood stabilisers, the risk of switching is not increased, however when taking SSRI’s as a monotherapy, the risk of switching may be twice or three times that of the average. The changes are not often easy to detect and require monitoring by family and mental health professionals. This switch might happen even with no prior (hypo)manic episodes and might therefore not be foreseen by the psychiatrist.

Interactions

The following drugs may precipitate serotonin syndrome in people on SSRIs:

  • Linezolid.
  • Monoamine oxidase inhibitors (MAOIs) including moclobemide, phenelzine, tranylcypromine, selegiline and methylene blue.
  • Lithium.
  • Sibutramine.
  • MDMA (ecstasy).
  • Dextromethorphan.
  • Tramadol.
  • 5-HTP.
  • Pethidine/meperidine.
  • St. John’s wort.
  • Yohimbe.
  • Tricyclic antidepressants (TCAs).
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs).
  • Buspirone.
  • Triptan.
  • Mirtazapine.

Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs and may compound the increased risk of gastrointestinal bleeds caused by SSRI use. NSAIDs include:

  • Aspirin.
  • Ibuprofen (Advil, Nurofen).
  • Naproxen (Aleve).

There are a number of potential pharmacokinetic interactions between the various individual SSRIs and other medications. Most of these arise from the fact that every SSRI has the ability to inhibit certain P450 cytochromes.

Drug NameCYP1A2CYP2C9CYP2C19CYP2D6CYP3A4CYP2B6
Citalopram+00+00
Escitalopram000+00
Fluoxetine++++/+++++++
Fluvoxamine+++++++++++
Paroxetine++++++++++
Sertraline+++/+++++

Legend:

  • 0 = no inhibition.
  • + = mild inhibition.
  • ++ = moderate inhibition.
  • +++ = strong inhibition.

The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone, codeine and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively), which in turn undergo phase 2 glucuronidation. These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with SSRIs. The concomitant use of some SSRIs (paroxetine and fluoxetine) with codeine may decrease the plasma concentration of active metabolite morphine, which may result in reduced analgesic efficacy.

Another important interaction of certain SSRIs involves paroxetine, a potent inhibitor of CYP2D6, and tamoxifen, an agent used commonly in the treatment and prevention of breast cancer. Tamoxifen is a prodrug that is metabolised by the hepatic cytochrome P450 enzyme system, especially CYP2D6, to its active metabolites. Concomitant use of paroxetine and tamoxifen in women with breast cancer is associated with a higher risk of death, as much as a 91% in women who used it the longest.

List of SSRIs

Marketed

  • Antidepressants
    • Citalopram (Celexa).
    • Escitalopram (Lexapro).
    • Fluoxetine (Prozac).
    • Fluvoxamine (Luvox).
    • Paroxetine (Paxil).
    • Sertraline (Zoloft).
  • Others:
    • Dapoxetine (Priligy).

Discontinued

  • Antidepressants:
    • Indalpine (Upstène).
    • Zimelidine (Zelmid).

Never Marketed

  • Antidepressants:
    • Alaproclate (GEA-654).
    • Centpropazine.
    • Cericlamine (JO-1017).
    • Femoxetine (Malexil; FG-4963).
    • Ifoxetine (CGP-15210).
    • Omiloxetine.
    • Panuramine (WY-26002).
    • Pirandamine (AY-23713).
    • Seproxetine ((S)-norfluoxetine).

Related Drugs

Although described as SNRIs, duloxetine (Cymbalta), venlafaxine (Effexor), and desvenlafaxine (Pristiq) are in fact relatively selective as serotonin reuptake inhibitors (SRIs). They are about at least 10-fold selective for inhibition of serotonin reuptake over norepinephrine reuptake. The selectivity ratios are approximately 1:30 for venlafaxine, 1:10 for duloxetine, and 1:14 for desvenlafaxine. At low doses, these SNRIs act mostly as SSRIs; only at higher doses do they also prominently inhibit norepinephrine reuptake. Milnacipran (Ixel, Savella) and its stereoisomer levomilnacipran (Fetzima) are the only widely marketed SNRIs that inhibit serotonin and norepinephrine to similar degrees, both with ratios close to 1:1.

Vilazodone (Viibryd) and vortioxetine (Trintellix) are SRIs that also act as modulators of serotonin receptors and are described as serotonin modulators and stimulators (SMS). Vilazodone is a 5-HT1A receptor partial agonist while vortioxetine is a 5-HT1A receptor agonist and 5-HT3 and 5-HT7 receptor antagonist. Litoxetine (SL 81-0385) and lubazodone (YM-992, YM-35995) are similar drugs that were never marketed. They are SRIs and litoxetine is also a 5-HT3 receptor antagonist while lubazodone is also a 5-HT2A receptor antagonist.

Mechanism of Action

Serotonin Reuptake Inhibition

In the brain, messages are passed from a nerve cell to another via a chemical synapse, a small gap between the cells. The presynaptic cell that sends the information releases neurotransmitters including serotonin into that gap. The neurotransmitters are then recognised by receptors on the surface of the recipient postsynaptic cell, which upon this stimulation, in turn, relays the signal. About 10% of the neurotransmitters are lost in this process; the other 90% are released from the receptors and taken up again by monoamine transporters into the sending presynaptic cell, a process called reuptake.

SSRIs inhibit the reuptake of serotonin. As a result, the serotonin stays in the synaptic gap longer than it normally would, and may repeatedly stimulate the receptors of the recipient cell. In the short run, this leads to an increase in signalling across synapses in which serotonin serves as the primary neurotransmitter. On chronic dosing, the increased occupancy of post-synaptic serotonin receptors signals the pre-synaptic neuron to synthesize and release less serotonin. Serotonin levels within the synapse drop, then rise again, ultimately leading to downregulation of post-synaptic serotonin receptors. Other, indirect effects may include increased norepinephrine output, increased neuronal cyclic AMP levels, and increased levels of regulatory factors such as BDNF and CREB. Owing to the lack of a widely accepted comprehensive theory of the biology of mood disorders, there is no widely accepted theory of how these changes lead to the mood-elevating and anti-anxiety effects of SSRIs. Any direct effects of SSRIs are limited by their inability to cross the blood-brain barrier; their effects on serotonin blood levels, which take weeks to take effect, appear to be largely responsible for their slow-to-appear psychiatric effects.

Sigma Receptor Ligands

In addition to their actions as reuptake inhibitors of serotonin, some SSRIs are also, coincidentally, ligands of the sigma receptors. Fluvoxamine is an agonist of the σ1 receptor, while sertraline is an antagonist of the σ1 receptor, and paroxetine does not significantly interact with the σ1 receptor. None of the SSRIs have significant affinity for the σ2 receptor, and the SNRIs, unlike the SSRIs, do not interact with either of the sigma receptors. Fluvoxamine has by far the strongest activity of the SSRIs at the σ1 receptor. High occupancy of the σ1 receptor by clinical dosages of fluvoxamine has been observed in the human brain in positron emission tomography (PET) research. It is thought that agonism of the σ1 receptor by fluvoxamine may have beneficial effects on cognition. In contrast to fluvoxamine, the relevance of the σ1 receptor in the actions of the other SSRIs is uncertain and questionable due to their very low affinity for the receptor relative to the SERT.

MedicationSERTσ1σ1σ2σ1 / SERT
Citalopram1.16292-404Agonist5,410252-348
Escitalopram2.5288AgonistNDND
Fluoxetine0.81191-240Agonist16,100296-365
Fluvoxamine2.217-36Agonist8,4397.7-16.4
Paroxetine0.13≥1,893ND22,870≥14,562
Sertraline0.2932-57Antagonist5,297110-197
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Anti-Inflammatory Effects

The role of inflammation and the immune system in depression has been extensively studied. The evidence supporting this link has been shown in numerous studies over the past ten years. Nationwide studies and meta-analyses of smaller cohort studies have uncovered a correlation between pre-existing inflammatory conditions such as type 1 diabetes, rheumatoid arthritis (RA), or hepatitis, and an increased risk of depression. Data also shows that using pro-inflammatory agents in the treatment of diseases like melanoma can lead to depression. Several meta-analytical studies have found increased levels of proinflammatory cytokines and chemokines in depressed patients. This link has led scientists to investigate the effects of antidepressants on the immune system.

SSRIs were originally invented with the goal of increasing levels of available serotonin in the extracellular spaces. However, the delayed response between when patients first begin SSRI treatment to when they see effects has led scientists to believe that other molecules are involved in the efficacy of these drugs. To investigate the apparent anti-inflammatory effects of SSRIs, both Kohler et al. and Więdłocha et al. conducted meta-analyses which have shown that after antidepressant treatment the levels of cytokines associated with inflammation are decreased. A large cohort study conducted by researchers in the Netherlands investigated the association between depressive disorders, symptoms, and antidepressants with inflammation. The study showed decreased levels of interleukin (IL)-6, a cytokine that has proinflammatory effects, in patients taking SSRIs compared to non-medicated patients.

Treatment with SSRIs has shown reduced production of inflammatory cytokines such as IL-1β, tumour necrosis factor (TNF)-α, IL-6, and interferon (IFN)-γ, which leads to a decrease in inflammation levels and subsequently a decrease in the activation level of the immune response. These inflammatory cytokines have been shown to activate microglia which are specialised macrophages that reside in the brain. Macrophages are a subset of immune cells responsible for host defence in the innate immune system. Macrophages can release cytokines and other chemicals to cause an inflammatory response. Peripheral inflammation can induce an inflammatory response in microglia and can cause neuroinflammation. SSRIs inhibit proinflammatory cytokine production which leads to less activation of microglia and peripheral macrophages. SSRIs not only inhibit the production of these proinflammatory cytokines, they also have been shown to upregulate anti-inflammatory cytokines such as IL-10. Taken together, this reduces the overall inflammatory immune response.

In addition to affecting cytokine production, there is evidence that treatment with SSRIs has effects on the proliferation and viability of immune system cells involved in both innate and adaptive immunity. Evidence shows that SSRIs can inhibit proliferation in T-cells, which are important cells for adaptive immunity and can induce inflammation. SSRIs can also induce apoptosis, programmed cell death, in T-cells. The full mechanism of action for the anti-inflammatory effects of SSRIs is not fully known. However, there is evidence for various pathways to have a hand in the mechanism. One such possible mechanism is the increased levels of cyclic adenosine monophosphate (cAMP) as a result of interference with activation of protein kinase A (PKA), a cAMP dependent protein. Other possible pathways include interference with calcium ion channels, or inducing cell death pathways like MAPK and Notch signalling pathway.

The anti-inflammatory effects of SSRIs have prompted studies of the efficacy of SSRIs in the treatment of autoimmune diseases such as multiple sclerosis, RA, inflammatory bowel diseases, and septic shock. These studies have been performed in animal models but have shown consistent immune regulatory effects. Fluoxetine, an SSRI, has also shown efficacy in animal models of graft vs. host disease. SSRIs have also been used successfully as pain relievers in patients undergoing oncology treatment. The effectiveness of this has been hypothesized to be at least in part due to the anti-inflammatory effects of SSRIs.

Pharmacogenetics

Refer to Pharmacogenetics.

Large bodies of research are devoted to using genetic markers to predict whether patients will respond to SSRIs or have side effects that will cause their discontinuation, although these tests are not yet ready for widespread clinical use.

Versus TCAs

SSRIs are described as ‘selective’ because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants, which affect other monoamine neurotransmitters as well, and as a result, SSRIs have fewer side effects.

There appears to be no significant difference in effectiveness between SSRIs and tricyclic antidepressants, which were the most commonly used class of antidepressants before the development of SSRIs. However, SSRIs have the important advantage that their toxic dose is high, and, therefore, they are much more difficult to use as a means to commit suicide. Further, they have fewer and milder side effects. Tricyclic antidepressants also have a higher risk of serious cardiovascular side effects, which SSRIs lack.

SSRIs act on signal pathways such as cyclic adenosine monophosphate (cAMP) on the postsynaptic neuronal cell, which leads to the release of brain-derived neurotrophic factor (BDNF). BDNF enhances the growth and survival of cortical neurons and synapses.

Controversy

Refer to Biopsychiatry Controversy and Biological Psychiatry.

A study examining publication of results from FDA-evaluated antidepressants concluded that those with favourable results were much more likely to be published than those with negative results. Furthermore, an investigation of 185 meta-analyses on antidepressants found that 79% of them had authors affiliated in some way to pharmaceutical companies and that they were reluctant to report caveats for antidepressants.

David Healy has argued that warning signs were available for many years prior to regulatory authorities moving to put warnings on antidepressant labels that they might cause suicidal thoughts. At the time these warnings were added, others argued that the evidence for harm remained unpersuasive and others continued to do so after the warnings were added.

What is the Biopsychiatry Controversy?

Introduction

The biopsychiatry controversy is a dispute over which viewpoint should predominate and form a basis of psychiatric theory and practice.

The debate is a criticism of a claimed strict biological view of psychiatric thinking. Its critics include disparate groups such as the antipsychiatry movement and some academics.

Overview of Opposition to Biopsychiatry

Biological psychiatry or biopsychiatry aims to investigate determinants of mental disorders devising remedial measures of a primarily somatic nature.

This has been criticised by Alvin Pam for being a “stilted, unidimensional, and mechanistic world-view”, so that subsequent “research in psychiatry has been geared toward discovering which aberrant genetic or neurophysiological factors underlie and cause social deviance”. According to Pam the “blame the body” approach, which typically offers medication for mental distress, shifts the focus from disturbed behaviour in the family to putative biochemical imbalances.

Research Issues

2003 Status in Biopsychiatric Research

Biopsychiatric research has produced reproducible abnormalities of brain structure and function, and a strong genetic component for a number of psychiatric disorders (although the latter has never been shown to be causative, merely correlative). It has also elucidated some of the mechanisms of action of medications that are effective in treating some of these disorders. Still, by their own admission, this research has not progressed to the stage that they can identify clear biomarkers of these disorders.

Research has shown that serious neurobiological disorders such as schizophrenia reveal reproducible abnormalities of brain structure (such as ventricular enlargement) and function. Compelling evidence exists that disorders including schizophrenia, bipolar disorder, and autism to name a few have a strong genetic component. Still, brain science has not advanced to the point where scientists or clinicians can point to readily discernible pathologic lesions or genetic abnormalities that in and of themselves serve as reliable or predictive biomarkers of a given mental disorder or mental disorders as a group. Ultimately, no gross anatomical lesion such as a tumour may ever be found; rather, mental disorders will likely be proven to represent disorders of intercellular communication; or of disrupted neural circuitry. Research already has elucidated some of the mechanisms of action of medications that are effective for depression, schizophrenia, anxiety, attention deficit, and cognitive disorders such as Alzheimer’s disease. These medications clearly exert influence on specific neurotransmitters, naturally occurring brain chemicals that effect, or regulate, communication between neurons in regions of the brain that control mood, complex reasoning, anxiety, and cognition. In 1970, The Nobel Prize was awarded to Julius Axelrod, Ph.D., of the National Institute of Mental Health, for his discovery of how anti-depressant medications regulate the availability of neurotransmitters such as norepinephrine in the synapses, or gaps, between nerve cells. (American Psychiatric Association, Statement on Diagnosis and Treatment of Mental Disorders, 26 September 2003).

Focus on Genetic Factors

Researchers have proposed that most common psychiatric and drug abuse disorders can be traced to a small number of dimensions of genetic risk and reports show significant associations between specific genomic regions and psychiatric disorders. Though, to date only a few genetic lesions have been demonstrated to be mechanistically responsible for psychiatric conditions. For example, one reported finding suggests that in persons diagnosed as schizophrenic as well as in their relatives with chronic psychiatric illnesses, the gene that encodes phosphodiesterase 4B (PDE4B) is disrupted by a balanced translocation.

The reasons for the relative lack of genetic understanding is because the links between genes and mental states defined as abnormal appear highly complex, involve extensive environmental influences and can be mediated in numerous different ways, for example by personality, temperament or life events. Therefore, while twin studies and other research suggests that personality is heritable to some extent, finding the genetic basis for particular personality or temperament traits, and their links to mental health problems, is “at least as hard as the search for genes involved in other complex disorders.” Theodore Lidz and The Gene Illusion argue that biopsychiatrists use genetic terminology in an unscientific way to reinforce their approach. Joseph maintains that biopsychiatrists disproportionately focus on understanding the genetics of those individuals with mental health problems at the expense of addressing the problems of the living in the environments of some extremely abusive families or societies.

Focus on Biochemical Factors

The chemical imbalance hypothesis states that a chemical imbalance within the brain is the main cause of psychiatric conditions and that these conditions can be improved with medication which corrects this imbalance. In that, emotions within a “normal” spectrum reflect a proper balance of neurotransmitter function, but abnormally extreme emotions which are severe enough to impact the daily functioning of patients (as seen in schizophrenia) reflect a profound imbalance. It is the goal of psychiatric intervention, therefore, to regain the homeostasis (via psychopharmacological approaches) that existed prior to the onset of disease.

This conceptual framework has been debated within the scientific community, although no other demonstrably superior hypothesis has emerged. Recently, the biopsychosocial approach to mental illness has been shown to be the most comprehensive and applicable theory in understanding psychiatric disorders. However, there is still much to be discovered in this area of inquiry. As a prime example – while great strides have been made in the field of understanding certain psychiatric disorders (such as schizophrenia) others (such as major depressive disorder) operate via multiple different neurotransmitters and interact in a complex array of systems which are (as yet) not completely understood.

Reductionism

Niall McLaren emphasizes in his books Humanizing Madness and Humanizing Psychiatry that the major problem with psychiatry is that it lacks a unified model of the mind and has become entrapped in a biological reductionist paradigm. The reasons for this biological shift are intuitive as reductionism has been very effective in other fields of science and medicine. However, despite reductionism’s efficacy in explaining the smallest parts of the brain this does not explain the mind, which is where he contends the majority of psychopathology stems from. An example would be that every aspect of a computer can be understood scientifically down to the last atom; however, this does not reveal the program that drives this hardware. He also argues that the widespread acceptance of the reductionist paradigm leads to a lack of openness to self-criticism and therefore halts the very engine of scientific progress. He has proposed his own natural dualist model of the mind, the biocognitive model, which is rooted in the theories of David Chalmers and Alan Turing and does not fall into the dualist’s trap of spiritualism.

Economic Influences on Psychiatric Practice

American Psychiatric Association president Steven S. Sharfstein, M.D. has stated that when the profit motive of pharmaceutical companies and human good are aligned, the results are mutually beneficial for all. In that, “Pharmaceutical companies have developed and brought to market medications that have transformed the lives of millions of psychiatric patients. The proven effectiveness of antidepressant, mood-stabilising, and antipsychotic medications has helped sensitize the public to the reality of mental illness and taught them that treatment works[citation needed]. In this way, Big Pharma has helped reduce stigma associated with psychiatric treatment and with psychiatrists.” However, Sharfstein acknowledged that the goals of individual physicians who deliver direct patient care can be different from the pharmaceutical and medical device industry. Conflicts arising from this disparity raise natural concerns in this regard including:

  • A “broken health care system” that allows “many patients [to be] prescribed the wrong drugs or drugs they don’t need”;
  • “medical education opportunities sponsored by pharmaceutical companies [that] are often biased toward one product or another”;
  • “[d]irect marketing to consumers [that] also leads to increased demand for medications and inflates expectations about the benefits of medications”;
  • “drug companies [paying] physicians to allow company reps to sit in on patient sessions to learn more about care for patients.”

Nevertheless, Sharfstein acknowledged that without pharmaceutical companies developing and producing modern medicines – virtually every medical specialty would have few (if any) treatments for the patients that they care for.

Pharmaceutical Industry Influences in Psychiatry

Studies have shown that promotional marketing by pharmaceutical and other companies has the potential to influence physician decision making. Pharmaceutical manufacturers (and other advocates) would argue that in today’s modern world – physicians simply do not have the time to continually update their knowledge base on the status of the latest research and that by providing educational materials for both physicians and patients, they are providing an educational perspective and that it is up to the individual physician to decide what treatment is best for their patients. The idea of pure promotion (e.g. lavish dinners) is a remnant of bygone era. It has been replaced by educationally-based activities that became the basis for the legal and industry reforms involving physician gifts, influence in graduate medical education, physician disclosure of conflicts of interest, and other promotional activities.

In an essay on the effect of advertisements for marketed anti-depressants there is some evidence that both patients and physicians can be influenced by media advertisements and this has the possibility of increasing the frequency of certain medicines being prescribed over others.

What is Biological Psychiatry?

Introduction

Biological psychiatry or biopsychiatry is an approach to psychiatry that aims to understand mental disorder in terms of the biological function of the nervous system. It is interdisciplinary in its approach and draws on sciences such as neuroscience, psychopharmacology, biochemistry, genetics, epigenetics and physiology to investigate the biological bases of behaviour and psychopathology. Biopsychiatry is the branch of medicine which deals with the study of the biological function of the nervous system in mental disorders.

There is some overlap with neurology, which focuses on disorders where gross or visible pathology of the nervous system is apparent, such as epilepsy, cerebral palsy, encephalitis, neuritis, Parkinson’s disease and multiple sclerosis. There is also some overlap with neuropsychiatry, which typically deals with behavioral disturbances in the context of apparent brain disorder. In contrast biological psychiatry describes the basic principles and then delves deeper into various disorders. It is structured to follow the organisation of the DSM-IV, psychiatry’s primary diagnostic and classification guide. The contributions of this field explore functional neuroanatomy, imaging, and neuropsychology and pharmacotherapeutic possibilities for depression, anxiety and mood disorders, substance abuse and eating disorders, schizophrenia and psychotic disorders, and cognitive and personality disorders.

Biological psychiatry and other approaches to mental illness are not mutually exclusive, but may simply attempt to deal with the phenomena at different levels of explanation. Because of the focus on the biological function of the nervous system, however, biological psychiatry has been particularly important in developing and prescribing drug-based treatments for mental disorders.

In practice, however, psychiatrists may advocate both medication and psychological therapies when treating mental illness. The therapy is more likely to be conducted by clinical psychologists, psychotherapists, occupational therapists or other mental health workers who are more specialised and trained in non-drug approaches.

The history of the field extends back to the ancient Greek physician Hippocrates, but the phrase biological psychiatry was first used in peer-reviewed scientific literature in 1953. The phrase is more commonly used in the United States than in some other countries such as the UK. However the term “biological psychiatry” is sometimes used as a phrase of disparagement in controversial dispute.

Brief History

Early 20th Century

Sigmund Freud was originally focused on the biological causes of mental illness. Freud’s professor and mentor, Ernst Wilhelm von Brücke, strongly believed that thought and behaviour were determined by purely biological factors. Freud initially accepted this and was convinced that certain drugs (particularly cocaine) functioned as antidepressants. He spent many years trying to “reduce” personality to neurology, a cause he later gave up on before developing his now well-known psychoanalytic theories.

Nearly 100 years ago, Harvey Cushing, the father of neurosurgery, noted that pituitary gland problems often cause mental health disorders. He wondered whether the depression and anxiety he observed in patients with pituitary disorders were caused by hormonal abnormalities, the physical tumour itself, or both.

Mid 20th Century

An important point in modern history of biological psychiatry was the discovery of modern antipsychotic and antidepressant drugs. Chlorpromazine (also known as Thorazine), an antipsychotic, was first synthesized in 1950. In 1952, iproniazid, a drug being trialled against tuberculosis, was serendipitously discovered to have anti-depressant effects, leading to the development of monoamine oxidase inhibitors (MAOIs) as the first class of antidepressants. In 1959 imipramine, the first tricyclic antidepressant, was developed. Research into the action of these drugs led to the first modern biological theory of mental health disorders called the catecholamine theory, later broadened to the monoamine theory, which included serotonin. These were popularly called the “chemical imbalance” theory of mental health disorders.

Late 20th Century

Starting with fluoxetine (marketed as Prozac) in 1988, a series of monoamine-based antidepressant medications belonging to the class of selective serotonin reuptake inhibitors were approved. These were no more effective than earlier antidepressants, but generally had fewer side effects. Most operate on the same principle, which is modulation of monoamines (neurotransmitters) in the neuronal synapse. Some drugs modulate a single neurotransmitter (typically serotonin). Others affect multiple neurotransmitters, called dual action or multiple action drugs. They are no more effective clinically than single action versions. That most antidepressants invoke the same biochemical method of action may explain why they are each similarly effective in rough terms. Recent research indicates antidepressants often work but are less effective than previously thought.

Problems with Catecholamine/Monoamine Hypotheses

The monoamine hypothesis was compelling, especially based on apparently successful clinical results with early antidepressant drugs, but even at the time there were discrepant findings. Only a minority of patients given the serotonin-depleting drug reserpine became depressed; in fact reserpine even acted as an antidepressant in many cases. This was inconsistent with the initial monoamine theory which said depression was caused by neurotransmitter deficiency.

Another problem was the time lag between antidepressant biological action and therapeutic benefit. Studies showed the neurotransmitter changes occurred within hours, yet therapeutic benefit took weeks.

To explain these behaviours, more recent modifications of the monoamine theory describe a synaptic adaptation process which takes place over several weeks. Yet this alone does not appear to explain all of the therapeutic effects.

Scope and Detailed Definition

Biological psychiatry is a branch of psychiatry where the focus is chiefly on researching and understanding the biological basis of major mental disorders such as unipolar and bipolar affective (mood) disorders, schizophrenia and organic mental disorders such as Alzheimer’s disease. This knowledge has been gained using imaging techniques, psychopharmacology, neuroimmunochemistry and so on. Discovering the detailed interplay between neurotransmitters and the understanding of the neurotransmitter fingerprint of psychiatric drugs such as clozapine has been a helpful result of the research.

On a research level, it includes all possible biological bases of behaviour – biochemical, genetic, physiological, neurological and anatomical. On a clinical level, it includes various therapies, such as drugs, diet, avoidance of environmental contaminants, exercise, and alleviation of the adverse effects of life stress, all of which can cause measurable biochemical changes. The biological psychiatrist views all of these as possible aetiologies of or remedies for mental health disorders.

However, the biological psychiatrist typically does not discount talk therapies. Medical psychiatric training generally includes psychotherapy and biological approaches. Accordingly, psychiatrists are usually comfortable with a dual approach: “psychotherapeutic methods […] are as indispensable as psychopharmacotherapy in a modern psychiatric clinic”.

Basis for Biological Psychiatry

Sigmund Freud developed psychotherapy in the early 1900s, and through the 1950s this technique was prominent in treating mental health disorders.

However, in the late 1950s, the first modern antipsychotic and antidepressant drugs were developed: chlorpromazine (also known as Thorazine), the first widely used antipsychotic, was synthesized in 1950, and iproniazid, one of the first antidepressants, was first synthesized in 1957. In 1959 imipramine, the first tricyclic antidepressant, was developed.

Based significantly on clinical observations of the above drug results, in 1965 the seminal paper “The catecholamine hypothesis of affective disorders” was published. It articulated the “chemical imbalance” hypothesis of mental health disorders, especially depression. It formed much of the conceptual basis for the modern era in biological psychiatry.

The hypothesis has been extensively revised since its advent in 1965. More recent research points to deeper underlying biological mechanisms as the possible basis for several mental health disorders.

Modern brain imaging techniques allow non-invasive examination of neural function in patients with mental health disorders, however this is currently experimental. With some disorders it appears the proper imaging equipment can reliably detect certain neurobiological problems associated with a specific disorder. If further studies corroborate these experimental results, future diagnosis of certain mental health disorders could be expedited using such methods.

Another source of data indicating a significant biological aspect of some mental health disorders is twin studies. Identical twins have the same nuclear DNA, so carefully constructed studies may indicate the relative importance of environmental and genetic factors on the development of a particular mental health disorder.

The results from this research and the associated hypotheses form the basis for biological psychiatry and the treatment approaches in a clinical setting.

Scope of Clinical Biological Psychiatric Treatment

Since various biological factors can affect mood and behaviour, psychiatrists often evaluate these before initiating further treatment. For example, dysfunction of the thyroid gland may mimic a major depressive episode, or hypoglycaemia (low blood sugar) may mimic psychosis.

While pharmacological treatments are used to treat many mental disorders, other non-drug biological treatments are used as well, ranging from changes in diet and exercise to transcranial magnetic stimulation and electroconvulsive therapy. Types of non-biological treatments such as cognitive therapy, behavioural therapy, and psychodynamic psychotherapy are often used in conjunction with biological therapies. Biopsychosocial models of mental illness are widely in use, and psychological and social factors play a large role in mental disorders, even those with an organic basis such as schizophrenia.

Diagnostic Process

Correct diagnosis is important for mental health disorders, otherwise the condition could worsen, resulting in a negative impact on both the patient and the healthcare system. Another problem with misdiagnosis is that a treatment for one condition might exacerbate other conditions. In other cases apparent mental health disorders could be a side effect of a serious biological problem such as concussion, brain tumour, or hormonal abnormality, which could require medical or surgical intervention.

Examples of Biologic Treatments

  • Seasonal affective disorder: light therapy, SSRIs (Like fluoxetine and paroxetine).
  • Clinical depression: SSRIs, serotonin-norepinephrine reuptake inhibitors (venlafaxine), dopamine reuptake inhibitors: (bupropion), tricyclic antidepressants, monoamine oxidase inhibitors, electroconvulsive therapy, transcranial magnetic stimulation, fish oil, St. John’s wort.
  • Bipolar disorder: lithium carbonate, antipsychotics (like olanzapine or quetiapine), anticonvulsants (like valproic acid, lamotrigine and topiramate).
  • Schizophrenia: antipsychotics such as haloperidol, clozapine, olanzapine, risperidone and quetiapine.
  • Generalized anxiety disorder: SSRIs, benzodiazepines, buspirone.
  • Obsessive-compulsive disorder: tricyclic antidepressants, SSRIs.
  • ADHD: clonidine, D-amphetamine, methamphetamine, and methylphenidate.

Latest Biological Hypotheses of Mental Health Disorders

New research indicates different biological mechanisms may underlie some mental health disorders, only indirectly related to neurotransmitters and the monoamine chemical imbalance hypothesis.

Recent research indicates a biological “final common pathway” may exist which both electroconvulsive therapy and most current antidepressant drugs have in common. These investigations show recurrent depression may be a neurodegenerative disorder, disrupting the structure and function of brain cells, destroying nerve cell connections, even killing certain brain cells, and precipitating a decline in overall cognitive function.

In this new biological psychiatry viewpoint, neuronal plasticity is a key element. Increasing evidence points to various mental health disorders as a neurophysiological problem which inhibits neuronal plasticity.

This is called the neurogenic hypothesis of depression. It promises to explain pharmacological antidepressant action, including the time lag from taking the drug to therapeutic onset, why downregulation (not just upregulation) of neurotransmitters can help depression, why stress often precipitates mood disorders, and why selective modulation of different neurotransmitters can help depression. It may also explain the neurobiological mechanism of other non-drug effects on mood, including exercise, diet and metabolism. By identifying the neurobiological “final common pathway” into which most antidepressants funnel, it may allow rational design of new medications which target only that pathway. This could yield drugs which have fewer side effects, are more effective and have quicker therapeutic onset.

There is significant evidence that oxidative stress plays a role in schizophrenia.

Criticism

A number of patients, activists, and psychiatrists dispute biological psychiatry as a scientific concept or as having a proper empirical basis, for example arguing that there are no known biomarkers for recognized psychiatric conditions. This position has been represented in academic journals such as The Journal of Mind and Behaviour and Ethical Human Psychology and Psychiatry, which publishes material specifically countering “the idea that emotional distress is due to an underlying organic disease.” Alternative theories and models instead view mental disorders as non-biomedical and might explain it in terms of, for example, emotional reactions to negative life circumstances or to acute trauma.

Fields such as social psychiatry, clinical psychology, and sociology may offer non-biomedical accounts of mental distress and disorder for certain ailments and are sometimes critical of biopsychiatry. Social critics believe biopsychiatry fails to satisfy the scientific method because they believe there is no testable biological evidence of mental disorders. Thus, these critics view biological psychiatry as a pseudoscience attempting to portray psychiatry as a biological science.

R.D. Laing argued that attributing mental disorders to biophysical factors was often flawed due to the diagnostic procedure. The “complaint” is often made by a family member, not the patient, the “history” provided by someone other than patient, and the “examination” consists of observing strange, incomprehensible behaviour. Ancillary tests (EEG, PET) are often done after diagnosis, when treatment has begun, which makes the tests non-blind and incurs possible confirmation bias. The psychiatrist Thomas Szasz commented frequently on the limitations of the medical approach to psychiatry and argued that mental illnesses are medicalised problems in living.

Silvano Arieti, while approving of the use of medication in some cases of schizophrenia, preferred intensive psychotherapy without medication if possible. He was also known for approving the use of electroconvulsive therapy on those with disorganised schizophrenia in order to make them reachable by psychotherapy. The views he expressed in Interpretation of Schizophrenia are nowadays known as the trauma model of mental disorders, an alternative to the biopsychiatric model.