In connection with our previous post ‘Yes or No: There is a Link Between Depression and Serotonin?’, a small study (of 25 participants over 6-9 years) reported in the New Scientist (Klein, 2020) suggests that brain electrodes may be a long-lasting aid for those suffering with depression (Bergfeld et al., 2022).
Bergfeld, I.O., Ooms, P., Lok, A., de Rue, L., Vissers, P., de Knijff, D., Horst, F., Beute, G., van den Munckhof, P., Schuurman, P.R & Denys, D. (2022) Efficacy and Quality of Life after 6-9 Years of Deep Brain Stimulation for Depression. Brain Stimulation. 15(4), pp.957-964. https://www.brainstimjrnl.com/article/S1935-861X(22)00114-0/fulltext.
Klein, A. (2022) Brain Electrodes May Be Long-Lasting Aid for Depression. New Scientist. 09 July 2022, pp.12.
Every year many suffering with depression are prescribed antidepressants to manage their condition, with antidepressants being described – by a spokesperson for the Royal College of Psychiatrists – as “an effective evidence-based treatment” (The Pharmaceutical Journal, 2022).
Within England, UK, “From 2021-22, there was a 5% rise in the number of adults receiving them – from 7.9 million in the previous 12 months to 8.3 million. [… with …] “An estimated 83.4 million antidepressant drug items were prescribed between 2021 and 2022, which marks a 5% increase from the previous year.” (BBC, 2022).
Within the US, Brody and Gu (2020) reported that “During 2015–2018, 13.2% of adults aged 18 and over used antidepressant medications in the past 30 days. [… and … ] In 2018, an estimated 7.2% of American adults had a major depressive episode in the past year. Carey and Geberloff reported in 2018 that “Nearly 25 million adults, like Ms. Toline, have been on antidepressants for at least two years, a 60 percent increase since 2010.”
Now it is important to remember that:
Depression is associated with diminished quality of life and increased disability;
Antidepressants are one of the primary treatments for depression;
Antidepressants are among the most frequently used therapeutic medications in the UK and US; and
There is research to suggest antidepressants work, at least in some people.
However, a new major analysis (by Moncrief et al., 2022) reported in the New Scientist suggests there is no link between serotonin levels and depression, raising questions about antidepressants that focus on this brain-signalling molecule (Wild, 2022, p.20).
Although this analysis suggests antidepressants might not be as effective as previously stated, brain electrodes might be. Read our next post about brain electrodes and depression here.
BBC (British Broadcasting Corporation). (2022) Nearly Half a Million More Adults on Antidepressants in England. Available from World Wide Web: https://www.bbc.co.uk/news/health-62094744. [Accessed: 17 November, 2022].
Moncrief, J., Cooper, R.E., Stockman, T., Amendola, S., Hengartner, M.P. & Horowitz, M.A. (2022) The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence. Molecular Psychiatry. doi.org/gqh6nd.
Butriptyline, sold under the brand name Evadyne among others, is a tricyclic antidepressant (TCA) that has been used in the United Kingdom and several other European countries for the treatment of depression but appears to no longer be marketed. Along with trimipramine, iprindole, and amoxapine, it has been described as an “atypical” or “second-generation” TCA due to its relatively late introduction and atypical pharmacology. It was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.
Butriptyline was developed by Wyeth, an American pharmaceutical company, and introduced in the United Kingdom in either 1974 or 1975.
Butriptyline was used in the treatment of depression. It was usually used at dosages of 150-300 mg/day.
Butriptyline is closely related to amitriptyline, and produces similar effects as other TCAs, but its side effects like sedation are said to be reduced in severity and it has a lower risk of interactions with other medications.
Butriptyline has potent antihistamine effects, resulting in sedation and somnolence. It also has potent anticholinergic effects, resulting in side effects like dry mouth, constipation, urinary retention, blurred vision, and cognitive/memory impairment. The drug has relatively weak effects as an alpha-1 blocker and has no effects as a norepinephrine reuptake inhibitor, so is associated with little to no antiadrenergic and adrenergic side effects.
Refer to Tricyclic Antidepressant Overdose.
In vitro, butriptyline is a strong antihistamine and anticholinergic, moderate 5-HT2 and α1-adrenergic receptor antagonist, and very weak or negligible monoamine reuptake inhibitor. These actions appear to confer a profile similar to that of iprindole and trimipramine with serotonin-blocking effects as the apparent predominant mediator of mood-lifting efficacy.
However, in small clinical trials, using similar doses, butriptyline was found to be similarly effective to amitriptyline and imipramine as an antidepressant, despite the fact that both of these TCAs are far stronger as both 5-HT2 antagonists and serotonin–norepinephrine reuptake inhibitors. As a result, it may be that butriptyline has a different mechanism of action, or perhaps functions as a prodrug in the body to a metabolite with different pharmacodynamics.
Therapeutic concentrations of butriptyline are in the range of 60-280 ng/mL (204-954 nmol/L). Its plasma protein binding is greater than 90%.
Butriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzocycloheptadiene TCAs include amitriptyline, nortriptyline, and protriptyline. Butriptyline is an analogue of amitriptyline with an isobutyl side chain instead of a propylidene side chain. It is a tertiary amine TCA, with its side chain-demethylated metabolite norbutriptyline being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of butriptyline is 3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-yl)-N,N,2-trimethylpropan-1-amine and its free base form has a chemical formula of C21H27N with a molecular weight of 293.446 g/mol. The drug has been used commercially both as the free base and as the hydrochloride salt. The CAS Registry Number of the free base is 15686-37-0 and of the hydrochloride is 5585-73-9.
Society and Culture
Butriptyline is the English and French generic name of the drug and its International Non-Propriety Name (INN), British Approved Name (BAN), and Denomination Commune Francaise (DCF), while butriptyline hydrochloride is its BANM and (United States Adopted Name (USAN). Its generic name in Latin is butriptylinum, in German is butriptylin, and in Spanish is butriptylina.
Butriptyline has been marketed under the brand names Evadene, Evadyne, Evasidol, and Centrolese.
Butriptyline has been marketed in Europe, including in the United Kingdom, Belgium, Luxembourg, Austria, and Italy.
This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Butriptyline >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.
The efficacy of sertraline for depression is similar to that of other antidepressants, and the differences are mostly confined to side effects. Sertraline is better tolerated than the older tricyclic antidepressants, and it may work better than fluoxetine for some subtypes of depression. Sertraline is effective for panic disorder, social anxiety disorder, generalised anxiety disorder (GAD), and obsessive-compulsive disorder (OCD). However, for OCD, cognitive behavioural therapy (CBT), particularly in combination with sertraline, is a better treatment. Although approved for post-traumatic stress disorder, sertraline leads to only modest improvement in this condition. Sertraline also alleviates the symptoms of premenstrual dysphoric disorder and can be used in sub-therapeutic doses or intermittently for its treatment.
Sertraline shares the common side effects and contraindications of other SSRIs, with high rates of nausea, diarrhoea, insomnia, and sexual side effects, but it appears not to lead to much weight gain, and its effects on cognitive performance are mild. Similar to other antidepressants, the use of sertraline for depression may be associated with a higher rate of suicidal thoughts and behaviour in people under the age of 25. It should not be used together with MAO inhibitor medication: this combination causes serotonin syndrome. Sertraline taken during pregnancy is associated with a significant increase in congenital heart defects in newborns.
Sertraline was invented and developed by scientists at Pfizer and approved for medical use in the United States in 1991. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2016, sertraline was the most commonly prescribed psychiatric medication in the US and in 2019, it was the twelfth most commonly prescribed medication in the US, with over 37 million prescriptions.
The history of sertraline dates back to the early 1970s, when Pfizer chemist Reinhard Sarges invented a novel series of psychoactive compounds, including lometraline, based on the structures of the neuroleptics thiothixene and pinoxepin. Further work on these compounds led to tametraline, a norepinephrine and weaker dopamine reuptake inhibitor. Development of tametraline was soon stopped because of undesired stimulant effects observed in animals. A few years later, in 1977, pharmacologist Kenneth Koe, after comparing the structural features of a variety of reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch generated a number of potent norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogues was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo by animal behavioural scientist Albert Weissman. The most potent and selective (+)-isomer was taken into further development and eventually named sertraline. Weissman and Koe recalled that the group did not set up to produce an antidepressant of the SSRI type – in that sense their inquiry was not “very goal driven”, and the discovery of the sertraline molecule was serendipitous. According to Welch, they worked outside the mainstream at Pfizer, and even “did not have a formal project team”. The group had to overcome initial bureaucratic reluctance to pursue sertraline development, as Pfizer was considering licensing an antidepressant candidate from another company.
Sertraline was approved by the US Food and Drug Administration (FDA) in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee; it had already become available in the United Kingdom the previous year. The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of major depression. During the discussion, Paul Leber, the director of the FDA Division of Neuropharmacological Drug Products, noted that granting approval was a “tough decision”, since the treatment effect on outpatients with depression had been “modest to minimal”. Other experts emphasized that the drug’s effect on inpatients had not differed from placebo and criticised poor design of the clinical trials by Pfizer. For example, 40% of participants dropped out of the trials, significantly decreasing their validity.
Until 2002, sertraline was only approved for use in adults ages 18 and over; that year, it was approved by the FDA for use in treating children aged 6 or older with severe OCD. In 2003, the UK Medicines and Healthcare products Regulatory Agency issued a guidance that, apart from fluoxetine (Prozac), SSRIs are not suitable for the treatment of depression in patients under 18. However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents. In 2005, the FDA added a boxed warning concerning paediatric suicidal behaviour to all antidepressants, including sertraline. In 2007, labelling was again changed to add a warning regarding suicidal behaviour in young adults ages 18 to 24.
Sertraline has been approved for major depressive disorder (MDD), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder, and social anxiety disorder (SAD). Sertraline is not approved for use in children except for those with OCD.
Multiple controlled clinical trials established efficacy of sertraline for the treatment of depression. Sertraline is also an effective antidepressant in the routine clinical practice. Continued treatment with sertraline prevents both a relapse of the current depressive episode and future episodes (recurrence of depression).
In several double-blind studies, sertraline was consistently more effective than placebo for dysthymia, a more chronic variety of depression, and comparable to imipramine in that respect. Sertraline also improves the depression of dysthymic patients to a greater degree than psychotherapy.
Limited paediatric data also demonstrates reduction in depressive symptoms in the paediatric population though remains a second line therapy after fluoxetine.
Comparison with Other Antidepressants
In general, sertraline efficacy is similar to that of other antidepressants. For example, a meta-analysis of 12 new-generation antidepressants showed that sertraline and escitalopram are the best in terms of efficacy and acceptability in the acute-phase treatment of adults with depression. Comparative clinical trials demonstrated that sertraline is similar in efficacy against depression to moclobemide, nefazodone, escitalopram, bupropion, citalopram, fluvoxamine, paroxetine, venlafaxine, and mirtazapine. Sertraline may be more efficacious for the treatment of depression in the acute phase (first 4 weeks) than fluoxetine.
There are differences between sertraline and some other antidepressants in their efficacy in the treatment of different subtypes of depression and in their adverse effects. For severe depression, sertraline is as good as clomipramine but is better tolerated. Sertraline appears to work better in melancholic depression than fluoxetine, paroxetine, and mianserin and is similar to the tricyclic antidepressants such as amitriptyline and clomipramine. In the treatment of depression accompanied by OCD, sertraline performs significantly better than desipramine on the measures of both OCD and depression. Sertraline is equivalent to imipramine for the treatment of depression with co-morbid panic disorder, but it is better tolerated. Compared with amitriptyline, sertraline offered a greater overall improvement in quality of life of depressed patients.
Depression in Elderly
Sertraline used for the treatment of depression in elderly (older than 60) patients is superior to placebo and comparable to another SSRI fluoxetine, and tricyclic antidepressants (TCAs) amitriptyline, nortriptyline and imipramine. Sertraline has much lower rates of adverse effects than these TCAs, with the exception of nausea, which occurs more frequently with sertraline. In addition, sertraline appears to be more effective than fluoxetine or nortriptyline in the older-than-70 subgroup. Accordingly, a meta-analysis of antidepressants in older adults found that sertraline, paroxetine and duloxetine were better than placebo. On the other hand, in a 2003 trial the effect size was modest, and there was no improvement in quality of life as compared to placebo. With depression in dementia, there is no benefit of sertraline treatment compared to either placebo or mirtazapine.
Sertraline is effective for the treatment of OCD in adults and children. It was better tolerated and, based on intention-to-treat analysis, performed better than the gold standard of OCD treatment clomipramine. Continuing sertraline treatment helps prevent relapses of OCD with long-term data supporting its use for up to 24 months. It is generally accepted that the sertraline dosages necessary for the effective treatment of OCD are higher than the usual dosage for depression. The onset of action is also slower for OCD than for depression. The treatment recommendation is to start treatment with a half of maximal recommended dose for at least two months. After that, the dose can be raised to the maximal recommended in the cases of unsatisfactory response.
CBT alone was superior to sertraline in both adults and children; however, the best results were achieved using a combination of these treatments.
Sertraline is superior to placebo for the treatment of panic disorder. The response rate was independent of the dose. In addition to decreasing the frequency of panic attacks by about 80% (vs. 45% for placebo) and decreasing general anxiety, sertraline resulted in improvement of quality of life on most parameters. The patients rated as “improved” on sertraline reported better quality of life than the ones who “improved” on placebo. The authors of the study argued that the improvement achieved with sertraline is different and of a better quality than the improvement achieved with placebo. Sertraline is equally effective for men and women, and for patients with or without agoraphobia. Previous unsuccessful treatment with benzodiazepines does not diminish its efficacy. However, the response rate was lower for the patients with more severe panic. Starting treatment simultaneously with sertraline and clonazepam, with subsequent gradual discontinuation of clonazepam, may accelerate the response.
Double-blind comparative studies found sertraline to have the same effect on panic disorder as paroxetine or imipramine. While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents (clomipramine, imipramine, clonazepam, alprazolam, and fluvoxamine) indicates approximate equivalence of these medications.
Other Anxiety Disorders
Sertraline has been successfully used for the treatment of social anxiety disorder. All three major domains of the disorder (fear, avoidance, and physiological symptoms) respond to sertraline. Maintenance treatment, after the response is achieved, prevents the return of the symptoms. The improvement is greater among the patients with later, adult onset of the disorder. In a comparison trial, sertraline was superior to exposure therapy, but patients treated with the psychological intervention continued to improve during a year-long follow-up, while those treated with sertraline deteriorated after treatment termination. The combination of sertraline and CBT appears to be more effective in children and young people than either treatment alone.
Sertraline has not been approved for the treatment of generalised anxiety disorder; however, several guidelines recommend it as a first-line medication referring to good quality controlled clinical trials.
Premenstrual Dysphoric Disorder
Sertraline is effective in alleviating the symptoms of premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome. Significant improvement was observed in 50-60% of cases treated with sertraline vs. 20-30% of cases on placebo. The improvement began during the first week of treatment, and in addition to mood, irritability, and anxiety, improvement was reflected in better family functioning, social activity and general quality of life. Work functioning and physical symptoms, such as swelling, bloating and breast tenderness, were less responsive to sertraline. Taking sertraline only during the luteal phase, that is, the 12-14 days before menses, was shown to work as well as continuous treatment. Continuous treatment with sub-therapeutic doses of sertraline (25 mg vs. usual 50-100 mg) is also effective.
Sertraline is approved for the treatment of post-traumatic stress disorder (PTSD). National Institute of Clinical Excellence recommends it for patients who prefer drug treatment to a psychological one. Other guidelines also suggest sertraline as a first-line option for pharmacological therapy. When necessary, long-term pharmacotherapy can be beneficial. There are both negative and positive clinical trial results for sertraline, which may be explained by the types of psychological traumas, symptoms, and comorbidities included in the various studies. Positive results were obtained in trials that included predominantly women (75%) with a majority (60%) having physical or sexual assault as the traumatic event. Contrary to the above suggestions, a meta-analysis of sertraline clinical trials for PTSD found it to be not significantly better than placebo. Another meta-analysis relegated sertraline to the second line, proposing trauma focused psychotherapy as a first-line intervention. The authors noted that Pfizer had declined to submit the results of a negative trial for the inclusion into the meta-analysis making the results unreliable.
Sertraline when taken daily can be useful for the treatment of premature ejaculation. A disadvantage of sertraline is that it requires continuous daily treatment to delay ejaculation significantly.
A 2019 systematic review suggested that sertraline may be a good way to control anger, irritability and hostility in depressed patients and patients with other comorbidities.
Sertraline is contraindicated in individuals taking monoamine oxidase inhibitors or the antipsychotic pimozide. Sertraline concentrate contains alcohol and is therefore contraindicated with disulfiram. The prescribing information recommends that treatment of the elderly and patients with liver impairment “must be approached with caution”. Due to the slower elimination of sertraline in these groups, their exposure to sertraline may be as high as three times the average exposure for the same dose.
Nausea, ejaculation failure, insomnia, diarrhoea, dry mouth, somnolence, dizziness, tremor, headache, excessive sweating, fatigue, and decreased libido are the common adverse effects associated with sertraline with the greatest difference from placebo. Those that most often resulted in interruption of the treatment are nausea, diarrhoea and insomnia. The incidence of diarrhoea is higher with sertraline – especially when prescribed at higher doses – in comparison with other SSRIs.
Over more than six months of sertraline therapy for depression, people showed a nonsignificant weight increase of 0.1%. Similarly, a 30-month-long treatment with sertraline for OCD resulted in a mean weight gain of 1.5% (1 kg). Although the difference did not reach statistical significance, the average weight gain was lower for fluoxetine (1%) but higher for citalopram, fluvoxamine and paroxetine (2.5%). Of the sertraline group, 4.5% gained a large amount of weight (defined as more than 7% gain). This result compares favourably with placebo, where, according to the literature, 3-6% of patients gained more than 7% of their initial weight. The large weight gain was observed only among female members of the sertraline group; the significance of this finding is unclear because of the small size of the group.
Over a two-week treatment of healthy volunteers, sertraline slightly improved verbal fluency but did not affect word learning, short-term memory, vigilance, flicker fusion time, choice reaction time, memory span, or psychomotor coordination. In spite of lower subjective rating, that is, feeling that they performed worse, no clinically relevant differences were observed in the objective cognitive performance in a group of people treated for depression with sertraline for 1.5 years as compared to healthy controls. In children and adolescents taking sertraline for six weeks for anxiety disorders, 18 out of 20 measures of memory, attention and alertness stayed unchanged. Divided attention was improved and verbal memory under interference conditions decreased marginally. Because of the large number of measures taken, it is possible that these changes were still due to chance. The unique effect of sertraline on dopaminergic neurotransmission may be related to these effects on cognition and vigilance.
Sertraline has a low level of exposure of an infant through the breast milk and is recommended as the preferred option for the antidepressant therapy of breast-feeding mothers. There is 29-42% increase in congenital heart defects among children whose mothers were prescribed sertraline during pregnancy, with sertraline use in the first trimester associated with 2.7-fold increase in septal heart defects.
Abrupt interruption of sertraline treatment may result in withdrawal or discontinuation syndrome. Dizziness, insomnia, anxiety, agitation, and irritability are its common symptoms. It typically occurs within a few days from drug discontinuation and lasts a few weeks. The withdrawal symptoms for sertraline are less severe and frequent than for paroxetine, and more frequent than for fluoxetine. In most cases symptoms are mild, short-lived, and resolve without treatment. More severe cases are often successfully treated by temporary reintroduction of the drug with a slower tapering off rate.
Sertraline and SSRI antidepressants in general may be associated with bruxism and other movement disorders. Sertraline appears to be associated with microscopic colitis, a rare condition of unknown aetiology.
Like other SSRIs, sertraline is associated with sexual side effects, including sexual arousal disorder, erectile dysfunction and difficulty achieving orgasm. While nefazodone and bupropion do not have negative effects on sexual functioning, 67% of men on sertraline experienced ejaculation difficulties versus 18% before the treatment. Sexual arousal disorder, defined as “inadequate lubrication and swelling for women and erectile difficulties for men”, occurred in 12% of people on sertraline as compared with 1% of patients on placebo. The mood improvement resulting from the treatment with sertraline sometimes counteracted these side effects, so that sexual desire and overall satisfaction with sex stayed the same as before the sertraline treatment. However, under the action of placebo the desire and satisfaction slightly improved. Some people continue experiencing sexual side effects after they stop taking SSRIs.
The US Food and Drug Administration (FDA) requires all antidepressants, including sertraline, to carry a boxed warning stating that antidepressants increase the risk of suicide in persons younger than 25 years. This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a 100% increase of suicidal thoughts and behaviour in children and adolescents, and a 50% increase – in the 18-24 age group.
Suicidal ideation and behaviour in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, sertraline use in adults decreased the odds of suicidal behaviour with a marginal statistical significance by 37% or 50% depending on the statistical technique used. The authors of the FDA analysis note that “given the large number of comparisons made in this review, chance is a very plausible explanation for this difference”. The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidal behaviour. Similarly, the analysis conducted by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the patients on sertraline as compared to the ones on placebo.
Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia and seizures. Plasma, serum or blood concentrations of sertraline and norsertraline, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalised patients or to aid in the medicolegal investigation of fatalities. As with most other SSRIs its toxicity in overdose is considered relatively low.
As with other SSRIs, sertraline may increase the risk of bleeding with NSAIDs (non-steroidal anti-inflammatory drugs such as ibuprofen, naproxen, mefenamic acid), antiplatelet drugs, anticoagulants, omega-3 fatty acids, vitamin E, and garlic supplements due to sertraline’s inhibitory effects on platelet aggregation via blocking serotonin transporters on platelets. Sertraline, in particular, may potentially diminish the efficacy of levothyroxine.
Sertraline is a moderate inhibitor of CYP2D6 and CYP2B6 in vitro. Accordingly, in human trials it caused increased blood levels of CYP2D6 substrates such as metoprolol, dextromethorphan, desipramine, imipramine and nortriptyline, as well as the CYP3A4/CYP2D6 substrate haloperidol. This effect is dose-dependent; for example, co-administration with 50 mg of sertraline resulted in 20% greater exposure to desipramine, while 150 mg of sertraline led to a 70% increase. In a placebo-controlled study, the concomitant administration of sertraline and methadone caused a 40% increase in blood levels of the latter, which is primarily metabolized by CYP2B6.
Sertraline had a slight inhibitory effect on the metabolism of diazepam, tolbutamide and warfarin, which are CYP2C9 or CYP2C19 substrates; the clinical relevance of this effect was unclear. As expected from in vitro data, sertraline did not alter the human metabolism of the CYP3A4 substrates erythromycin, alprazolam, carbamazepine, clonazepam, and terfenadine; neither did it affect metabolism of the CYP1A2 substrate clozapine.
Sertraline had no effect on the actions of digoxin and atenolol, which are not metabolised in the liver. Case reports suggest that taking sertraline with phenytoin or zolpidem may induce sertraline metabolism and decrease its efficacy, and that taking sertraline with lamotrigine may increase the blood level of lamotrigine, possibly by inhibition of glucuronidation.
CYP2C19 inhibitor esomeprazole increased sertraline concentrations in blood plasma by approximately 40%.
Clinical reports indicate that interaction between sertraline and the MAOIs isocarboxazid and tranylcypromine may cause serotonin syndrome. In a placebo-controlled study in which sertraline was co-administered with lithium, 35% of the subjects experienced tremors, while none of those taking placebo did.
Sertraline may interact with grapefruit juice.
Sertraline is a selective serotonin reuptake inhibitor (SSRI). By binding serotonin transporter (SERT) it inhibits neuronal reuptake of serotonin and potentiates serotonergic activity in the central nervous system. Over time, this leads to a downregulation of pre-synaptic 5-HT1A receptors, which is associated with an improvement in passive stress tolerance, and delayed downstream increase in expression of brain-derived neurotrophic factor (BDNF), which may contribute to a reduction in negative affective biases. It does not significantly affect norepinephrine transporter (NET), serotonin, dopamine, adrenergic, histamine, acetylcholine, GABA or benzodiazepine receptors.
Sertraline also shows relatively high activity as an inhibitor of the dopamine transporter (DAT) and antagonist of the sigma σ1 receptor (but not the σ2 receptor). However, sertraline affinity for its main target (SERT) is much greater than its affinity for σ1 receptor and DAT. Although there could be a role for the σ1 receptor in the pharmacology of sertraline, the significance of this receptor in its actions is unclear. Similarly, the clinical relevance of sertraline’s blockade of the dopamine transporter is uncertain.
Following a single oral dose of sertraline, mean peak blood levels of sertraline occur between 4.5 and 8.4 hours. Bioavailability is likely linear and dose-proportional over a dose range of 150 to 200 mg. Concomitant intake of sertraline with food slightly increases sertraline peak levels and total exposure. There is an approximate 2-fold accumulation of sertraline with continuous administration and steady-state levels are reached within one week.
Sertraline is highly plasma protein bound (98.5%) across a concentration range of 20 to 500 ng/mL. Despite the high plasma protein binding, sertraline and its metabolite desmethylsertraline at respective tested concentrations of 300 ng/mL and 200 ng/mL were found not to interfere with the plasma protein binding of warfarin and propranolol, two other highly plasma protein-bound drugs.
Sertraline is subject to extensive first-pass metabolism, as indicated by a small study of radiolabelled sertraline in which less than 5% of plasma radioactivity was unchanged sertraline in two males. The principal metabolic pathway for sertraline is N-demethylation into desmethylsertraline (N-desmethylsertraline) mainly by CYP2B6. Reduction, hydroxylation, and glucuronide conjugation of both sertraline and desmethylsertraline also occur. Desmethylsertraline, while pharmacologically active, is substantially (50-fold) weaker than sertraline as a serotonin reuptake inhibitor and its influence on the clinical effects of sertraline is thought to be negligible. Based on in vitro studies, sertraline is metabolized by multiple cytochrome 450 isoforms; however, it appears that in the human body CYP2C19 plays the most important role, followed by CYP2B6. In addition to the cytochrome P450 system, sertraline can be oxidatively deaminated in vitro by monoamine oxidases; however, this metabolic pathway has never been studied in vivo.
The elimination half-life of sertraline is on average 26 hours, with a range of 13 to 45 hours. The half-life of sertraline is longer in women (32 hours) than in men (22 hours), which leads to 1.5-fold higher exposure to sertraline in women compared to men. The elimination half-life of desmethylsertraline is 62 to 104 hours.
In a small study of two males, sertraline was excreted to similar degrees in urine and faeces (40 to 45% each within 9 days). Unchanged sertraline was not detectable in urine, whereas 12 to 14% unchanged sertraline was present in faeces.
CYP2C19 and CYP2B6 are thought to be the key cytochrome P450 enzymes involved in the metabolism of sertraline. Relative to CYP2C19 normal (extensive) metabolisers, poor metabolisers have 2.7-fold higher levels of sertraline and intermediate metabolisers have 1.4-fold higher levels. In contrast, CYP2B6 poor metabolisers have 1.6-fold higher levels of sertraline and intermediate metabolisers have 1.2-fold higher levels.
Society and Culture
The US patent for Zoloft expired in 2006, and sertraline is available in generic form and is marketed under many brand names worldwide.
In May 2020, the FDA placed Zoloft on the list of drugs currently facing a shortage.
Lass-Flörl et al., 2003 finds sertraline significantly inhibits phospholipase B in the fungal genus Candida, reducing virulence. It is also a very effective leishmanicide. Specifically, Palit & Ali 2008 find that sertraline kills almost all promastigotes of Leishmania donovani.
This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Sertraline >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.
Hospital Anxiety and Depression Scale (HADS) was originally developed by Zigmond and Snaith (1983) and is commonly used by doctors to determine the levels of anxiety and depression that a person is experiencing.
The HADS is a fourteen item scale that generates: Seven of the items that relate to anxiety and seven that relate to depression. Zigmond and Snaith created this outcome measure specifically to avoid reliance on aspects of these conditions that are also common somatic symptoms of illness, for example fatigue and insomnia or hypersomnia. This, it was hoped, would create a tool for the detection of anxiety and depression in people with physical health problems.
Items on the Questionnaire
The items on the questionnaire that relate to anxiety are
I feel tense or wound up.
I get a sort of frightened feeling as if something awful is about to happen.
Worrying thoughts go through my mind.
I can sit at ease and feel relaxed.
I get a sort of frightened feeling like ‘butterflies’ in the stomach.
I feel restless as I have to be on the move.
I get sudden feelings of panic.
The items that relate to depression are:
I still enjoy the things I used to enjoy.
I can laugh and see the funny side of things.
I feel cheerful.
I feel as if I am slowed down.
I have lost interest in my appearance.
I look forward with enjoyment to things.
I can enjoy a good book or radio or TV programme.
Scoring the Questionnaire
Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression.
Caseness of Anxiety and Depression
A number of researchers have explored HADS data to establish the cut-off points for caseness of anxiety or depression. Bjelland et al. (2002) through a literature review of a large number of studies identified a cut-off point of 8/21 for anxiety or depression. For anxiety (HADS-A) this gave a specificity of 0.78 and a sensitivity of 0.9. For depression (HADS-D) this gave a specificity of 0.79 and a sensitivity of 0.83.
There are a large number of studies that have explored the underlying factor structure of the HADS. Many support the two-factor structure but there are others that suggest a three or four factor structure. Some argue that the tool is best used as a unidimensional measure of psychological distress.
The factor structure of the HADS has been questioned. Coyne and Sonderen argue in a letter published in the same issue, that Cosco, et al. provides grounds for abandoning HADS altogether. The HADS has also been criticised for its over reliance on anhedonia as being the core symptom of depression, how single-item measures of depression may have the same predictive value as the HADS scale, as well as its use of British colloquial expressions which can be difficult to translate.
Can magic mushrooms cure depression? This documentary follows the first medical trial to explore the use of psilocybin as a treatment for clinical depression.
In 2012 a team of medical researchers asked themselves, “what would happen if we gave psilocybin (magic mushrooms) to people suffering from severe depression”? It took them three years to get the necessary permissions to find out.
With exclusive access to a ground-breaking trial, this film asks if psychedelic drugs combined with psychological support can help tackle one of the biggest medical challenges we face – depression.
The Psychedelic Drug Trial has exclusive access to a ground-breaking new trial at Imperial College London. The trial sees, for the first time ever under controlled conditions, a psychedelic drug tested head-to-head against a standard antidepressant as a treatment for depression.
The film follows a pioneering team of scientists and psychotherapists, led by Professor David Nutt, Dr Robin Carhart-Harris and Dr Rosalind Watts, as they compare the effects of psilocybin (the active ingredient of magic mushrooms) with an antidepressant (an SSRI called escitalopram) on a small group of participants with clinical depression. This is scientific research at its most cutting edge. With over seven million people being prescribed antidepressants each year in England alone, this drug trial is an important milestone in understanding a completely different treatment for depression.
Filmed over 16 months, this film explores both the immediate and long-term impacts of the trial on the lives of participants. It investigates whether psychedelic drugs combined with psychological support could help tackle one of the biggest medical challenges faced today and what it takes to conduct research in uncharted scientific territory.
How do psychedelic drugs measure up against the industry-standard antidepressants that have been popular since the 1990s? The empirical results of the trial are explored alongside the participants’ powerful lived experience.
About the Trial
All psychedelic drug use shown in this programme was part of a carefully controlled clinical trial under the supervision of specially trained psychotherapists.
The trial was run by Professor Nutt, Dr Carhart-Harris and Dr Watts and their team at Imperial College from 2019 to 2020. Fifty-nine participants took part, the trial is now finished.
The psychedelic drugs used in the trial are illegal in the UK and not available for medical treatment. You should always consult your doctor before you stop, change or start any new treatment.
Production & Filming Details
Caroline Lai … line producer.
Alice Martineau … producer.
Anna Murphy … executive producer.
Sabine Pusch … edit producer.
Caroline Willis … line producer.
Richard Jephcote … director of photography.
Zoe Davis … editor.
Alex Spence … assistant editor.
BBC Two (2021) (UK) (TV).
British Broadcasting Corporation (BBC) (2021) (UK) (all media).
The Depression and Bipolar Support Alliance (DBSA), formerly the National Depressive and Manic Depressive Association (NDMDA), is a non-profit organisation providing support groups for people who live with depression or bipolar disorder as well as their friends and family.
DBSA’s scope, also includes outreach, education and advocacy regarding depression and bipolar disorder. DBSA employs a small staff and operates with the guidance of a Scientific Advisory Board.
DBSA sponsors online and “face to face” support groups. A nonrandomized study found participants in such groups reported their coping skills, medication compliance, and acceptance of their illness correlated with participation. Member hospitalization decreased by 49% (from 82% to 33%). Following an initial meeting, members were found to be 6.8 times more likely to attend subsequent meetings if accompanied by a member the first time.
DBSA is a not-for-profit 501(c)(3) organisation and receives over 21 million hits per year on their combined websites. Each month, DBSA distributes nearly 20,000 educational materials free of charge to anyone requesting information about mood disorders. DBSA reaches nearly five million people through their educational materials and programs, exhibit materials, and media activities.
The Depression and Bipolar Support Alliance (DBSA) Greater Houston is a 501(c)(3) non-profit organisation located in Houston, Texas.
DBSA provides free and confidential support groups for individuals living with, or family and friends affected by, depression or bipolar disorder. Each support group is led by a facilitator trained by the organisation. Select groups target specific populations including veterans, adolescents, and parents of adolescents, young adults, senior citizens, LGBT Community, homeless individuals and Spanish-speaking individuals.
Established in 1979, the Depressive and Manic Disorder Association (DMDA) of Greater Houston sponsored up to five weekly support groups for those with depressive or manic depressive disorders. In 2003, DMDA Greater Houston changed its name to DBSA Greater Houston and formed its own 501(c) (3) corporation. Currently, DBSA Greater Houston sponsors nearly 70 weekly support groups at 50 different locations throughout the Houston metropolitan area. The Houston organisation is the largest of the nation’s DBSA chapters, serving over 1,000 support group participants annually.
The Depression and Bipolar Support Alliance of Greater Houston is a chapter member of the National Depression and Bipolar Support Alliance organisation based in Chicago, Illinois. Additionally, the organisation has developed collaborations with a number of Houston area mental health and social service providers including the Texas Department of Corrections, the Harris County judicial system, the Michael DeBakey VA Hospital, Mental Health of America, National Alliance on Mental Illness and the AIDS Foundation of Houston. Every group provided by DBSA Greater Houston is a collaboration with another organisation in the community. For a list of collaborations, visit the organisations website.
DBSA Greater Houston utilises 75 trained volunteer and professional facilitators to provide nearly 70 weekly support groups. According to an independently conducted demographics study in 2008, 64% of DBSA Greater Houston participants were female, 36% were male; 77% were diagnosed individuals while 23% were family members; 66% reported a diagnosis and/or symptoms of depression, 69% were diagnosed with bipolar disorder; 88% were prescribed psychotropic medications and 65% were in professional therapy.
The Depression and Bipolar Support Alliance of Greater Houston conducts an annual satisfaction survey for participants. In 2013, the results continued to show a high rating of satisfaction with a score of 4.28 out of a possible 5, which represents excellence. Also, it was found that the longer a person attends group, the more satisfied they are with the experience and the more skills they learn to manage their disorder.
In 2006 DBSA Greater received the Chapter of the Year award from the national Depression and Bipolar Support Alliance.
On 24 September 2013, the Depression and Bipolar Support Alliance of Greater Houston hosted its second annual Help, Hope, and Healing Luncheon with speakers Jessie Close and actress, Glenn Close. Jessie lives with Bipolar Disorder and Glenn talked about the perspective of the family and gave 2 monologues.
The Depression and Bipolar Support Alliance of Greater Houston hosted its first annual Help, Hope, and Healing luncheon at the River Oaks Country Club on 24 September 2012 featuring Jane Pauley as the speaker. Jane Pauley is known for her work on Dateline NBC and the Today Show. Ms. Pauley lives with Bipolar Disorder.
In the fall of 2008, DBSA Greater Houston published an outcome study independently conducted by Dr. Ralph Culler, former Associate Dean of Research at the Hogg Foundation for Mental Health. The outcome study was designed to analyse the effectiveness of the DBSA Greater Houston support group model. The study provided tools for DBSA Greater Houston to:
Provide quantitative and qualitative evidence that its support group model is effective;
Prove DBSA Greater Houston’s accountability to individuals utilising its services; and
Learn how the benefits of DBSA occur.
This study provided evidenced-based results that the DBSA Greater Houston support group model was effective in a number of areas. The study used an outcome questionnaire which asked a broad range of questions regarding demographics, medical data, outcome assessments and satisfaction with the support group experience. On average 89% of group participants experienced an improvement in their quality of life as a direct benefit of their participation in the DBSA groups. 93% of participants reported high or very high satisfaction with their DBSA support group experience.
Scientific studies have found that different brain areas show altered activity in people with major depressive disorder (MDD), and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes.
Factors spanning these causative groups include nutritional deficiencies in magnesium, vitamin D, and tryptophan with situational origin but biological impact. Several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around monoamine neurotransmitters, neuroplasticity, neurogenesis, inflammation and the circadian rhythm. Physical illnesses, including hypothyroidism and mitochondrial disease, can also trigger depressive symptoms.
Neural circuits implicated in depression include those involved in the generation and regulation of emotion, as well as in reward. Abnormalities are commonly found in the lateral prefrontal cortex whose putative function is generally considered to involve regulation of emotion. Regions involved in the generation of emotion and reward such as the amygdala, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and striatum are frequently implicated as well. These regions are innervated by a monoaminergic nuclei, and tentative evidence suggests a potential role for abnormal monoaminergic activity.
Difficulty of Gene Studies
Historically, candidate gene studies have been a major focus of study. However, as the number of genes reduces the likelihood of choosing a correct candidate gene, Type I errors (false positives) are highly likely. Candidate genes studies frequently possess a number of flaws, including frequent genotyping errors and being statistically underpowered. These effects are compounded by the usual assessment of genes without regard for gene-gene interactions. These limitations are reflected in the fact that no candidate gene has reached genome-wide significance.
The 5-HTTLPR, or serotonin transporter promoter gene’s short allele, has been associated with increased risk of depression; since the 1990s, however, results have been inconsistent. Other genes that have been linked to a gene-environment interaction include CRHR1, FKBP5 and BDNF, the first two of which are related to the stress reaction of the HPA axis, and the latter of which is involved in neurogenesis. Candidate gene analysis of 5-HTTLPR on depression was inconclusive on its effect, either alone or in combination with life stress.
A 2003 study proposed that a gene-environment interaction (GxE) may explain why life stress is a predictor for depressive episodes in some individuals, but not in others, depending on an allelic variation of the serotonin-transporter-linked promoter region (5-HTTLPR). This hypothesis was widely-discussed in both the scientific literature and popular media, where it was dubbed the “Orchid gene”, but has conclusively failed to replicate in much larger samples, and the observed effect sizes in earlier work are not consistent with the observed polygenicity of depression.
BDNF polymorphisms have also been hypothesized to have a genetic influence, but early findings and research failed to replicate in larger samples, and the effect sizes found by earlier estimates are inconsistent with the observed polygenicity of depression.
SIRT1 and LHPP
A 2015 GWAS study in Han Chinese women positively identified two variants in intronic regions near SIRT1 and LHPP with a genome-wide significant association.
Norepinephrine Transporter Polymorphisms
Attempts to find a correlation between norepinephrine transporter polymorphisms and depression have yielded negative results.
One review identified multiple frequently studied candidate genes. The genes encoding for the 5-HTT and 5-HT2A receptor were inconsistently associated with depression and treatment response. Mixed results were found for brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. Polymorphisms in the tryptophan hydroxylase gene was found to be tentatively associated with suicidal behaviour. A meta analysis of 182 case controlled genetic studies published in 2008 found Apolipoprotein E verepsilon 2 to be protective, and GNB3 825T, MTHFR 677T, SLC6A4 44bp insertion or deletions, and SLC6A3 40 bpVNTR 9/10 genotype to confer risk.
Depression may be related to abnormalities in the circadian rhythm, or biological clock.
A well synchronised circadian rhythm is critical for maintaining optimal health. Adverse changes and alterations in the circadian rhythm have been associated various neurological disorders and mood disorders including depression.
Sleep disturbance is the most prominent symptom in depressive patients. Studies about sleep electroencephalograms have shown characteristic changes in depression such as reductions in non-rapid eye movement sleep production, disruptions of sleep continuity and disinhibition of rapid eye movement (REM) sleep. Rapid eye movement (REM) sleep – the stage in which dreaming occurs – may be quick to arrive and intense in depressed people. REM sleep depends on decreased serotonin levels in the brain stem, and is impaired by compounds, such as antidepressants, that increase serotonergic tone in brain stem structures. Overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation activates serotonergic neurons, leading to processes similar to the therapeutic effect of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Depressed individuals can exhibit a significant lift in mood after a night of sleep deprivation. SSRIs may directly depend on the increase of central serotonergic neurotransmission for their therapeutic effect, the same system that impacts cycles of sleep and wakefulness.
Research on the effects of light therapy on seasonal affective disorder suggests that light deprivation is related to decreased activity in the serotonergic system and to abnormalities in the sleep cycle, particularly insomnia. Exposure to light also targets the serotonergic system, providing more support for the important role this system may play in depression. Sleep deprivation and light therapy both target the same brain neurotransmitter system and brain areas as antidepressant drugs, and are now used clinically to treat depression. Light therapy, sleep deprivation and sleep time displacement (sleep phase advance therapy) are being used in combination quickly to interrupt a deep depression in people who are hospitalised for MDD.
Increased and decreased sleep length appears to be a risk factor for depression. People with MDD sometimes show diurnal and seasonal variation of symptom severity, even in non-seasonal depression. Diurnal mood improvement was associated with activity of dorsal neural networks. Increased mean core temperature was also observed. One hypothesis proposed that depression was a result of a phase shift.
Daytime light exposure correlates with decreased serotonin transporter activity, which may underlie the seasonality of some depression.
Monoamines are neurotransmitters that include serotonin, dopamine, norepinephrine, and epinephrine.
Monoamine Hypothesis of Depression
Many antidepressant drugs acutely increase synaptic levels of the monoamine neurotransmitter, serotonin, but they may also enhance the levels of norepinephrine and dopamine. The observation of this efficacy led to the monoamine hypothesis of depression, which postulates that the deficit of certain neurotransmitters is responsible for depression, and even that certain neurotransmitters are linked to specific symptoms. Normal serotonin levels have been linked to mood and behaviour regulation, sleep, and digestion; norepinephrine to the fight-or-flight response; and dopamine to movement, pleasure, and motivation. Some have also proposed the relationship between monoamines and phenotypes such as serotonin in sleep and suicide, norepinephrine in dysphoria, fatigue, apathy, cognitive dysfunction, and dopamine in loss of motivation and psychomotor symptoms. The main limitation for the monoamine hypothesis of depression is the therapeutic lag between initiation of antidepressant treatment and perceived improvement of symptoms. One explanation for this therapeutic lag is that the initial increase in synaptic serotonin is only temporary, as firing of serotonergic neurons in the dorsal raphe adapt via the activity of 5-HT1A autoreceptors. The therapeutic effect of antidepressants is thought to arise from autoreceptor desensitization over a period of time, eventually elevating firing of serotonergic neurons.
Initial studies of serotonin in depression examined peripheral measures such as the serotonin metabolite 5-Hydroxyindoleacetic acid (5-HIAA) and platelet binding. The results were generally inconsistent, and may not generalise to the central nervous system. However evidence from receptor binding studies and pharmacological challenges provide some evidence for dysfunction of serotonin neurotransmission in depression. Serotonin may indirectly influence mood by altering emotional processing biases that are seen at both the cognitive/behavioural and neural level. Pharmacologically reducing serotonin synthesis, and pharmacologically enhancing synaptic serotonin can produce and attenuate negative affective biases, respectively. These emotional processing biases may explain the therapeutic gap.
While various abnormalities have been observed in dopaminergic systems, results have been inconsistent. People with MDD have an increased reward response to dextroamphetamine compared to controls, and it has been suggested that this results from hypersensitivity of dopaminergic pathways due to natural hypoactivity. While polymorphisms of the D4 and D3 receptor have been implicated in depression, associations have not been consistently replicated. Similar inconsistency has been found in post-mortem studies, but various dopamine receptor agonists show promise in treating MDD. There is some evidence that there is decreased nigrostriatal pathway activity in people with melancholic depression (psychomotor retardation). Further supporting the role of dopamine in depression is the consistent finding of decreased cerebrospinal fluid and jugular metabolites of dopamine, as well as post mortem findings of altered Dopamine receptor D3 and dopamine transporter expression. Studies in rodents have supported a potential mechanism involving stress-induced dysfunction of dopaminergic systems.
A number of lines of evidence indicative of decreased adrenergic activity in depression have been reported. Findings include the decreased activity of tyrosine hydroxylase, decreased size of the locus coeruleus, increased alpha 2 adrenergic receptor density, and decreased alpha 1 adrenergic receptor density. Furthermore, norepinephrine transporter knockout in mice models increases their tolerance to stress, implicating norepinephrine in depression.
One method used to study the role of monoamines is monoamine depletion. Depletion of tryptophan (the precursor of serotonin), tyrosine and phenylalanine (precursors to dopamine) does result in decreased mood in those with a predisposition to depression, but not in persons lacking the predisposition. On the other hand, inhibition of dopamine and norepinephrine synthesis with alpha-methyl-para-tyrosine does not consistently result in decreased mood.
An offshoot of the monoamine hypothesis suggests that monoamine oxidase A (MAO-A), an enzyme which metabolises monoamines, may be overly active in depressed people. This would, in turn, cause the lowered levels of monoamines. This hypothesis received support from a PET study, which found significantly elevated activity of MAO-A in the brain of some depressed people. In genetic studies, the alterations of MAO-A-related genes have not been consistently associated with depression. Contrary to the assumptions of the monoamine hypothesis, lowered but not heightened activity of MAO-A was associated with depressive symptoms in adolescents. This association was observed only in maltreated youth, indicating that both biological (MAO genes) and psychological (maltreatment) factors are important in the development of depressive disorders. In addition, some evidence indicates that disrupted information processing within neural networks, rather than changes in chemical balance, might underlie depression.
Since the 1990s, research has uncovered multiple limitations of the monoamine hypothesis, and its inadequacy has been criticised within the psychiatric community. For one thing, serotonin system dysfunction cannot be the sole cause of depression. Not all patients treated with antidepressants show improvements despite the usually rapid increase in synaptic serotonin. If significant mood improvements do occur, this is often not for at least two to four weeks. One possible explanation for this lag is that the neurotransmitter activity enhancement is the result of auto receptor desensitization, which can take weeks. Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in people with MDD. The antidepressants that do not act through the monoamine system, such as tianeptine and opipramol, have been known for a long time. There have also been inconsistent findings with regard to levels of serum 5-HIAA, a metabolite of serotonin. Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people. Another problem that presents is that drugs that deplete monoamines may actually have antidepressant properties. Further, some have argued that depression may be marked by a hyperserotonergic state. Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.
As of 2012, efforts to determine differences in neurotransmitter receptor expression or for function in the brains of people with MDD using positron emission tomography (PET) had shown inconsistent results. Using the PET imaging technology and reagents available as of 2012, it appeared that the D1 receptor may be under-expressed in the striatum of people with MDD. 5-HT1A receptor binding literature is inconsistent; however, it leans towards a general decrease in the mesiotemporal cortex. 5-HT2A receptor binding appears to be unregulated in people with MDD. Results from studies on 5-HTT binding are variable, but tend to indicate higher levels in people with MDD. Results with D2/D3 receptor binding studies are too inconsistent to draw any conclusions. Evidence supports increased MAO activity in people with MDD, and it may even be a trait marker (not changed by response to treatment). Muscarinic receptor binding appears to be increased in depression, and, given ligand binding dynamics, suggests increased cholinergic activity.
Four meta analyses on receptor binding in depression have been performed, two on serotonin transporter (5-HTT), one on 5-HT1A, and another on dopamine transporter (DAT). One meta analysis on 5-HTT reported that binding was reduced in the midbrain and amygdala, with the former correlating with greater age, and the latter correlating with depression severity. Another meta-analysis on 5-HTT including both post-mortem and in vivo receptor binding studies reported that while in vivo studies found reduced 5-HTT in the striatum, amygdala and midbrain, post mortem studies found no significant associations. 5-HT1A was found to be reduced in the anterior cingulate cortex, mesiotemporal lobe, insula, and hippocampus, but not in the amygdala or occipital lobe. The most commonly used 5-HT1A ligands are not displaced by endogenous serotonin, indicating that receptor density or affinity is reduced. Dopamine transporter binding is not changed in depression.
Emotional Processing and Neural Circuits
People with MDD show a number of biases in emotional processing, such as a tendency to rate happy faces more negatively, and a tendency to allocate more attentional resources to sad expressions. Depressed people also have impaired recognition of happy, angry, disgusted, fearful and surprised, but not sad faces. Functional neuroimaging has demonstrated hyperactivity of various brain regions in response to negative emotional stimuli, and hypoactivity in response to positive stimuli. One meta analysis reported that depressed subjects showed decreased activity in the left dorsolateral prefrontal cortex and increased activity in the amygdala in response to negative stimuli. Another meta analysis reported elevated hippocampus and thalamus activity in a subgroup of depressed subjects who were medication naïve, not elderly, and had no comorbidities. The therapeutic lag of antidepressants has been suggested to be a result of antidepressants modifying emotional processing leading to mood changes. This is supported by the observation that both acute and sub-chronic SSRI administration increases response to positive faces. Antidepressant treatment appears to reverse mood congruent biases in limbic, prefrontal, and fusiform areas. dlPFC response is enhanced and amygdala response is attenuated during processing of negative emotions, the former or which is thought to reflect increased top down regulation. The fusiform gyrus and other visual processing areas respond more strongly to positive stimuli with antidepressant treatment, which is thought to reflect the a positive processing bias. These effects do not appear to be unique to serotonergic or noradrenergic antidepressants, but also occur in other forms of treatment such as deep brain stimulation.
One meta analysis of functional neuroimaging in depression observed a pattern of abnormal neural activity hypothesized to reflect an emotional processing bias. Relative to controls, people with MDD showed hyperactivity of circuits in the salience network (SN), composed of the pulvinar nuclei, the insula, and the dorsal anterior cingulate cortex (dACC), as well as decreased activity in regulatory circuits composed of the striatum and dlPFC.
A neuroanatomical model called the limbic-cortical model has been proposed to explain early biological findings in depression. The model attempts to relate specific symptoms of depression to neurological abnormalities. Elevated resting amygdala activity was proposed to underlie rumination, as stimulation of the amygdala has been reported to be associated with the intrusive recall of negative memories. The ACC was divided into pregenual (pgACC) and subgenual regions (sgACC), with the former being electrophysiologically associated with fear, and the latter being metabolically implicated in sadness in healthy subjects. Hyperactivity of the lateral orbitofrontal and insular regions, along with abnormalities in lateral prefrontal regions was suggested to underlie maladaptive emotional responses, given the regions roles in reward learning. This model and another termed “the cortical striatal model”, which focused more on abnormalities in the cortico-basal ganglia-thalamo-cortical loop, have been supported by recent literature. Reduced striatal activity, elevated OFC activity, and elevated sgACC activity were all findings consistent with the proposed models. However, amygdala activity was reported to be decreased, contrary to the limbic-cortical model. Furthermore, only lateral prefrontal regions were modulated by treatment, indicating that prefrontal areas are state markers (i.e. dependent upon mood), while subcortical abnormalities are trait markers (i.e. reflect a susceptibility).
While depression severity as a whole is not correlated with a blunted neural response to reward, anhedonia is directly correlated to reduced activity in the reward system. The study of reward in depression is limited by heterogeneity in the definition and conceptualisations of reward and anhedonia. Anhedonia is broadly defined as a reduced ability to feel pleasure, but questionnaires and clinical assessments rarely distinguish between motivational “wanting” and consummatory “liking”. While a number of studies suggest that depressed subjects rate positive stimuli less positively and as less arousing, a number of studies fail to find a difference. Furthermore, response to natural rewards such as sucrose does not appear to be attenuated. General affective blunting may explain “anhedonic” symptoms in depression, as meta analysis of both positive and negative stimuli reveal reduced rating of intensity. As anhedonia is a prominent symptom of depression, direct comparison of depressed with healthy subjects reveals increased activation of the subgenual anterior cingulate cortex (sgACC), and reduced activation of the ventral striatum, and in particular the nucleus accumbens (NAcc) in response to positive stimuli. Although the finding of reduced NAcc activity during reward paradigms is fairly consistent, the NAcc is made up of a functionally diverse range of neurons, and reduced blood-oxygen-level dependent (BOLD) signal in this region could indicate a variety of things including reduced afferent activity or reduced inhibitory output. Nevertheless, these regions are important in reward processing, and dysfunction of them in depression is thought to underlie anhedonia. Residual anhedonia that is not well targeted by serotonergic antidepressants is hypothesized to result from inhibition of dopamine release by activation of 5-HT2C receptors in the striatum. The response to reward in the medial orbitofrontal cortex (OFC) is attenuated in depression, while lateral OFC response is enhanced to punishment. The lateral OFC shows sustained response to absence of reward or punishment, and it is thought to be necessary for modifying behaviour in response to changing contingencies. Hypersensitivity in the lOFC may lead to depression by producing a similar effect to learned helplessness in animals.
Elevated response in the sgACC is a consistent finding in neuroimaging studies using a number of paradigms including reward related tasks. Treatment is also associated with attenuated activity in the sgACC, and inhibition of neurons in the rodent homologue of the sgACC, the infralimbic cortex (IL), produces an antidepressant effect. Hyperactivity of the sgACC has been hypothesized to lead to depression via attenuating the somatic response to reward or positive stimuli. Contrary to studies of functional magnetic resonance imaging response in the sgACC during tasks, resting metabolism is reduced in the sgACC. However, this is only apparent when correcting for the prominent reduction in sgACC volume associated with depression; structural abnormalities are evident at a cellular level, as neuropathological studies report reduced sgACC cell markers. The model of depression proposed from these findings by Drevets et al. suggests that reduced sgACC activity results in enhanced sympathetic nervous system activity and blunted HPA axis feedback. Activity in the sgACC may also not be causal in depression, as the authors of one review that examined neuroimaging in depressed subjects during emotional regulation hypothesized that the pattern of elevated sgACC activity reflected increased need to modulate automatic emotional responses in depression. More extensive sgACC and general prefrontal recruitment during positive emotional processing was associated with blunted subcortical response to positive emotions, and subject anhedonia. This was interpreted by the authors to reflect a downregulation of positive emotions by the excessive recruitment of the prefrontal cortex.
While a number of neuroimaging findings are consistently reported in people with major depressive disorder, the heterogeneity of depressed populations presents difficulties interpreting these findings. For example, averaging across populations may hide certain subgroup related findings; while reduced dlPFC activity is reported in depression, a subgroup may present with elevated dlPFC activity. Averaging may also yield statistically significant findings, such as reduced hippocampal volumes, that are actually present in a subgroup of subjects. Due to these issues and others, including the longitudinal consistency of depression, most neural models are likely inapplicable to all depression.
Meta analyses performed using seed-based d mapping have reported grey matter reductions in a number of frontal regions. One meta analysis of early onset general depression reported grey matter reductions in the bilateral anterior cingulate cortex (ACC) and dorsomedial prefrontal cortex (dmPFC). One meta analysis on first episode depression observed distinct patterns of grey matter reductions in medication free, and combined populations; medication free depression was associated with reductions in the right dorsolateral prefrontal cortex, right amygdala, and right inferior temporal gyrus; analysis on a combination of medication free and medicated depression found reductions in the left insula, right supplementary motor area, and right middle temporal gyrus. Another review distinguishing medicated and medication free populations, albeit not restricted to people with their first episode of MDD, found reductions in the combined population in the bilateral superior, right middle, and left inferior frontal gyrus, along with the bilateral parahippocampus. Increases in thalamic and ACC grey matter was reported in the medication free and medicated populations respectively. A meta analysis performed using “activation likelihood estimate” reported reductions in the paracingulate cortex, dACC and amygdala.
Using statistical parametric mapping, one meta analysis replicated previous findings of reduced grey matter in the ACC, medial prefrontal cortex, inferior frontal gyrus, hippocampus and thalamus; however reductions in the OFC and ventromedial prefrontal cortex grey matter were also reported.
Two studies on depression from the ENIGMA consortium have been published, one on cortical thickness, and the other on subcortical volume. Reduced cortical thickness was reported in the bilateral OFC, ACC, insula, middle temporal gyri, fusiform gyri, and posterior cingulate cortices, while surface area deficits were found in medial occipital, inferior parietal, orbitofrontal and precentral regions. Subcortical abnormalities, including reductions in hippocampus and amygdala volumes, which were especially pronounced in early onset depression.
Multiple meta analysis have been performed on studies assessing white matter integrity using fractional anisotropy (FA). Reduced FA has been reported in the corpus callosum (CC) in both first episode medication naïve, and general major depressive populations. The extent of CC reductions differs from study to study. People with MDD who have not taken antidepressants before have been reported to have reductions only in the body of the CC and only in the genu of the CC. On the other hand, general MDD samples have been reported to have reductions in the body of the CC, the body and genu of the CC, and only the genu of the CC. Reductions of FA have also been reported in the anterior limb of the internal capsule (ALIC) and superior longitudinal fasciculus.
Studies of resting state activity have utilised a number of indicators of resting state activity, including regional homogeneity (ReHO), amplitude of low frequency fluctuations (ALFF), fractional amplitude of low frequency fluctuations (fALFF), arterial spin labelling (ASL), and positron emission tomography measures of regional cerebral blood flow or metabolism.
Studies using ALFF and fALFF have reported elevations in ACC activity, with the former primarily reporting more ventral findings, and the latter more dorsal findings. A conjunction analysis of ALFF and CBF studies converged on the left insula, with previously untreated people having increased insula activity. Elevated caudate CBF was also reported A meta analysis combining multiple indicators of resting activity reported elevated anterior cingulate, striatal, and thalamic activity and reduced left insula, post-central gyrus and fusiform gyrus activity. An activation likelihood estimate (ALE) meta analysis of PET/SPECT resting state studies reported reduced activity in the left insula, pregenual and dorsal anterior cingulate cortex and elevated activity in the thalamus, caudate, anterior hippocampus and amygdala. Compared to the ALE meta analysis of PET/SPECT studies, a study using multi-kernel density analysis reported hyperactivity only in the pulvinar nuclei of the thalamus.
Research on the brains of people with MDD usually shows disturbed patterns of interaction between multiple parts of the brain. Several areas of the brain are implicated in studies seeking to more fully understand the biology of depression:
Studies have shown that Brodmann area 25, also known as subgenual cingulate, is metabolically overactive in treatment-resistant depression. This region is extremely rich in serotonin transporters and is considered as a governor for a vast network involving areas like hypothalamus and brain stem, which influences changes in appetite and sleep; the amygdala and insula, which affect the mood and anxiety; the hippocampus, which plays an important role in memory formation; and some parts of the frontal cortex responsible for self-esteem. Thus disturbances in this area or a smaller than normal size of this area contributes to depression. Deep brain stimulation has been targeted to this region in order to reduce its activity in people with treatment resistant depression.
One review reported hypoactivity in the prefrontal cortex of those with depression compared to controls. The prefrontal cortex is involved in emotional processing and regulation, and dysfunction of this process may be involved in the aetiology of depression. One study on antidepressant treatment found an increase in PFC activity in response to administration of antidepressants. One meta analysis published in 2012 found that areas of the prefrontal cortex were hypoactive in response to negative stimuli in people with MDD. One study suggested that areas of the prefrontal cortex are part of a network of regions including dorsal and pregenual cingulate, bilateral middle frontal gyrus, insula and superior temporal gyrus that appear to be hypoactive in people with MDD. However the authors cautioned that the exclusion criteria, lack of consistency and small samples limit results.
The amygdala, a structure involved in emotional processing appears to be hyperactive in those with major depressive disorder. The amygdala in unmedicated depressed persons tended to be smaller than in those that were medicated, however aggregate data shows no difference between depressed and healthy persons. During emotional processing tasks right amygdala is more active than the left, however there is no differences during cognitive tasks, and at rest only the left amygdala appears to be more hyperactive. One study, however, found no difference in amygdala activity during emotional processing tasks.
Atrophy of the hippocampus has been observed during depression, consistent with animal models of stress and neurogenesis.
Stress can cause depression and depression-like symptoms through monoaminergic changes in several key brain regions as well as suppression in hippocampal neurogenesis. This leads to alteration in emotion and cognition related brain regions as well as HPA axis dysfunction. Through the dysfunction, the effects of stress can be exacerbated including its effects on 5-HT. Furthermore, some of these effects are reversed by antidepressant action, which may act by increasing hippocampal neurogenesis. This leads to a restoration in HPA activity and stress reactivity, thus restoring the deleterious effects induced by stress on 5-HT.
The hypothalamic-pituitary-adrenal axis is a chain of endocrine structures that are activated during the body’s response to stressors of various sorts. The HPA axis involves three structure, the hypothalamus which release CRH that stimulates the pituitary gland to release ACTH which stimulates the adrenal glands to release cortisol. Cortisol has a negative feedback effect on the pituitary gland and hypothalamus. In people with MDD this often shows increased activation in depressed people, but the mechanism behind this is not yet known. Increased basal cortisol levels and abnormal response to dexamethasone challenges have been observed in people with MDD. Early life stress has been hypothesized as a potential cause of HPA dysfunction. HPA axis regulation may be examined through a dexamethasone suppression tests, which tests the feedback mechanisms. Non-suppression of dexamethasone is a common finding in depression, but is not consistent enough to be used as a diagnostic tool. HPA axis changes may be responsible for some of the changes such as decreased bone mineral density and increased weight found in people with MDD. One drug, ketoconazole, currently under development has shown promise in treating MDD.
Reduced hippocampal neurogenesis leads to a reduction in hippocampal volume. A genetically smaller hippocampus has been linked to a reduced ability to process psychological trauma and external stress, and subsequent predisposition to psychological illness. Depression without familial risk or childhood trauma has been linked to a normal hippocampal volume but localised dysfunction.
A number of animal models exist for depression, but they are limited in that depression involves primarily subjective emotional changes. However, some of these changes are reflected in physiology and behaviour, the latter of which is the target of many animal models. These models are generally assessed according to four facets of validity; the reflection of the core symptoms in the model; the predictive validity of the model; the validity of the model with regard to human characteristics of aetiology; and the biological plausibility.
Different models for inducing depressive behaviours have been utilised; neuroanatomical manipulations such as olfactory bulbectomy or circuit specific manipulations with optogenetics; genetic models such as 5-HT1A knockout or selectively bred animals; models involving environmental manipulation associated with depression in humans, including chronic mild stress, early life stress and learned helplessness. The validity of these models in producing depressive behaviours may be assessed with a number of behavioural tests. Anhedonia and motivational deficits may, for example, be assessed via examining an animal’s level of engagement with rewarding stimuli such as sucrose or intracranial self-stimulation. Anxious and irritable symptoms may be assessed with exploratory behaviour in the presence of a stressful or novelty environment, such as the open field test, novelty suppressed feeding, or the elevated plus-maze. Fatigue, psychomotor poverty, and agitation may be assessed with locomotor activity, grooming activity, and open field tests.
Animal models possess a number of limitations due to the nature of depression. Some core symptoms of depression, such as rumination, low self-esteem, guilt, and depressed mood cannot be assessed in animals as they require subjective reporting. From an evolutionary standpoint, the behaviour correlates of defeats of loss are thought to be an adaptive response to prevent further loss. Therefore, attempts to model depression that seeks to induce defeat or despair may actually reflect adaption and not disease. Furthermore, while depression and anxiety are frequently comorbid, dissociation of the two in animal models is difficult to achieve. Pharmacological assessment of validity is frequently disconnected from clinical pharmacotherapeutics in that most screening tests assess acute effects, while antidepressants normally take a few weeks to work in humans.
Regions involved in reward are common targets of manipulation in animal models of depression, including the nucleus accumbens (NAc), ventral tegmental area (VTA), ventral pallidum (VP), lateral habenula (LHb) and medial prefrontal cortex (mPFC). Tentative fMRI studies in humans demonstrate elevated LHb activity in depression. The lateral habenula projects to the RMTg to drive inhibition of dopamine neurons in the VTA during omission of reward. In animal models of depression, elevated activity has been reported in LHb neurons that project to the ventral tegmental area (ostensibly reducing dopamine release). The LHb also projects to aversion reactive mPFC neurons, which may provide an indirect mechanism for producing depressive behaviours. Learned helplessness induced potentiation of LHb synapses are reversed by antidepressant treatment, providing predictive validity. A number of inputs to the LHb have been implicated in producing depressive behaviours. Silencing GABAergic projections from the NAc to the LHb reduces conditioned place preference induced in social aggression, and activation of these terminals induces CPP. Ventral pallidum firing is also elevated by stress induced depression, an effect that is pharmacologically valid, and silencing of these neurons alleviates behavioural correlates of depression. Tentative in vivo evidence from people with MDD suggests abnormalities in dopamine signalling. This led to early studies investigating VTA activity and manipulations in animal models of depression. Massive destruction of VTA neurons enhances depressive behaviours, while VTA neurons reduce firing in response to chronic stress. However, more recent specific manipulations of the VTA produce varying results, with the specific animal model, duration of VTA manipulation, method of VTA manipulation, and subregion of VTA manipulation all potentially leading to differential outcomes. Stress and social defeat induced depressive symptoms, including anhedonia, are associated with potentiation of excitatory inputs to Dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) and depression of excitatory inputs to Dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs). Optogenetic excitation of D1-MSNs alleviates depressive symptoms and is rewarding, while the same with D2-MSNs enhances depressive symptoms. Excitation of glutaminergic inputs from the ventral hippocampus reduces social interactions, and enhancing these projections produces susceptibility to stress-induced depression. Manipulations of different regions of the mPFC can produce and attenuate depressive behaviours. For example, inhibiting mPFC neurons specifically in the intralimbic cortex attenuates depressive behaviours. The conflicting findings associated with mPFC stimulation, when compared to the relatively specific findings in the infralimbic cortex, suggest that the prelimbic cortex and infralimbic cortex may mediate opposing effects. mPFC projections to the raphe nuclei are largely GABAergic and inhibit the firing of serotonergic neurons. Specific activation of these regions reduce immobility in the forced swim test but do not affect open field or forced swim behaviour. Inhibition of the raphe shifts the behavioural phenotype of uncontrolled stress to a phenotype closer to that of controlled stress.
Recent studies have called attention to the role of altered neuroplasticity in depression. A review found a convergence of three phenomena:
Chronic stress reduces synaptic and dendritic plasticity;
Depressed subjects show evidence of impaired neuroplasticity (e.g. shortening and reduced complexity of dendritic trees); and
Anti-depressant medications may enhance neuroplasticity at both a molecular and dendritic level.
The conclusion is that disrupted neuroplasticity is an underlying feature of depression, and is reversed by antidepressants.
Blood levels of BDNF in people with MDD increase significantly with antidepressant treatment and correlate with decrease in symptoms. Post mortem studies and rat models demonstrate decreased neuronal density in the prefrontal cortex thickness in people with MDD. Rat models demonstrate histological changes consistent with MRI findings in humans, however studies on neurogenesis in humans are limited. Antidepressants appear to reverse the changes in neurogenesis in both animal models and humans.
Various reviews have found that general inflammation may play a role in depression. One meta analysis of cytokines in people with MDD found increased levels of pro-inflammatory IL-6 and TNF-a levels relative to controls. The first theories came about when it was noticed that interferon therapy caused depression in a large number of people receiving it. Meta analysis on cytokine levels in people with MDD have demonstrated increased levels of IL-1, IL-6, C-reactive protein, but not IL-10. Increased numbers of T-Cells presenting activation markers, levels of neopterin, IFN gamma, sTNFR, and IL-2 receptors have been observed in depression. Various sources of inflammation in depressive illness have been hypothesized and include trauma, sleep problems, diet, smoking and obesity. Cytokines, by manipulating neurotransmitters, are involved in the generation of sickness behaviour, which shares some overlap with the symptoms of depression. Neurotransmitters hypothesized to be affected include dopamine and serotonin, which are common targets for antidepressant drugs. Induction of indolamine-2,3 dioxygenease by cytokines has been proposed as a mechanism by which immune dysfunction causes depression. One review found normalization of cytokine levels after successful treatment of depression. A meta analysis published in 2014 found the use of anti-inflammatory drugs such as NSAIDs and investigational cytokine inhibitors reduced depressive symptoms. Exercise can act as a stressor, decreasing the levels of IL-6 and TNF-a and increasing those of IL-10, an anti-inflammatory cytokine.
Inflammation is also intimately linked with metabolic processes in humans. For example, low levels of Vitamin D have been associated with greater risk for depression. The role of metabolic biomarkers in depression is an active research area. Recent work has explored the potential relationship between plasma sterols and depressive symptom severity.
A marker of DNA oxidation, 8-Oxo-2′-deoxyguanosine, has been found to be increased in both the plasma and urine of people with MDD. This along with the finding of increased F2-isoprostanes levels found in blood, urine and cerebrospinal fluid indicate increased damage to lipids and DNA in people with MDD. Studies with 8-Oxo-2′ Deoxyguanosine varied by methods of measurement and type of depression, but F2-Isoprostane level was consistent across depression types. Authors suggested lifestyle factors, dysregulation of the HPA axis, immune system and autonomics nervous system as possible causes. Another meta-analysis found similar results with regards to oxidative damage products as well as decreased oxidative capacity. Oxidative DNA damage may play a role in MDD.
Increased markers of oxidative stress relative to controls have been found in people with MDD. These markers include high levels of RNS and ROS which have been shown to influence chronic inflammation, damaging the electron transport chain and biochemical cascades in mitochondria. This lowers the activity of enzymes in the respiratory chain resulting in mitochondrial dysfunction. The brain is a highly energy-consuming and has little capacity to store glucose as glycogen and so depends greatly on mitochondria. Mitochondrial dysfunction has been linked to the dampened neuroplasticity observed in depressed brains.
Large-Scale Brain Network Theory
Instead of studying one brain region, studying large scale brain networks is another approach to understanding psychiatric and neurological disorders, supported by recent research that has shown that multiple brain regions are involved in these disorders. Understanding the disruptions in these networks may provide important insights into interventions for treating these disorders. Recent work suggests that at least three large-scale brain networks are important in psychopathology.
Central Executive Network
The central executive network is made up of fronto-parietal regions, including dorsolateral prefrontal cortex and lateral posterior parietal cortex. This network is involved in high level cognitive functions such as maintaining and using information in working memory, problem solving, and decision making. Deficiencies in this network are common in most major psychiatric and neurological disorders, including depression. Because this network is crucial for everyday life activities, those who are depressed can show impairment in basic activities like test taking and being decisive.
Default Mode Network
The default mode network includes hubs in the prefrontal cortex and posterior cingulate, with other prominent regions of the network in the medial temporal lobe and angular gyrus. The default mode network is usually active during mind-wandering and thinking about social situations. In contrast, during specific tasks probed in cognitive science (for example, simple attention tasks), the default network is often deactivated. Research has shown that regions in the default mode network (including medial prefrontal cortex and posterior cingulate) show greater activity when depressed participants ruminate (that is, when they engage in repetitive self-focused thinking) than when typical, healthy participants ruminate. People with MDD also show increased connectivity between the default mode network and the subgenual cingulate and the adjoining ventromedial prefrontal cortex in comparison to healthy individuals, individuals with dementia or with autism. Numerous studies suggest that the subgenual cingulate plays an important role in the dysfunction that characterizes major depression. The increased activation in the default mode network during rumination and the atypical connectivity between core default mode regions and the subgenual cingulate may underlie the tendency for depressed individual to get “stuck” in the negative, self-focused thoughts that often characterise depression. However, further research is needed to gain a precise understanding of how these network interactions map to specific symptoms of depression.
The salience network is a cingulate-frontal operculum network that includes core nodes in the anterior cingulate and anterior insula. A salience network is a large-scale brain network involved in detecting and orienting the most pertinent of the external stimuli and internal events being presented. Individuals who have a tendency to experience negative emotional states (scoring high on measures of neuroticism) show an increase in the right anterior insula during decision-making, even if the decision has already been made. This atypically high activity in the right anterior insula is thought to contribute to the experience of negative and worrisome feelings. In MDD, anxiety is often a part of the emotional state that characterises depression.