Common side effects include nausea, trouble sleeping, sexual problems, shakiness, feeling tired, and sweating. Serious side effects include an increased risk of suicide in those under the age of 25, serotonin syndrome, glaucoma, and QT prolongation. It should not be used in persons who take or have recently taken a MAO inhibitor. Antidepressant discontinuation syndrome may occur when stopped. There are concerns that use during pregnancy may harm the foetus.
Citalopram was approved for medical use in the United States in 1998. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2019, it was the 30th most commonly prescribed medication in the United States, with more than 21 million prescriptions.
Citalopram was first synthesized in 1972 by chemist Klaus Bøgesø and his research group at the pharmaceutical company Lundbeck and was first marketed in 1989 in Denmark. It was first marketed in the US in 1998. The original patent expired in 2003, allowing other companies to legally produce and market generic versions.
In the United States, citalopram is approved to treat major depressive disorder. Citalopram appears to have comparable efficacy and superior tolerability relative to other antidepressants. In the National Institute for Health and Clinical Excellence ranking of ten antidepressants for efficacy and cost-effectiveness, citalopram is fifth in effectiveness (after mirtazapine, escitalopram, venlafaxine, and sertraline) and fourth in cost-effectiveness. The ranking results were based on a 2009 meta-analysis by Andrea Cipriani; an update of the analysis in 2018 produced broadly similar results.
Evidence for effectiveness of citalopram for treating depression in children is uncertain.
Citalopram is licensed in the UK and other European countries for panic disorder, with or without agoraphobia.
Citalopram may be used off-label to treat anxiety, and dysthymia, premenstrual dysphoric disorder, body dysmorphic disorder, and obsessive-compulsive disorder (OCD).
It appears to be as effective as fluvoxamine and paroxetine in OCD. Some data suggest the effectiveness of intravenous infusion of citalopram in resistant OCD. Citalopram is well tolerated and as effective as moclobemide in social anxiety disorder. There are studies suggesting that citalopram can be useful in reducing aggressive and impulsive behaviour. It appears to be superior to placebo for behavioural disturbances associated with dementia. It has also been used successfully for hypersexuality in early Alzheimer’s disease.
A meta-analysis, including studies with fluoxetine, paroxetine, sertraline, escitalopram, and citalopram versus placebo, showed SSRIs to be effective in reducing symptoms of premenstrual syndrome, whether taken continuously or just in the luteal phase. For alcoholism, citalopram has produced a modest reduction in alcoholic drink intake and increase in drink-free days in studies of alcoholics, possibly by decreasing desire or reducing the reward.
While on its own citalopram is less effective than amitriptyline in the prevention of migraines, in refractory cases, combination therapy may be more effective.
Citalopram and other SSRIs can be used to treat hot flashes.
A 2009 multisite randomised controlled study found no benefit and some adverse effects in autistic children from citalopram, raising doubts whether SSRIs are effective for treating repetitive behaviour in children with autism.
Some research suggests citalopram interacts with cannabinoid protein-couplings in the rat brain, and this is put forward as a potential cause of some of the drug’s antidepressant effect.
Citalopram is typically taken in one dose, either in the morning or evening. It can be taken with or without food. Its absorption does not increase when taken with food, but doing so can help prevent nausea. Nausea is often caused when the 5HT3 receptors actively absorb free serotonin, as this receptor is present within the digestive tract. The 5HT3 receptors stimulate vomiting. This side effect, if present, should subside as the body adjusts to the medication.
Citalopram is considered safe and well tolerated in the therapeutic dose range. Distinct from some other agents in its class, it exhibits linear pharmacokinetics and minimal drug interaction potential, making it a better choice for the elderly or comorbid patients.
Sexual dysfunction is often a side effect with SSRIs.
Citalopram theoretically causes side effects by increasing the concentration of serotonin in other parts of the body (e.g. the intestines). Other side effects, such as increased apathy and emotional flattening, may be caused by the decrease in dopamine release associated with increased serotonin. Citalopram is also a mild antihistamine, which may be responsible for some of its sedating properties.
Other common side effects of citalopram include drowsiness, insomnia, nausea, weight changes (usually weight gain), increase in appetite, vivid dreaming, frequent urination, dry mouth, increased sweating, trembling, diarrhoea, excessive yawning, severe tinnitus, and fatigue. Less common side effects include bruxism, vomiting, cardiac arrhythmia, blood pressure changes, dilated pupils, anxiety, mood swings, headache, hyperactivity and dizziness. Rare side effects include convulsions, hallucinations, severe allergic reactions and photosensitivity. If sedation occurs, the dose may be taken at bedtime rather than in the morning. Some data suggests citalopram may cause nightmares. Citalopram is associated with a higher risk of arrhythmia than other SSRIs.
Withdrawal symptoms can occur when this medicine is suddenly stopped, such as paraesthesia, sleeping problems (difficulty sleeping and intense dreams), feeling dizzy, agitated or anxious, nausea, vomiting, tremors, confusion, sweating, headache, diarrhoea, palpitations, changes in emotions, irritability, and eye or eyesight problems. Treatment with citalopram should be reduced gradually when treatment is finished.
Citalopram and other SSRIs can induce a mixed state, especially in those with undiagnosed bipolar disorder. According to an article published in 2020, one of the other rare side effects of Citalopram could be triggering visual snow syndrome; which does not resolve after the discontinuation of the medicine.
Some people experience persistent sexual side effects after they stop taking SSRIs. This is known as Post-SSRI Sexual Dysfunction (PSSD). Common symptoms in these cases include genital anaesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication issues, and nipple insensitivity in women. The prevalence of PSSD is unknown, and there is no established treatment.
Abnormal Heart Rhythm
In August 2011, the US Food and Drug Administration (FDA) announced, “Citalopram causes dose-dependent QT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day”. A further clarification issued in March 2012, restricted the maximum dose to 20 mg for subgroups of patients, including those older than 60 years and those taking an inhibitor of cytochrome P450 2C19.7.
As with other SSRIs, citalopram can cause an increase in serum prolactin level. Citalopram has no significant effect on insulin sensitivity in women of reproductive age and no changes in glycaemic control were seen in another trial.
Exposure in Pregnancy
Antidepressant exposure (including citalopram) during pregnancy is associated with shorter duration of gestation (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). Antidepressant exposure is not associated with an increased risk of spontaneous abortion. It is uncertain whether there is an increased prevalence of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy.
Citalopram should not be taken with St John’s wort, tryptophan or 5-HTP as the resulting drug interaction could lead to serotonin syndrome. With St John’s wort, this may be caused by compounds in the plant extract reducing the efficacy of the hepatic cytochrome P450 enzymes that process citalopram. It has also been suggested that such compounds, including hypericin, hyperforin and flavonoids, could have SSRI-mimetic effects on the nervous system, although this is still subject to debate. One study found that Hypericum extracts had similar effects in treating moderate depression as citalopram, with fewer side effects.
Tryptophan and 5-HTP are precursors to serotonin. When taken with an SSRI, such as citalopram, this can lead to levels of serotonin that can be lethal. This may also be the case when SSRIs are taken with SRAs (serotonin releasing agents) such as in the case of MDMA. It is possible that SSRIs could reduce the effects associated due to an SRA, since SSRIs stop the reuptake of Serotonin by blocking SERT. This would allow less serotonin in and out of the transporters, thus decreasing the likelihood of neurotoxic effects. However, these concerns are still disputed as the exact pharmacodynamic effects of citalopram and MDMA have yet to be fully identified.
SSRIs, including citalopram, can increase the risk of bleeding, especially when coupled with aspirin, NSAIDs, warfarin, or other anticoagulants. Citalopram is contraindicated in individuals taking MAOIs, owing to a potential for serotonin syndrome.
Taking citalopram with omeprazole may cause higher blood levels of citalopram. This is a potentially dangerous interaction, so dosage adjustments may be needed or alternatives may be prescribed.
SSRI discontinuation syndrome has been reported when treatment is stopped. It includes sensory, gastrointestinal symptoms, dizziness, lethargy, and sleep disturbances, as well as psychological symptoms such as anxiety/agitation, irritability, and poor concentration. Electric shock-like sensations are typical for SSRI discontinuation. Tapering off citalopram therapy, as opposed to abrupt discontinuation, is recommended in order to diminish the occurrence and severity of discontinuation symptoms. Some doctors choose to switch a patient to Prozac (fluoxetine) when discontinuing citalopram as fluoxetine has a much longer half-life (i.e. stays in the body longer compared to citalopram). This may avoid many of the severe withdrawal symptoms associated with citalopram discontinuation. This can be done either by administering a single 20 mg dose of fluoxetine or by beginning on a low dosage of fluoxetine and slowly tapering down. Either of these prescriptions may be written in liquid form to allow a very slow and gradual tapering down in dosage. Alternatively, a patient wishing to stop taking citalopram may visit a compounding pharmacy where their prescription may be re-arranged into progressively smaller dosages.
Overdosage may result in vomiting, sedation, disturbances in heart rhythm, dizziness, sweating, nausea, tremor, and rarely amnesia, confusion, coma, or convulsions. Overdose deaths have occurred, sometimes involving other drugs, but also with citalopram as the sole agent. Citalopram and N-desmethylcitalopram may be quantified in blood or plasma to confirm a diagnosis of poisoning in hospitalised patients or to assist in a medicolegal death investigation. Blood or plasma citalopram concentrations are usually in a range of 50-400 μg/l in persons receiving the drug therapeutically, 1000-3000 μg/l in patients who survive acute overdosage and 3-30 mg/l in those who do not survive. It is the most dangerous of SSRIs in overdose.
In the United States, citalopram carries a boxed warning stating it may increase suicidal thinking and behaviour in those under age 24.
Citalopram has one stereocentre, to which a 4-fluoro phenyl group and an N, N-dimethyl-3-aminopropyl group bind. As a result of this chirality, the molecule exists in (two) enantiomeric forms (mirror images). They are termed S-(+)-citalopram and R-(–)-citalopram.
Citalopram is sold as a racemic mixture, consisting of 50% (R)-(−)-citalopram and 50% (S)-(+)-citalopram. Only the (S)-(+) enantiomer has the desired antidepressant effect. Lundbeck now markets the (S)-(+) enantiomer, the generic name of which is escitalopram. Whereas citalopram is supplied as the hydrobromide, escitalopram is sold as the oxalate salt (hydrooxalate). In both cases, the salt forms of the amine make these otherwise lipophilic compounds water-soluble.
Citalopram is metabolised in the liver mostly by CYP2C19, but also by CYP3A4 and CYP2D6. Metabolites desmethylcitalopram and didesmethylcitalopram are significantly less energetic and their contribution to the overall action of citalopram is negligible. The half-life of citalopram is about 35 hours. Approximately 80% is cleared by the liver and 20% by the kidneys. The elimination process is slower in the elderly and in patients with liver or kidney failure. With once-daily dosing, steady plasma concentrations are achieved in about a week. Potent inhibitors of CYP2C19 and 3A4 might decrease citalopram clearance. Tobacco smoke exposure was found to inhibit the biotransformation of citalopram in animals, suggesting that the elimination rate of citalopram is decreased after tobacco smoke exposure. After intragastric administration, the half-life of the racemic mixture of citalopram was increased by about 287%.
Society and Culture
Citalopram is sold under these brand names:
Akarin (Denmark, Nycomed).
C Pram S (India).
Celapram (Australia and New Zealand).
Celexa (US and Canada, Forest Laboratories, Inc.).
Ciazil (Australia and New Zealand).
Cilate (South Africa).
Cilift (South Africa).
Cimal (South America, by Roemmers and Recalcine).
Cipralex (South Africa).
Cipram (Denmark and Turkey, H. Lundbeck A/S).
Cipramil (Australia, Brazil, Belgium, Chile, Finland, Germany, Netherlands, Iceland, Ireland, Israel, New Zealand, Norway, Russia, South Africa, Sweden, and the United Kingdom).
Cipraned, Cinapen (Greece).
Citabax, Citaxin (Poland).
Citalec (Czech Republic and Slovakia).
Citalex (Iran and Serbia).
Citalo (Australia, Egypt, and Pakistan).
Citalopram (Canada, Denmark, Finland, Germany, Ireland, New Zealand, Spain, Sweden, Switzerland, United Kingdom, the US).
Citrol (Europe and Australia).
Dalsan (Eastern Europe).
Humorap (Peru, Bolivia).
Oropram (Iceland, Actavis).
Recital (Israel, Thrima Inc. for Unipharm Ltd.).
Seropram (various European countries, including Czech Republic).
Talam (Europe and Australia).
Temperax (Argentina, Chile, and Peru).
Zentius (South America, by Roemmers and Recalcine).
Cipratal (Kuwait, GCC).
European Commission Fine
On 19 June 2013, the European Commission imposed a fine of €93.8 million on the Danish pharmaceutical company Lundbeck, plus a total of €52.2 million on several generic pharmaceutical-producing companies. This was in response to Lundbeck entering an agreement with the companies to delay their sales of generic citalopram after Lundbeck’s patent on the drug had expired, thus reducing competition in breach of European antitrust law.
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.
Light therapy – or phototherapy, classically referred to as heliotherapy – is a method recognised by scientific medicine for the treatment of various diseases. It includes exposure to outdoor daylight or specific indoor artificial light sources.
The care guideline for unipolar depression recommends light therapy especially for depression that follows a seasonal pattern (seasonal affective disorder). There is tentative evidence to support its use to treat depressive disorders that are not seasonally dependent. As a treatment for disorders of the skin, the second kind of light therapy, called ultraviolet light therapy, is meant to treat neurodermatitis, psoriasis, acne vulgaris, eczema and neonatal jaundice.
Many ancient cultures practiced various forms of heliotherapy, including people of Ancient Greece, Ancient Egypt, and Ancient Rome. The Inca, Assyrian and early German settlers also worshipped the sun as a health bringing deity. Indian medical literature dating to 1500 BCE describes a treatment combining herbs with natural sunlight to treat non-pigmented skin areas. Buddhist literature from about 200 CE and 10th-century Chinese documents make similar references.
The Faroese physician Niels Finsen is believed to be the father of modern phototherapy. He developed the first artificial light source for this purpose. Finsen used short wavelength light to treat lupus vulgaris, a skin infection caused by Mycobacterium tuberculosis. He thought that the beneficial effect was due to ultraviolet light killing the bacteria, but recent studies showed that his lens and filter system did not allow such short wavelengths to pass through, leading instead to the conclusion that light of approximately 400 nanometers generated reactive oxygen that would kill the bacteria. Finsen also used red light to treat smallpox lesions. He received the Nobel Prize in Physiology or Medicine in 1903. Scientific evidence for some of his treatments is lacking, and later eradication of smallpox and development of antibiotics for tuberculosis rendered light therapy obsolete for these diseases.
From the late nineteenth century until the early 1930s, light therapy was considered an effective and mainstream medical therapy in the UK for conditions such as varicose ulcer, ‘sickly children’ and a wide range of other conditions. Controlled trials by the medical scientist Dora Colebrook, supported by the Medical Research Council, indicated that light therapy was not effective for such a wide range of conditions.
Light therapy treatments for the skin usually involve exposure to ultraviolet light. The exposures can be to a small area of the skin or over the whole body surface, as in a tanning bed. The most common treatment is with narrowband UVB, which has a wavelength of approximately 311-313 nanometers. Exposure to photons (light) at these specific wavelengths enables the body to produce vitamin D. Full body phototherapy can be delivered at a doctor’s office or at home using a large high-power UVB booth. Tanning beds, however, generate mostly UVA light, and only 4% to 10% of tanning bed light is in the UVB spectrum.
Light therapy is considered one of the best monotherapy treatments for atopic dermatitis (AD) when applied to patients who have not responded to traditional topical treatments. The therapy offers a wide range of options: UVA1 for acute AD, NB-UVB for chronic AD, and balneophototherapy have proven their efficacy. Patients tolerate the therapy safely but, as in any therapy, there are potential adverse effects and care must be taken in its application, particularly to children.
For psoriasis, UVB phototherapy has been shown to be effective. A feature of psoriasis is localised inflammation mediated by the immune system. Ultraviolet radiation is known to suppress the immune system and reduce inflammatory responses. Light therapy for skin conditions like psoriasis usually use 313 nanometer UVB though it may use UVA (315-400 nm wavelength) or a broader spectrum UVB (280-315 nm wavelength). UVA combined with psoralen, a drug taken orally, is known as PUVA treatment. In UVB phototherapy the exposure time is very short, seconds to minutes depending on intensity of lamps and the person’s skin pigment and sensitivity.
About 1% of the human population suffers from vitiligo which causes painless distinct light-coloured patches of the skin on the face, hands, and legs. Phototherapy is an effective treatment because it forces skin cells to manufacture melanin to protect the body from UV damage. Prescribed treatment is generally 3 times a week in a clinic or daily at home. About 1 month usually results in re-pigmentation in the face and neck, and 2-4 months in the hands and legs. Narrowband UVB is more suitable to the face and neck and PUVA is more effective at the hands and legs.]
As of 2012 evidence for light therapy and lasers in the treatment of acne vulgaris was not sufficient to recommend them. There is moderate evidence for the efficacy of blue and blue-red light therapies in treating mild acne, but most studies are of low quality. While light therapy appears to provide short-term benefit, there is a lack of long-term outcome data or data in those with severe acne.
According to the American Cancer Society, there is some evidence that ultraviolet light therapy may be effective in helping treat certain kinds of skin cancer, and ultraviolet blood irradiation therapy is established for this application. However, alternative uses of light for cancer treatment – light box therapy and coloured light therapy – are not supported by evidence. Photodynamic therapy (often with red light) is used to treat certain superficial non-melanoma skin cancers.
Other Skin Conditions
Some types of phototherapy may be effective in the treatment of polymorphous light eruption, cutaneous T-cell lymphoma and lichen planus. Narrowband UVB between 311-313 nanometers is the most common treatment.
Low level laser therapy has been studied as a potential treatment for chronic wounds, and higher-power lasers have sometimes been successfully used to close acute wounds as an alternative to stitching. However, as of 2012 and due to inconsistent results and the low quality of extant research, reviews in the scientific literature have not supported its widespread application.
There is preliminary evidence that light therapy is an effective treatment for diabetic retinopathy and diabetic macular oedema.
Mood and Sleep Related
Seasonal Affective Disorder
The effectiveness of light therapy for treating seasonal affective disorder (SAD) may be linked to the fact that light therapy makes up for lost sunlight exposure and resets the body’s internal clock. Studies show that light therapy helps reduce the debilitating and depressive behaviours of SAD, such as excessive sleepiness and fatigue, with results lasting for at least 1 month. Light therapy is preferred over antidepressants in the treatment of SAD because it is a relatively safe and easy therapy. Two methods of light therapy, bright light and dawn simulation, have similar success rates in the treatment of SAD.
It is possible that response to light therapy for SAD could be season dependent. Morning therapy has provided the best results because light in the early morning aids in regulating the circadian rhythm. People affected by SAD have low levels of energy and have difficulty concentrating. They usually have a change in appetite and experience trouble sleeping.
A 2007 systematic review by the Swedish agency SBU found insufficient evidence that light therapy was able to alleviate symptoms of depression or seasonal affective disorder. The report recommended that: “Approximately 100 participants are required to establish whether the therapy is moderately more effective than placebo”. Although treatment in light therapy rooms was well established in Sweden, no satisfactory, controlled studies had been published on the subject. This led to the closure of a number of clinics offering light therapy in Sweden.
A Cochrane review conducted in 2019 states the evidence that light therapy’s effectiveness as a treatment for the prevention of seasonal affective disorder is limited, although the risk of adverse effects are minimal. Therefore, the decision to use light therapy should be based on a person’s preference of treatment.
Light therapy has also been suggested in the treatment of non-seasonal depression and other psychiatric mood disturbances, including major depressive disorder, bipolar disorder and postpartum depression. A meta-analysis by the Cochrane Collaboration concluded that “for patients suffering from non-seasonal depression, light therapy offers modest though promising antidepressive efficacy.” A 2008 systematic review concluded that “overall, bright light therapy is an excellent candidate for inclusion into the therapeutic inventory available for the treatment of nonseasonal depression today, as adjuvant therapy to antidepressant medication, or eventually as stand-alone treatment for specific subgroups of depressed patients.” A 2015 review found that supporting evidence for light therapy was limited due to serious methodological flaws.
A 2016 meta-analysis showed that bright light therapy appeared to be efficacious, particularly when administered for 2-5 weeks’ duration and as monotherapy.
Chronic Circadian Rhythm Sleep Disorders (CRSD)
In the management of circadian rhythm disorders such as delayed sleep phase disorder (DSPD), the timing of light exposure is critical. Light exposure administered to the eyes before or after the nadir of the core body temperature rhythm can affect the phase response curve. Use upon awakening may also be effective for non-24-hour sleep-wake disorder. Some users have reported success with lights that turn on shortly before awakening (dawn simulation). Evening use is recommended for people with advanced sleep phase disorder. Some, but not all, totally blind people whose retinae are intact, may benefit from light therapy.
Light therapy has been tested for individuals with shift work sleep disorder and for jet lag.
Sleep Disorder in Parkinson’s Disease
Light therapy has been trialled in treating sleep disorders experienced by patients with Parkinson’s disease.
Sleep Disorder in Alzheimer’s Disease
Studies have shown that daytime and evening light therapy for nursing home patients with Alzheimer’s disease, who often struggle with agitation and fragmented wake/rest cycles effectively led to more consolidated sleep and an increase in circadian rhythm stability.
Neonatal Jaundice (Postnatal Jaundice)
Light therapy is used to treat cases of neonatal jaundice. Bilirubin, a yellow pigment normally formed in the liver during the breakdown of old red blood cells, cannot always be effectively cleared by a neonate’s liver causing neonatal jaundice. Accumulation of excess bilirubin can cause central nervous system damage, and so this buildup of bilirubin must be treated. Phototherapy uses the energy from light to isomerize the bilirubin and consequently transform it into compounds that the newborn can excrete via urine and stools. Bilirubin is most successful absorbing light in the blue region of the visible light spectrum, which falls between 460-490 nm. Therefore light therapy technologies that utilise these blue wavelengths are the most successful at isomerising bilirubin.
Photodynamic therapy is a form of phototherapy using nontoxic light-sensitive compounds that are exposed selectively to light, whereupon they become toxic to targeted malignant and other diseased cells.
One of the treatments is using blue light with aminolevulinic acid for the treatment of actinic keratosis. This is not a U.S. FDA-approved treatment for acne vulgaris.
The production of the hormone melatonin, a sleep regulator, is inhibited by light and permitted by darkness as registered by photosensitive ganglion cells in the retina. To some degree, the reverse is true for serotonin, which has been linked to mood disorders. Hence, for the purpose of manipulating melatonin levels or timing, light boxes providing very specific types of artificial illumination to the retina of the eye are effective.
Light therapy uses either a light box which emits up to 10,000 lux of light at a specified distance, much brighter than a customary lamp, or a lower intensity of specific wavelengths of light from the blue (460 nm) to the green (525 nm) areas of the visible spectrum. A 1995 study showed that green light therapy at doses of 350 lux produces melatonin suppression and phase shifts equivalent to 10,000 lux white light therapy, but another study published in May 2010 suggests that the blue light often used for SAD treatment should perhaps be replaced by green or white illumination, because of a possible involvement of the cones in melatonin suppression.
Risks and Complications
Ultraviolet light causes progressive damage to human skin and erythema even from small doses. This is mediated by genetic damage, collagen damage, as well as destruction of vitamin A and vitamin C in the skin and free radical generation. Ultraviolet light is also known to be a factor in formation of cataracts. Ultraviolet radiation exposure is strongly linked to incidence of skin cancer.
Optical radiation of any kind with enough intensity can cause damage to the eyes and skin including photoconjunctivitis and photokeratitis. Researchers have questioned whether limiting blue light exposure could reduce the risk of age-related macular degeneration. According to the American Academy of Ophthalmology, there is no scientific evidence showing that exposure to blue light emitting devices result in eye damage. According to Harriet Hall, blue light exposure is reported to suppress the production of melatonin, which affects our body’s circadian rhythm and can decrease sleep quality. It is reported that bright light therapy may activate the production of reproductive hormones, such as testosterone, luteinizing hormone, follicle-stimulating hormone, and estradiol.
Modern phototherapy lamps used in the treatment of seasonal affective disorder and sleep disorders either filter out or do not emit ultraviolet light and are considered safe and effective for the intended purpose, as long as photosensitising drugs are not being taken at the same time and in the absence of any existing eye conditions. Light therapy is a mood altering treatment, and just as with drug treatments, there is a possibility of triggering a manic state from a depressive state, causing anxiety and other side effects. While these side effects are usually controllable, it is recommended that patients undertake light therapy under the supervision of an experienced clinician, rather than attempting to self-medicate.
Contraindications to light therapy for seasonal affective disorder include conditions that might render the eyes more vulnerable to phototoxicity, tendency toward mania, photosensitive skin conditions, or use of a photosensitising herb (such as St. John’s wort) or medication. Patients with porphyria should avoid most forms of light therapy. Patients on certain drugs such as methotrexate or chloroquine should use caution with light therapy as there is a chance that these drugs could cause porphyria.
Side effects of light therapy for sleep phase disorders include jumpiness or jitteriness, headache, eye irritation and nausea. Some non-depressive physical complaints, such as poor vision and skin rash or irritation, may improve with light therapy.
It is used for the treatment of obsessive-compulsive disorder (OCD), panic disorder, major depressive disorder (MDD), and chronic pain. It may increase the risk of suicide in those under the age of 25. It is taken by mouth. It has also been used to treat premature ejaculation.
Common side effects include dry mouth, constipation, loss of appetite, sleepiness, weight gain, sexual dysfunction, and trouble urinating. Serious side effects include an increased risk of suicidal behaviour in those under the age of 25, seizures, mania, and liver problems. If stopped suddenly a withdrawal syndrome may occur with headaches, sweating, and dizziness. It is unclear if it is safe for use in pregnancy. Its mechanism of action is not entirely clear but is believed to involve increased levels of serotonin.
Clomipramine was discovered in 1964 by the Swiss drug manufacturer Ciba-Geigy. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication.
Clomipramine was developed by Geigy as a chlorinated derivative of Imipramine. It was first referenced in the literature in 1961 and was patented in 1963. The drug was first approved for medical use in Europe in the treatment of depression in 1970, and was the last of the major TCAs to be marketed. In fact, clomipramine was initially considered to be a “me-too drug” by the FDA, and in relation to this, was declined licensing for depression in the United States. As such, to this day, clomipramine remains the only TCA that is available in the United States that is not approved for the treatment of depression, in spite of the fact that it is a highly effective antidepressant. Clomipramine was eventually approved in the United States for the treatment of OCD in 1989 and became available in 1990. It was the first drug to be investigated and found effective in the treatment of OCD. The first reports of benefits in OCD were in 1967, and the first double-blind, placebo-controlled clinical trial of clomipramine for OCD was conducted in 1976, with more rigorous clinical studies that solidified its effectiveness conducted in the 1980s. It remained the “gold standard” for the treatment of OCD for many years until the introduction of the SSRIs, which have since largely superseded it due to greatly improved tolerability and safety (although notably not effectiveness). Clomipramine is the only TCA that has been shown to be effective in the treatment of OCD and that is approved by the US Food and Drug Administration (FDA) for the treatment of OCD; the other TCAs failed clinical trials for this indication, likely due to insufficient serotonergic activity.
Clomipramine has a number of uses in medicine including in the treatment of:
OCD which is its only US Food and Drug Administration (FDA)-labelled indication. Other regulatory agencies (such as the TGA of Australia and the MHRA of the UK) have also approved clomipramine for this indication.
MDD a popular off-label use in the US. It is approved by the Australian TGA and the United Kingdom MHRA for this indication. Some have suggested the possible superior efficacy of clomipramine compared to other antidepressants in the treatment of MDD, although at the current time the evidence is insufficient to adequately substantiate this claim.
Chronic pain with or without organic disease, particularly headache of the tension type.
Sleep paralysis, with or without narcolepsy.
Enuresis (involuntary urinating in sleep) in children. The effect may not be sustained following treatment, and alarm therapy may be more effective in both the short-term and the long-term. Combining a tricyclic (such as clomipramine) with anticholinergic medication, may be more effective for treating enuresis than the tricyclic alone.
In a meta-analysis of various trials involving fluoxetine (Prozac), fluvoxamine (Luvox), and sertraline (Zoloft) to test their relative efficacies in treating OCD, clomipramine was found to be the most effective.
Known hypersensitivity to clomipramine, or any of the excipients or cross-sensitivity to tricyclic antidepressants of the dibenzazepine group.
Recent myocardial infarction.
Any degree of heart block or other cardiac arrhythmias.
Severe liver disease.
Narrow angle glaucoma.
It must not be given in combination or within 3 weeks before or after treatment with a monoamine oxidase inhibitor (Moclobemide included, however clomipramine can be initiated sooner at 48 hours following discontinuation of moclobemide).
Pregnancy and Lactation
Clomipramine use during pregnancy is associated with congenital heart defects in the newborn. It is also associated with reversible withdrawal effects in the newborn. Clomipramine is also distributed in breast milk and hence nursing while taking clomipramine is advised against.
Clomipramine has been associated with the following side effects:
Very common (>10% frequency):
Dry mouth (Xerostomia).
Sexual dysfunction (erectile dysfunction and loss of libido).
Hyperhidrosis (profuse sweating).
Common (1-10% frequency):
Clinically irrelevant ECG changes (e.g. T- and ST-wave changes) in patients of normal cardiac status.
Tinnitus (hearing ringing in one’s ears).
Mydriasis (dilated pupils).
Increased Alkaline phosphatase.
Disturbance in attention.
Hallucinations (particularly in elderly patients and patients with Parkinson’s disease).
Galactorrhoea (lactation that is not associated with pregnancy or breastfeeding).
Dermatitis allergic (skin rash, urticaria).
Uncommon (0.1-1% frequency):
Elevated blood pressure.
Activation of psychotic symptoms.
Very rare (<0.01% frequency):
Pancytopaenia: An abnormally low amount of all the different types of blood cells in the blood (including platelets, white blood cells and red blood cells).
Leukopenia: A low white blood cell count.
Agranulocytosis: A more severe form of leukopenia; a dangerously low neutrophil count which leaves one open to life-threatening infections due to the role of the white blood cells in defending the body from invaders.
Thrombocytopenia: An abnormally low amount of platelets in the blood which are essential to clotting and hence this leads to an increased tendency to bruise and bleed, including, potentially, internally.
Eosinophilia: An abnormally high number of eosinophils – the cells that fight off parasitic infections – in the blood.
Syndrome of inappropriate secretion of antidiuretic hormone (SIADH): A potentially fatal reaction to certain medications that is due to an excessive release of antidiuretic hormone – a hormone that prevents the production of urine by increasing the reabsorption of fluids in the kidney – this results in the development of various electrolyte abnormalities (e.g. hyponatraemia [low blood sodium], hypokalaemia [low blood potassium], hypocalcaemia [low blood calcium]).
Oedema (local or generalised).
Alopecia (hair loss).
Hyperpyrexia (a high fever that is above 41.5 °C).
Hepatitis (liver swelling) with or without jaundice: The yellowing of the eyes, the skin, and mucous membranes due to impaired liver function.
Anaphylactic and anaphylactoid reactions including hypotension.
Neuroleptic malignant syndrome (NMS): A potentially fatal side effect of antidopaminergic agents such as antipsychotics, tricyclic antidepressants and antiemetics (drugs that relieve nausea and vomiting). NMS develops over a period of days or weeks and is characterised by the following symptoms:
Mental status change (such as confusion, delirium, mania, hypomania, agitation, coma, etc.).
Hyperthermia (high body temperature).
Tachycardia (high heart rate).
Blood pressure changes.
Diaphoresis (sweating profusely).
Alveolitis allergic (pneumonitis) with or without eosinophilia.
Conduction disorder (e.g. widening of QRS complex, prolonged QT interval, PR/PQ interval changes, bundle-branch block, torsade de pointes, particularly in patients with hypokalaemia).
Withdrawal symptoms may occur during gradual or particularly abrupt withdrawal of tricyclic antidepressant drugs. Possible symptoms include: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, anxiety, dizziness and worsening of psychiatric status. Differentiating between the return of the original psychiatric disorder and clomipramine withdrawal symptoms is important. Clomipramine withdrawal can be severe. Withdrawal symptoms can also occur in neonates when clomipramine is used during pregnancy. A major mechanism of withdrawal from tricyclic antidepressants is believed to be due to a rebound effect of excessive cholinergic activity due to neuroadaptations as a result of chronic inhibition of cholinergic receptors by tricyclic antidepressants. Restarting the antidepressant and slow tapering is the treatment of choice for tricyclic antidepressant withdrawal. Some withdrawal symptoms may respond to anticholinergics, such as atropine or benztropine mesylate.
Clomipramine overdose usually presents with the following symptoms:
Signs of central nervous system depression such as:
Athetoid and choreoathetoid movements.
Serotonin syndrome: A condition with many of the same symptoms as neuroleptic malignant syndrome but has a significantly more rapid onset.
Cardiovascular effects including:
Arrhythmias (including Torsades de pointes).
QTc interval prolongation.
There is no specific antidote for overdose and all treatment is purely supportive and symptomatic. Treatment with activated charcoal may be used to limit absorption in cases of oral overdose. Anyone suspected of overdosing on clomipramine should be hospitalised and kept under close surveillance for at least 72 hours. Clomipramine has been reported as being less toxic in overdose than most other TCAs in one meta-analysis but this may well be due to the circumstances surrounding most overdoses as clomipramine is more frequently used to treat conditions for which the rate of suicide is not particularly high such as OCD. In another meta-analysis, however, clomipramine was associated with a significant degree of toxicity in overdose.
Clomipramine may interact with a number of different medications, including the monoamine oxidase inhibitors which include isocarboxazid, moclobemide, phenelzine, selegiline and tranylcypromine, antiarrhythmic agents (due to the effects of TCAs like clomipramine on cardiac conduction. There is also a potential pharmacokinetic interaction with quinidine due to the fact that clomipramine is metabolised by CYP2D6 in vivo), diuretics (due to the potential for hypokalaemia (low blood potassium) to develop which increases the risk for QT interval prolongation and torsades de pointes), the selective serotonin reuptake inhibitors (SSRIs; due to both potential additive serotonergic effects leading to serotonin syndrome and the potential for a pharmacokinetic interaction with the SSRIs that inhibit CYP2D6 [e.g. fluoxetine and paroxetine]) and serotonergic agents such as triptans, other tricyclic antidepressants, tramadol, etc. (due to the potential for serotonin syndrome). Its use is also advised against in those concurrently on CYP2D6 inhibitors due to the potential for increased plasma levels of clomipramine and the resulting potential for CNS and cardiotoxicity.
Clomipramine is a reuptake inhibitor of serotonin and norepinephrine, or a serotonin-norepinephrine reuptake inhibitor (SNRI); that is, it blocks the reuptake of these neurotransmitters back into neurons by preventing them from interacting with their transporters, thereby increasing their extracellular concentrations in the synaptic cleft and resulting in increased serotonergic and noradrenergic neurotransmission. In addition, clomipramine also has antiadrenergic, antihistamine, antiserotonergic, antidopaminergic, and anticholinergic activities. It is specifically an antagonist of the α1-adrenergic receptor, the histamine H1 receptor, the serotonin 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, the dopamine D1, D2, and D3 receptors, and the muscarinic acetylcholine receptors (M1-M5). Like other TCAs, clomipramine weakly blocks voltage-dependent sodium channels as well.
Although clomipramine shows around 100- to 200-fold preference in affinity for the serotonin transporter (SERT) over the norepinephrine transporter (NET), its major active metabolite, desmethylclomipramine (norclomipramine), binds to the NET with very high affinity (Ki = 0.32 nM) and with dramatically reduced affinity for the SERT (Ki = 31.6 nM). Moreover, desmethylclomipramine circulates at concentrations that are approximately twice those of clomipramine. In accordance, occupancy of both the SERT and the NET has been shown with clomipramine administration in positron emission tomography studies with humans and non-human primates. As such, clomipramine is in fact a fairly balanced SNRI rather than only a serotonin reuptake inhibitor (SRI).
The antidepressant effects of clomipramine are thought to be due to reuptake inhibition of serotonin and norepinephrine, while serotonin reuptake inhibition only is thought to be responsible for the effectiveness of clomipramine in the treatment of OCD. Conversely, antagonism of the H1, α1-adrenergic, and muscarinic acetylcholine receptors is thought to contribute to its side effects. Blockade of the H1 receptor is specifically responsible for the antihistamine effects of clomipramine and side effects like sedation and somnolence (sleepiness). Antagonism of the α1-adrenergic receptor is thought to cause orthostatic hypotension and dizziness. Inhibition of muscarinic acetylcholine receptors is responsible for the anticholinergic side effects of clomipramine like dry mouth, constipation, urinary retention, blurred vision, and cognitive/memory impairment. In overdose, sodium channel blockade in the brain is believed to cause the coma and seizures associated with TCAs while blockade of sodium channels in the heart is considered to cause cardiac arrhythmias, cardiac arrest, and death. On the other hand, sodium channel blockade is also thought to contribute to the analgesic effects of TCAs, for instance in the treatment of neuropathic pain.
The exceptionally strong serotonin reuptake inhibition of clomipramine likely precludes the possibility of its antagonism of serotonin receptors (which it binds to with more than 100-fold lower affinity than the SERT) resulting in a net decrease in signalling by these receptors. In accordance, while serotonin receptor antagonists like cyproheptadine and chlorpromazine are effective as antidotes against serotonin syndrome, clomipramine is nonetheless capable of inducing this syndrome. In fact, while all TCAs are SRIs and serotonin receptor antagonists to varying extents, the only TCAs that are associated with serotonin syndrome are clomipramine and to a lesser extent its dechlorinated analogue imipramine, which are the two most potent SRIs of the TCAs (and in relation to this have the highest ratios of serotonin reuptake inhibition to serotonin receptor antagonism). As such, whereas other TCAs can be combined with monoamine oxidase inhibitors (with caution due to the risk of hypertensive crisis from NET inhibition; sometimes done in treatment-resistant depressives), clomipramine cannot be due to the risk of serotonin syndrome and death. Unlike the case of its serotonin receptor antagonism, orthostatic hypotension is a common side effect of clomipramine, suggesting that its blockade of the α1-adrenergic receptor is strong enough to overcome the stimulatory effects on the α1-adrenergic receptor of its NET inhibition.
Clomipramine is a very strong SRI. Its affinity for the SERT was reported in one study using human tissues to be 0.14 nM, which is considerably higher than that of other TCAs. For example, the TCAs with the next highest affinities for the SERT in the study were imipramine, amitriptyline, and dosulepin (dothiepin), with Ki values of 1.4 nM, 4.3 nM, and 8.3 nM, respectively. In addition, clomipramine has a terminal half-life that is around twice as long as that of amitriptyline and imipramine. In spite of these differences however, clomipramine is used clinically at the same usual dosages as other serotonergic TCAs (100-200 mg/day). It achieves typical circulating concentrations that are similar in range to those of other TCAs but with an upper limit that is around twice that of amitriptyline and imipramine. For these reasons, clomipramine is the most potent SRI among the TCAs and is far stronger as an SRI than other TCAs at typical clinical dosages. In addition, clomipramine is more potent as an SRI than any SSRIs, it is more potent than paroxetine, which is the strongest SSRI.
A positron emission tomography study found that a single low dose of 10 mg clomipramine to healthy volunteers resulted in 81.1% occupancy of the SERT, which was comparable to the 84.9% SERT occupancy by 50 mg fluvoxamine. In the study, single doses of 5 to 50 mg clomipramine resulted in 67.2 to 94.0% SERT occupancy while single doses of 12.5 to 50 mg fluvoxamine resulted in 28.4 to 84.9% SERT occupancy. Chronic treatment with higher doses was able to achieve up to 100.0% SERT occupancy with clomipramine and up to 93.6% SERT occupancy with fluvoxamine. Other studies have found 83% SERT occupancy with 20 mg/day paroxetine and 77% SERT occupancy with 20 mg/day citalopram. These results indicate that very low doses of clomipramine are able to substantially occupy the SERT and that clomipramine achieves higher occupancy of the SERT than SSRIs at comparable doses. Moreover, clomipramine may be able to achieve more complete occupancy of the SERT at high doses, at least relative to fluvoxamine.
If the ratios of the 80% SERT occupancy dosage and the approved clinical dosage range are calculated and compared for SSRIs, SNRIs, and clomipramine, it can be deduced that clomipramine is by far the strongest SRI used medically. The lowest approved dosage of clomipramine can be estimated to be roughly comparable in SERT occupancy to the maximum approved dosages of the strongest SSRIs and SNRIs. Because their mechanism of action was originally not known and dose-ranging studies were never conducted, first-generation antipsychotics were dramatically overdosed in patients. It has been suggested that the same may have been true for clomipramine and other TCAs.
Clomipramine was the first drug that was investigated for and found to be effective in the treatment of OCD. In addition, it was the first drug to be approved by the Food and Drug Administration (FDA) in the United States for the treatment of OCD. The effectiveness of clomipramine in the treatment of OCD is far greater than that of other TCAs, which are comparatively weak SRIs; a meta-analysis found pre- versus post-treatment effect sizes of 1.55 for clomipramine relative to a range of 0.67 for imipramine and 0.11 for desipramine. In contrast to other TCAs, studies have found that clomipramine and SSRIs, which are more potent SRIs, have similar effectiveness in the treatment of OCD. However, multiple meta-analyses have found that clomipramine nonetheless retains a significant effectiveness advantage relative to SSRIs; in the same meta-analysis mentioned previously, the effect sizes of SSRIs in the treatment of OCD ranged from 0.81 for fluoxetine to 1.36 for sertraline (relative to 1.55 for clomipramine). However, the effectiveness advantage for clomipramine has not been apparent in head-to-head comparisons of clomipramine versus SSRIs for OCD. The differences in effectiveness findings could be due to differences in methodologies across non-head-to-head studies.
Relatively high doses of SSRIs are needed for effectiveness in the treatment of OCD. Studies have found that high dosages of SSRIs above the normally recommended maximums are significantly more effective in OCD treatment than lower dosages (e.g. 250 to 400 mg/day sertraline versus 200 mg/day sertraline). In addition, the combination of clomipramine and SSRIs has also been found to be significantly more effective in alleviating OCD symptoms, and clomipramine is commonly used to augment SSRIs for this reason. Studies have found that intravenous clomipramine, which is associated with very high circulating concentrations of the drug and a much higher ratio of clomipramine to its metabolite desmethylclomipramine, is more effective than oral clomipramine in the treatment of OCD. There is a case report of complete remission from OCD for approximately one month following a massive overdose of fluoxetine, an SSRI with a uniquely long duration of action. Taken together, stronger serotonin reuptake inhibition has consistently been associated with greater alleviation of OCD symptoms, and since clomipramine, at the clinical dosages in which it is employed, is effectively the strongest SRI used medically, this may underlie its unique effectiveness in the treatment of OCD.
In addition to serotonin reuptake inhibition, clomipramine is also a mild but clinically significant antagonist of the dopamine D1, D2, and D3 receptors at high concentrations. Addition of antipsychotics, which are potent dopamine receptor antagonists, to SSRIs, has been found to significantly augment their effectiveness in the treatment of OCD. As such, besides strong serotonin reuptake inhibition, clomipramine at high doses might also block dopamine receptors to treat OCD symptoms, and this could additionally or alternatively be involved in its possible effectiveness advantage over SSRIs.
Although clomipramine is probably more effective in the treatment of OCD compared to SSRIs, it is greatly inferior to them in terms of tolerability and safety due to its lack of selectivity for the SERT and promiscuous pharmacological activity. In addition, clomipramine has high toxicity in overdose and can potentially result in death, whereas death rarely, if ever, occurs with overdose of SSRIs. It is for these reasons that clomipramine, in spite of potentially superior effectiveness to SSRIs, is now rarely used as a first-line agent in the treatment of OCD, with SSRIs being used as first-line therapies instead and clomipramine generally being reserved for more severe cases and as a second-line agent.
The oral bioavailability of clomipramine is approximately 50%. Peak plasma concentrations occur around 2-6 hours (with an average of 4.7 hours) after taking clomipramine orally and are in the range of 56-154 ng/mL (178-489 nmol/L). Steady-state concentrations of clomipramine are around 134-532 ng/mL (426-1,690 nmol/L), with an average of 218 ng/mL (692 nmol/L), and are reached after 7 to 14 days of repeated dosing. Steady-state concentrations of the active metabolite, desmethylclomipramine, are around 230-550 ng/mL (730-1,750 nmol/L). The volume of distribution (Vd) of clomipramine is approximately 17 L/kg. It binds approximately 97-98% to plasma proteins, primarily to albumin. Clomipramine is metabolised in the liver mainly by CYP2D6. It has a terminal half-life of 32 hours, and its N-desmethyl metabolite, desmethylclomipramine, has a terminal half-life of approximately 69 hours. Clomipramine is mostly excreted in urine (60%) and faeces (32%).
Clomipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include imipramine, desipramine, and trimipramine. Clomipramine is a derivative of imipramine with a chlorine atom added to one of its rings and is also known as 3-chloroimipramine. It is a tertiary amine TCA, with its side chain-demethylated metabolite desmethylclomipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of clomipramine is 3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H23ClN2 with a molecular weight of 314.857 g/mol. The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely. The CAS Registry Number of the free base is 303-49-1 and of the hydrochloride is 17321-77-6.
Society and Culture
Clomipramine is the English and French generic name of the drug and its INN, BAN, and DCF, while clomipramine hydrochloride is its USAN, USP, BANM, and JAN. Clomipramina is its generic name in Spanish, Portuguese and Italian and its DCIT, while clomipramin is its generic name in German and clomipraminum is its generic name in Latin.
Clomipramine is marketed throughout the world mainly under the brand names Anafranil and Clomicalm for use in humans and animals, respectively.
In the US, clomipramine is only licensed to treat separation anxiety in dogs for which it is sold under the brand name Clomicalm. It has proven effective in the treatment of OCD in cats and dogs. In dogs, it has also demonstrated similar efficacy to fluoxetine in treating tail chasing. In dogs some evidence suggests its efficacy in treating noise phobia.
Clomipramine has also demonstrated efficacy in treating urine spraying in cats. Various studies have been done on the effects of clomipramine on cats to reduce urine spraying/marking behaviour. It has been shown to be able to reduce this behaviour by up to 75% in a trial period of four weeks.
Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued.
BMS withdrew it from the market by 2004 due to decreasing sales due to the rare incidence of severe liver damage and the onset of generic competition. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 patient-years. Generic versions were introduced in 2003.
Nefazodone is a phenylpiperazine compound and is related to trazodone. It has been described as a serotonin antagonist and reuptake inhibitor (SARI) due to its combined actions as a potent serotonin 5-HT2A receptor and 5-HT2C receptor antagonist and weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).
Nefazodone was discovered by scientists at Bristol-Myers Squibb (BMS) who were seeking to improve on trazodone by reducing its sedating qualities.
BMS obtained marketing approvals worldwide for nefazodone in 1994. It was marketed in the US under the brand name Serzone and in Europe under the brand name Dutonin.
In 2002, the US Food and Drug Administration (FDA) obligated BMS to add a black box warning about potential fatal liver toxicity to the drug label. Worldwide sales in 2002 were $409 million.
In 2003 Public Citizen filed a citizen petition asking the FDA to withdraw the marketing authorisation in the US, and in early 2004 the organisation sued the FDA to attempt to force withdrawal of the drug. The FDA issued a response to the petition in June 2004 and filed a motion to dismiss, and Public Citizen withdrew the suit.
Generic versions were introduced in the US in 2003 and Health Canada withdrew the marketing authorization that year.
Sales of nefazodone were about $100 million in 2003. By that time it was also being marketed under the additional brand names Serzonil, Nefadar, and Rulivan.
In April 2004, BMS announced that it was going discontinue the sale of Serzone in the US in June 2004 and said that this was due to declining sales. By that time BMS had already withdrawn the drug from the market in Europe, Australia, New Zealand and Canada.
As of 2012 generic nefazodone was available in the US.
Nefazodone is available as 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg tablets for oral ingestion.
Nefazodone can cause severe liver damage, leading to a need for liver transplant, and death. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 patient-years. By the time that it started to be withdrawn in 2003, nefazodone had been associated with at least 53 cases of liver injury, with 11 deaths, in the United States, and 51 cases of liver toxicity, with 2 cases of liver transplantation, in Canada. In a Canadian study which found 32 cases in 2002, it was noted that databases like that used in the study tended to include only a small proportion of suspected drug reactions.
Common and mild side effects of nefazodone reported in clinical trials more often than placebo include dry mouth (25%), sleepiness (25%), nausea (22%), dizziness (17%), blurred vision (16%), weakness (11%), lightheadedness (10%), confusion (7%), and orthostatic hypotension (5%). Rare and serious adverse reactions may include allergic reactions, fainting, painful/prolonged erection, and jaundice.
Nefazodone is not especially associated with increased appetite and weight gain.
Nefazodone is a potent inhibitor of CYP3A4, and may interact adversely with many commonly used medications that are metabolized by CYP3A4.
Nefazodone acts primarily as a potent antagonist of the serotonin 5-HT2A receptor and to a lesser extent of the serotonin 5-HT2C receptor. It also has high affinity for the α1-adrenergic receptor and serotonin 5-HT1A receptor, and relatively lower affinity for the α2-adrenergic receptor and dopamine D2 receptor. Nefazodone has low but significant affinity for the serotonin, norepinephrine, and dopamine transporters as well, and therefore acts as a weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It has low but potentially significant affinity for the histamine H1 receptor, where it is an antagonist, and hence may have some antihistamine activity. Nefazodone has negligible activity at muscarinic acetylcholine receptors, and accordingly, has no anticholinergic effects.
The bioavailability of nefazodone is low and variable, about 20%. Its plasma protein binding is approximately 99%, but it is bound loosely.
Nefazodone is metabolized in the liver, with the main enzyme involved thought to be CYP3A4. The drug has at least four active metabolites, which include hydroxynefazodone, para-hydroxynefazodone, triazoledione, and meta-chlorophenylpiperazine. Nefazodone has a short elimination half-life of about 2 to 4 hours. Its metabolite hydroxynefazodone similarly has an elimination half-life of about 1.5 to 4 hours, whereas the elimination half-lives of triazoledione and mCPP are longer at around 18 hours and 4 to 8 hours, respectively. Due to its long elimination half-life, triazole is the major metabolite and predominates in the circulation during nefazodone treatment, with plasma levels that are 4 to 10 times higher than those of nefazodone itself. Conversely, hydroxynefazodone levels are about 40% of those of nefazodone at steady state. Plasma levels of mCPP are very low at about 7% of those of nefazodone; hence, mCPP is only a minor metabolite. mCPP is thought to be formed from nefazodone specifically by CYP2D6.
The ratios of brain-to-plasma concentrations of mCPP to nefazodone are 47:1 in mice and 10:1 in rats, suggesting that brain exposure to mCPP may be much higher than plasma exposure. Conversely, hydroxynefazodone levels in the brain are 10% of those in plasma in rats. As such, in spite of its relatively low plasma concentrations, brain exposure to mCPP may be substantial, whereas that of hydroxynefazodone may be minimal.
Nefazodone is a phenylpiperazine; it is an alpha-phenoxyl derivative of etoperidone which in turn was a derivative of trazodone.
Society and Culture
Nefazodone is the generic name of the drug and its INN and BAN, while néfazodone is its DCF and nefazodone hydrochloride is its USAN and USP.
Nefazodone has been marketed under a number of brand names including Dutonin (AT, ES, IE, UK), Menfazona (ES), Nefadar (CH, DE, NO, SE), Nefazodone BMS (AT), Nefazodone Hydrochloride Teva (US), Reseril (IT), Rulivan (ES), and Serzone (AU, CA, US). As of 2017, it remains available only on a limited basis as Nefazodone Hydrochloride Teva in the United States.
The use of nefazodone to prevent migraine has been studied, due to its antagonistic effects on the 5-HT2A and 5-HT2C receptors.
It asks about 32 behaviours and mental states that are either aspects of hypomania or features associated with mood disorders. It uses short phrases and simple language, making it easy to read. The University of Zurich holds the copyright, and the HCL-32 is available for use at no charge. More recent work has focused on validating translations and testing whether shorter versions still perform well enough to be helpful clinically. Recent meta-analyses find that it is one of the most accurate assessments available for detecting hypomania, doing better than other options at recognising bipolar II disorder.
Development and Brief History
The Hypomania Checklist was built as a more efficient screening measure for hypomania, to be used both in epidemiological research and in clinical use. Existing measures for bipolar disorder focused on identifying personality factors and symptom severity instead of the episodic nature of hypomania or the possible negative consequences in behavioural, affective, or cognitive changes associated. These measures were mostly used in non-clinical populations to identify individuals at risk and were not used as screening instruments. The HCL-32 is a measure intended to have high sensitivity to direct clinicians from many countries to diagnosing individuals in a clinical population with bipolar disorder, specifically bipolar II disorder.
Initially developed by Jules Angst and Thomas Meyer in German, the questionnaire was translated into English and translated back to German to ensure accuracy. The English version of the HCL has been used as the basis for translation in other languages through the same process. The original study that used the HCL in an Italian and a Swiss sample noted the measure’s high sensitivity and a lower sensitivity than other used measures.
The scale includes a checklist of 32 possible symptoms of hypomania, each rated yes or no. The rating “yes” would mean the symptom is present or this trait is “typical of me,” and “no” would mean that the symptom is not present or “not typical” for the person.
The HCL suffers from the same problems as other self-report inventories, in that scores can be easily exaggerated or minimised by the person completing them. Like all questionnaires, the way the instrument is administered can influence the final score. If a patient is asked to fill out the form in front of other people in a clinical environment, for instance, social expectations may elicit a different response compared to administration via a postal survey.
Similar reliability scores were found when only using 16 item assessments versus the traditional 32-item format of the HCL-32. A score of at least 8 items was found valid and reliable for distinguishing Bipolar Disorder and Major Depressive Disorder. In a study, 73% of patients who completed the HCL-32 R1 were true bipolar cases identified as potential bipolar cases. However, the HCL-32 R1 does not accurately differentiate between Bipolar I and Bipolar II. However, the 16-item HCL has not been tested as a standalone section in a hospital setting. In addition, while the HCL-32 is a sensitive instrument for hypomanic symptoms, it does not distinguish between bipolar I and bipolar-II disorders. The HCL-32 has not been compared with other commonly used screening tools for bipolar disorder, such as the Young Mania Rating Scale (YMRS)and the General Behaviour Inventory (GBI). The online version of the HCL has been shown to be as reliable as the paper version.
A mixed affective state, formerly known as a mixed-manic or mixed episode, has been defined as a state wherein features unique to both depression and mania – such as episodes of despair, doubt, anguish, rage or homicidal ideation, suicidal ideation, splitting, racing thoughts, sensory overload, pressure of activity, and heightened irritability – occur either simultaneously or in very short succession.
Previously, the diagnostic criteria for both a manic and depressive episode had to be met in a consistent and sustained fashion, with symptoms enduring for at least a week (or any duration if psychiatric hospitalisation was required), thereby restricting the official acknowledgement of mixed affective states to only a minority of patients with bipolar I disorder. In current DSM-5 nomenclature, however, a “mixed episode” no longer stands as an episode of illness unto itself; rather, the symptomology specifier “with mixed features” can be applied to any major affective episode (manic, hypomanic, or depressive), meaning that they are now officially recognised in patients with, in addition to bipolar I disorder, bipolar II disorder and, by convention, major depressive disorder. A depressive mixed state in a patient, however, even in the absence of discrete periods of mania or hypomania, effectively rules out unipolar depression.
As affirmed by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), the symptomology specifier “with mixed features” can be applied to manic episodes of bipolar I disorder, hypomanic episodes of either bipolar I disorder or bipolar II disorder and depressive episodes of either bipolar disorder or major depressive disorder, with at least three concurrent features of the opposite polarity being present. As a result, the presence of “mixed features” are now recognised in patients with bipolar II disorder and major depression; as earlier noted, however, although it is customary to withhold a diagnosis of a bipolar disorder until a manic or hypomanic episode appears, the presence of such features in a depressed patient even with no history of discrete mania or hypomania is strongly suggestive of the disorder.
Nevertheless, the DSM-5’s narrower definition of mixed episodes may result in fewer patients meeting mixed criteria compared to DSM-IV. A call was made by Tohen in 2017 for introducing changes from a currently phenomenological to a target oriented approach to DSM-5 mixed mood criteria in order to achieve more personalized medical attention.
Two features of both mania or hypomania and depression may superficially overlap and even resemble each other, namely “an increase in goal-directed activity” (psychomotor acceleration) vs. psychomotor agitation and “flight of ideas” and “racing thoughts” vs. depressive rumination. Attending to the patient’s experiences is very important. In the psychomotor agitation commonly seen in depression, the “nervous energy” is always overshadowed by a strong sense of exhaustion and manifests as purposeless movements (e.g. pacing, hand-wringing); in psychomotor acceleration, however, the excess in movement stems from an abundance of energy and is often channelled and purposeful. Likewise, in depressive rumination, the patient experiences the repetitive thoughts as heavy, leaden, and plodding; in psychic acceleration, however, (as seen in mania or hypomania) the thoughts move in a rapid progression, with many themes, rather than a singular one, being touched upon. Even when such experiences are accounted for on the basis of depression, the possibility does still exist, however, that the depressive episode may be complicated by other manic or hypomanic symptoms, in which case it is often prudent to attend to the patient’s personal and family history (e.g. family history of bipolar disorder, early age of onset) to determine whether or not the patient has bipolar disorder.
Treatment of mixed states is typically based upon administration of mood stabilising medication, which may include anticonvulsants such as valproic acid; atypical antipsychotics such as quetiapine, olanzapine, aripiprazole, and ziprasidone; or first-generation antipsychotics such as haloperidol. There is question of lithium’s efficacy for treatment of mixed states due to conflicting conclusions drawn from various trials and research. Mood stabilisers work to reduce the manic symptoms associated with the mixed state, but they are not considered particularly effective for improving concurrent depressive symptoms.
Desvenlafaxine, sold under the brand name Pristiq among others, is a medication used to treat depression.
It is recommended that the need for further treatment be occasionally reassessed. It may be less effective than its parent compound venlafaxine, although some studies have found comparable efficacy. It is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class and is taken by mouth.
Common side effects include dizziness, trouble sleeping, increased sweating, constipation, sleepiness, anxiety, and sexual problems. Serious side effects may include suicide in those under the age of 25, serotonin syndrome, bleeding, mania, and high blood pressure. A withdrawal syndrome may occur if the dose is rapidly decreased. It is unclear if use during pregnancy or breastfeeding is safe.
Desvenlafaxine was approved for medical use in the United States in 2008. In Europe its application for use was denied in 2009. In 2017, it was the 235th most commonly prescribed medication in the United States, with more than two million prescriptions.
Desvenlafaxine is primarily used as a treatment for major depressive disorder. Use has only been studied up to 8 weeks. It may be less effective than venlafaxine, although some studies have found comparable efficacy with a lower rate of nausea.
Doses of 50-400 mg/day appear effective for major depressive disorder, although no additional benefit was demonstrated at doses greater than 50 mg/day, and adverse events and discontinuations were more frequent at higher doses.
Desvenlafaxine improves the HAM-D17 score and measures of well being such as the Sheehan Disability Scale (SDS) and 5-item World Health Organisation Well-Being Index (WHO-5).
Desvenlafaxine is a synthetic form of the isolated major active metabolite of venlafaxine, and is categorised as a serotonin-norepinephrine reuptake inhibitor (SNRI). When most normal metabolisers take venlafaxine, approximately 70% of the dose is metabolised into desvenlafaxine, so the effects of the two drugs are expected to be very similar. It works by blocking the “reuptake” transporters for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline). It is approximately 10 times more potent at inhibiting serotonin uptake than norepinephrine uptake.
Wyeth announced on 23 January 2007 that it received an approvable letter from the Food and Drug Administration (FDA) for desvenlafaxine. Final approval to sell the drug was contingent on a number of things, including:
A satisfactory FDA inspection of Wyeth’s Guayama, Puerto Rico facility, where the drug is to be manufactured;
Several postmarketing surveillance commitments, and follow-up studies on low-dose use, relapse, and use in children;
Clarity by Wyeth around the company’s product education plan for physicians and patients;
Approval of desvenlafaxine’s proprietary name, Pristiq.
The FDA approved the drug for antidepressant use in February 2008, and was to be available in US pharmacies in May 2008.
In March 2017, the generic form of the drug was made available in the US.
On 04 February 2009, Health Canada approved use of desvenlafaxine for treatment of depression.
In 2009, an application to market desvenlafaxine for major depressive disorder in the European Union was declined. In 2012, Pfizer received authorization in Spain to market desvenlafaxine for the disorder but it is not being sold.
Desvenlafaxine is classified as a schedule 4 (prescription only) drug in Australia. It was listed on the PBS (Pharmaceutical Benefits Scheme) in 2008 for the treatment of major depressive disorders.
One review found that it is as effective as other antidepressants with similar discontinuation rates overall but less discontinuations due to side effects. Another review also found it was similarly effective to many other antidepressants.
Common side effects include weight gain, fatigue, liver problems, nausea, headaches, and anxiety. Due to potential liver problems ongoing blood tests are recommended. Its use is not recommended in people with dementia or over the age of 75. There is tentative evidence that it may have fewer side effects than some other antidepressants. It works by stimulating melatonin receptors and blocking serotonin receptors.
Agomelatine was approved for medical use in Europe in 2009 and Australia in 2010. Its use is not approved in the United States and efforts to get approval were ended in 2011. It was developed by the pharmaceutical company Servier.
Agomelatine was discovered and developed by the European pharmaceutical company Servier Laboratories Ltd. Servier continued to develop the drug and conduct phase III trials in the European Union.
In March 2005, Servier submitted agomelatine to the European Medicines Agency (EMA) under the trade names Valdoxan and Thymanax. On 27 July 2006, the Committee for Medical Products for Human Use (CHMP) of the EMA recommended a refusal of the marketing authorisation. The major concern was that efficacy had not been sufficiently shown, while there were no special concerns about side effects. In September 2007, Servier submitted a new marketing application to the EMA.
In March 2006, Servier announced it had sold the rights to market agomelatine in the United States to Novartis. It was undergoing several phase III clinical trials in the US, and until October 2011 Novartis listed the drug as scheduled for submission to the FDA no earlier than 2012. However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available.
It received approval from the European Medicines Agency (EMA) for marketing in the European Union in February 2009 and approval from the Therapeutic Goods Administration (TGA) for marketing in Australia in August 2010.
Major Depressive Disorder
Agomelatine is used for the treatment of major depressive episodes in adults in Europe. Ten placebo controlled trials have been performed to investigate the short term efficacy of agomelatine in major depressive disorder. At the end of treatment, significant efficacy was demonstrated in six of the ten short-term double-blind placebo-controlled studies. Two were considered “failed” trials, as comparators of established efficacy failed to differentiate from placebo. Efficacy was also observed in more severely depressed patients in all positive placebo-controlled studies. The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study. One meta-analysis found agomelatine to be as effective as standard antidepressants.
A meta-analysis found that agomelatine is effective in treating severe depression. Its antidepressant effect is greater for more severe depression. In people with a greater baseline score (>30 on HAMD17 scale), the agomelatine-placebo difference was of 4.53 points. Controlled studies in humans have shown that agomelatine is at least as effective as the SSRI antidepressants paroxetine, sertraline, escitalopram, and fluoxetine in the treatment of major depression. A 2018 meta-study comparing 21 antidepressants found agomelatine was one of the more tolerable, yet effective antidepressants.
However, the body of research on agomelatine has been substantially affected by publication bias, prompting analyses which take into account both published and unpublished studies. These have confirmed that agomelatine is approximately as effective as more commonly used antidepressants (e.g. SSRIs), but some qualified this as “marginally clinically relevant”, being only slightly above placebo. According to a 2013 review, agomelatine did not seem to provide an advantage in efficacy over other antidepressants for the acute-phase treatment of major depression.
Use in Special Populations
It is not recommended in Europe for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. However, a study reported in September, 2020, showed greater efficacy vs. placebo for agomelatine 25mg per day in youth age 7-18 years. Only limited data is available on use in elderly people ≥ 75 years old with major depressive episodes.
It is not recommended during pregnancy or breastfeeding.
Agomelatine is contraindicated in patients with kidney or liver impairment. According to information disclosed by Servier in 2012, guidelines for the follow-up of patients treated with Valdoxan have been modified in concert with the European Medicines Agency. As some patients may experience increased levels of liver enzymes in their blood during treatment with Valdoxan, doctors have to run laboratory tests to check that the liver is working properly at the initiation of the treatment and then periodically during treatment, and subsequently decide whether to pursue the treatment or not. No relevant modification in agomelatine pharmacokinetic parameters in patients with severe renal impairment has been observed. However, only limited clinical data on its use in depressed patients with severe or moderate renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing agomelatine to these patients.
Agomelatine does not alter daytime vigilance and memory in healthy volunteers. In depressed patients, treatment with the drug increased slow wave sleep without modification of REM (Rapid Eye Movement) sleep amount or REM latency. Agomelatine also induced an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients.
Agomelatine appears to cause fewer sexual side effects and discontinuation effects than paroxetine.
Common (1-10% incidence) adverse effects include:
Hyperhidrosis (excess sweating that is not proportionate to the ambient temperature).
Increased ALAT and ASAT (liver enzymes).
Uncommon (0.1-1%) adverse effects include:
Paraesthesia (abnormal sensations [e.g. itching, burning, tingling, etc.] due to malfunctioning of the peripheral nerves).
Weight gain or loss, which tends to be less significant than with SSRIs.
Dependence and Withdrawal
No dosage tapering is needed on treatment discontinuation. Agomelatine has no abuse potential as measured in healthy volunteer studies.
Agomelatine is expected to be relatively safe in overdose.
Agomelatine is a substrate of CYP1A2, CYP2C9 and CYP2C19. Inhibitors of these enzymes, e.g. the SSRI antidepressant fluvoxamine, reduce its clearance and can therefore lead to an increase in agomelatine exposure. There is also the potential for agomelatine to interact with alcohol to increase the risk of hepatotoxicity.
Agomelatine is a melatonin receptor agonist (MT1 (Ki 0.1 nM) and MT2 (Ki = 0.12 nM)) and serotonin 5-HT2C (Ki = 631 nM) and 5-HT2B receptor (Ki = 660 nM) antagonist. Binding studies indicate that it has no effect on monoamine uptake and no affinity for adrenergic, histamine, cholinergic, dopamine, and benzodiazepine receptors, nor other serotonin receptors.
Agomelatine resynchronizes circadian rhythms in animal models of delayed sleep phase syndrome. By antagonising 5-HT2C, it disinhibits/increases noradrenaline and dopamine release specifically in the frontal cortex. Therefore, it is sometimes classified as a norepinephrine-dopamine disinhibitor. It has no influence on the extracellular levels of serotonin. Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset.
Antagonism of 5-HT2B is an antidepressant property agomelatine shares with several atypical antipsychotics, such as aripiprazole, which are themselves used as atypical antidepressants. 5-HT2B antagonists are currently being investigated for their usefulness in reducing cardiotoxicity of drugs as well as being effective in reducing headache. Hence this particular receptor antagonism of agomelatine is useful for its antidepressant effectiveness as well as reducing the drug’s adverse effects.
The chemical structure of agomelatine is very similar to that of melatonin. Where melatonin has an indole ring system, agomelatine has a naphthalene bioisostere instead.
Agomelatine is under development by Servier for the treatment of generalised anxiety disorder and has reached phase III clinical trials for this indication, but in August 2017, Servier communicated that development for this indication is suspended.
Agomelatine is also studied for its effects on sleep regulation. Studies report various improvements in general quality of sleep metrics, as well as benefits in circadian rhythm disorders. It has been found more effective than placebo in the treatment of generalised anxiety disorder. A 2019 review suggested no recommendations of agomelatine in support of, or against, its use to treat individuals with seasonal affective disorder.
Common side effects include sleepiness, constipation, weight gain, and dry mouth. Other side effects include low blood pressure with standing, seizures, a prolonged erection, high blood sugar, tardive dyskinesia, and neuroleptic malignant syndrome. In older people with dementia, its use increases the risk of death. Use in the third trimester of pregnancy may result in a movement disorder in the baby for some time after birth. Quetiapine is believed to work by blocking a number of receptors including serotonin and dopamine.
Quetiapine was developed in 1985 and approved for medical use in the United States in 1997. It is available as a generic medication. In 2018, it was the 59th most commonly prescribed medication in the United States, with more than 12 million prescriptions.
AstraZeneca submitted a new drug application for a sustained-release version of quetiapine in the United States, Canada, and the European Union in the second half of 2006 for treatment of schizophrenia. AstraZeneca was to retain the exclusive right to market sustained-release quetiapine until 2017. The sustained-release quetiapine is marketed mainly as Seroquel XR. Other marketing names are Seroquel Prolong, Seroquel Depot and Seroquel XL
On 18 May 2007, AstraZeneca announced that the US Food and Drug Administration (FDA) had approved Seroquel XR for acute treatment of schizophrenia. During its 2007 Q2 earnings conference, AstraZeneca announced plans to launch Seroquel XR in the US during August 2007. However, Seroquel XR has become available in US pharmacies only after the FDA had approved Seroquel XR for use as maintenance treatment for schizophrenia, in addition to acute treatment of the illness, on 16 November 2007. The company has not provided a reason for the delay of Seroquel XR’s launch.
Health Canada approved sale of Seroquel XR on 27 September 2007.
In early October 2008, the FDA approved Seroquel XR for the treatment of bipolar depression and bipolar mania. According to AstraZeneca, Seroquel XR is “the first medication approved by the FDA for the once-daily acute treatment of both depressive and manic episodes associated with bipolar.”
On 31 July, 2008, Handa Pharmaceuticals, based in Fremont, California, announced that its abbreviated new drug application (“ANDA”) for quetiapine fumarate extended-release tablets, the generic version of AstraZeneca’s SEROQUEL XR, has been accepted by the FDA.
On 01 December 2008, Biovail announced that the FDA had accepted the company’s ANDA to market its own version of sustained-release quetiapine. Biovail’s sustained-release tablets will compete with AstraZeneca’s Seroquel XR.
On 24 December 2008, AstraZeneca notified shareholders that the FDA had asked for additional information on the company’s application to expand the use of sustained-release quetiapine for treatment of depression.
Quetiapine is primarily used to treat schizophrenia or bipolar disorder. Quetiapine targets both positive and negative symptoms of schizophrenia.
In a 2013 comparison of 15 antipsychotics in effectiveness in treating schizophrenia, quetiapine demonstrated standard effectiveness. It was 13-16% more effective than ziprasidone, chlorpromazine, and asenapine and approximately as effective as haloperidol and aripiprazole.
There is tentative evidence of the benefit of quetiapine versus placebo in schizophrenia; however, definitive conclusions are not possible due to the high rate of attrition in trials (greater than 50%) and the lack of data on economic outcomes, social functioning, or quality of life.
It is debatable whether, as a class, typical or atypical antipsychotics are more effective. Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. While quetiapine has lower rates of extrapyramidal side effects, there is greater sleepiness and rates of dry mouth.
A Cochrane review comparing quetiapine to other atypical antipsychotic agents tentatively concluded that it may be less efficacious than olanzapine and risperidone; produce fewer movement related side effects than paliperidone, aripiprazole, ziprasidone, risperidone and olanzapine; and produce weight gain similar to risperidone, clozapine and aripiprazole. They concluded that it produces suicide attempt, suicide; death; QTc prolongation, low blood pressure; tachycardia; sedation; gynaecomastia; galactorrhoea, menstrual irregularity and white blood cell count at a rate similar to first generation antipsychotics.
In those with bipolar disorder, quetiapine is used to treat depressive episodes; acute manic episodes associated with bipolar I disorder (as either monotherapy or adjunct therapy to lithium; valproate or lamotrigine); acute mixed episodes; and maintenance treatment of bipolar I disorder (as adjunct therapy to lithium or divalproex).
Major Depressive Disorder
Quetiapine is effective when used by itself and when used along with other medications in major depressive disorder (MDD). However, sedation is often an undesirable side effect.
In the United States, the United Kingdom and Australia (while not subsidised by the Australian Pharmaceutical Benefits Scheme for treatment of MDD), quetiapine is licensed for use as an add-on treatment in MDD.
Quetiapine does not decrease agitation among people with Alzheimer’s. Quetiapine worsens intellectual functioning in the elderly with dementia and therefore is not recommended.
The use of low doses of quetiapine for insomnia, while common, is not recommended; there is little evidence of benefit and concerns regarding adverse effects.
It is sometimes used off-label, often as an augmentation agent, to treat conditions such as Tourette syndrome, musical hallucinations and anxiety disorders.
Quetiapine and clozapine are the most widely used medications for the treatment of Parkinson’s disease psychosis due to their very low extrapyramidal side-effect liability. Owing to the risks associated with clozapine (e.g. agranulocytosis, diabetes mellitus, etc.), clinicians often attempt treatment with quetiapine first, although the evidence to support quetiapine’s use for this indication is significantly weaker than that of clozapine.
Very common (>10% incidence) adverse effects:
Drowsiness; of 15 antipsychotics quetiapine causes the 5th most sedation.
Extended release (XR) formulations tend to produce less sedation, dose-by-dose than the immediate release formulations.
Common (1–10% incidence) adverse effects:
High blood pressure.
High pulse rate.
High blood cholesterol.
Elevated serum triglycerides.
Increased liver enzymes.
Quetiapine and clozapine are noted for their relative lack of extrapyramidal side effects.
SMD 0.43 kg when compared to placebo. Produces roughly as much weight gain as risperidone, less weight gain than clozapine, olanzapine and zotepine and more weight gain than ziprasidone, lurasidone, aripiprazole and asenapine.
As with many other atypical antipsychotics, this action is likely due to its actions at the H1 histamine receptor and 5-HT2C receptor.
Rare (<1% incidence) adverse effects:
Prolonged QT interval.
Sudden cardiac death.
Restless legs syndrome.
Hyponatraemia, low blood sodium.
Jaundice, yellowing of the eyes, skin and mucous membranes due to an impaired ability of the body to clear bilirubin, a by product of haem breakdown.
Pancreatitis, pancreas swelling.
Agranulocytosis, a potentially fatal drop in white blood cell count.
Leukopenia, a drop in white blood cell count, not as severe as agranulocytosis.
Neutropenia, a drop in neutrophils, the cell of the immune cells that defends the body against bacterial infections.
Anaphylaxis, a potentially fatal allergic reaction.
Hypothyroidism, underactive thyroid gland.
Myocarditis, swelling of the myocardium.
Hepatitis, swelling of the liver.
A prolonged and painful erection.
A potentially fatal skin reaction.
Neuroleptic malignant syndrome:
A rare and potentially fatal complication of antipsychotic drug treatment.
It is characterised by the following symptoms: tremor, rigidity, hyperthermia, tachycardia, mental status changes (e.g. confusion), etc.
A rare and often irreversible neurological condition characterised by involuntary movements of the face, tongue, lips and rest of the body.
Most commonly occurs after prolonged treatment with antipsychotics.
It is believed to be particularly uncommon with atypical antipsychotics, especially quetiapine and clozapine
Both typical and atypical antipsychotics can cause tardive dyskinesia. According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%. Although quetiapine and clozapine are atypical antipsychotics, switching to these atypicals is an option to minimise symptoms of tardive dyskinesia caused by other atypicals.
Weight gain can be a problem for some, with quetiapine causing more weight gain than fluphenazine, haloperidol, loxapine, molindone, olanzapine, pimozide, risperidone, thioridazine, thiothixene, trifluoperazine, and ziprasidone, but less than chlorpromazine, clozapine, perphenazine, and sertindole.
As with some other anti-psychotics, quetiapine may lower the seizure threshold, and should be taken with caution in combination with drugs such as bupropion.
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Pregnancy and Lactation
Placental exposure is least for quetiapine compared to other atypical antipsychotics. The evidence is insufficient to rule out any risk to the foetus but available data suggests it is unlikely to result in any major foetal malformations. It is secreted in breast milk and hence quetiapine-treated mothers are advised not to breastfeed.
In contrast to most other antipsychotic drugs, which tend to be somewhat aversive and often show problems with patient compliance with prescribed medication regimes, quetiapine is sometimes associated with drug misuse and abuse potential, for its hypnotic and sedative effects. It has a limited potential for misuse, usually only in individuals with a history of polysubstance abuse and/or mental illness, and especially in those incarcerated in prisons or secure psychiatric facilities where access to alternative intoxicants is more limited. To a significantly greater extent than other atypical antipsychotic drugs, quetiapine was found to be associated with drug-seeking behaviours, and to have standardised street prices and slang terms associated with it, either by itself or in combination with other drugs (such as “Q-ball” for the intravenous injection of quetiapine mixed with cocaine). The pharmacological basis for this distinction from other second generation antipsychotic drugs is unclear, though it has been suggested that quetiapine’s comparatively lower dopamine receptor affinity and strong antihistamine activity might mean it could be regarded as more similar to sedating antihistamines in this context. While these issues have not been regarded as sufficient cause for placing quetiapine under increased legal controls, prescribers have been urged to show caution when prescribing quetiapine to individuals with characteristics that might place them at increased risk for drug misuse.
Most instances of acute overdosage result in only sedation, hypotension and tachycardia, but cardiac arrhythmia, coma and death have occurred in adults. Serum or plasma quetiapine concentrations are usually in the 1-10 mg/L range in overdose survivors, while postmortem blood levels of 10-25 mg/L are generally observed in fatal cases. Non-toxic levels in postmortem blood extend to around 0.8 mg/kg, but toxic levels in postmortem blood can begin at 0.35 mg/kg.
Quetiapine has the following pharmacological actions:
Dopamine D1, D2, D3, D4, and D5 receptor antagonist.
Serotonin 5-HT1A receptor partial agonist, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor antagonist, and 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptor ligand.
α1- and α2-adrenergic receptor antagonist.
Histamine H1 receptor antagonist.
Muscarinic acetylcholine receptor antagonist.
This means quetiapine is a dopamine, serotonin, and adrenergic antagonist, and a potent antihistamine with some anticholinergic properties. Quetiapine binds strongly to serotonin receptors; the drug acts as partial agonist at 5-HT1A receptors. Serial PET scans evaluating the D2 receptor occupancy of quetiapine have demonstrated that quetiapine very rapidly disassociates from the D2 receptor. Theoretically, this allows for normal physiological surges of dopamine to elicit normal effects in areas such as the nigrostriatal and tuberoinfundibular pathways, thus minimising the risk of side-effects such as pseudo-parkinsonism as well as elevations in prolactin. Some of the antagonised receptors (serotonin, norepinephrine) are actually autoreceptors whose blockade tends to increase the release of neurotransmitters.
At very low doses, quetiapine acts primarily as a histamine receptor blocker (antihistamine) and α1-adrenergic blocker. When the dose is increased, quetiapine activates the adrenergic system and binds strongly to serotonin receptors and autoreceptors. At high doses, quetiapine starts blocking significant amounts of dopamine receptors. Off-label prescriptions, e.g. for chronic insomnia, of low-dose quetiapine is not recommended due to the harmful side-effects.
When treating schizophrenia, antagonism of D2 receptor by quetiapine in the mesolimbic pathway relieves positive symptoms and antagonism of the 5HT2A receptor in the frontal cortex of the brain relieves negative symptoms. Quetiapine has fewer extrapyramidal side effects and is less likely to cause hyperprolactinemia when compared to other drugs used to treat schizophrenia, so is used as a first line treatment.
Peak levels of quetiapine occur 1.5 hours after a dose. The plasma protein binding of quetiapine is 83%. The major active metabolite of quetiapine is norquetiapine (N-desalkylquetiapine). Quetiapine has an elimination half-life of 6 or 7 hours. Its metabolite, norquetiapine, has a half-life of 9 to 12 hours. Quetiapine is excreted primarily via the kidneys (73%) and in faeces (20%) after hepatic metabolism, the remainder (1%) is excreted as the drug in its unmetabolised form.
Quetiapine is a tetracyclic compound and is closely related structurally to clozapine, olanzapine, loxapine, and other tetracyclic antipsychotics.
The synthesis of quetiapine begins with a dibenzothiazepinone. The lactam is first treated with phosphoryl chloride to produce a dibenzothiazepine. A nucleophilic substitution is used to introduce the sidechain.
Society and Culture
In the United States, the FDA has approved quetiapine for the treatment of schizophrenia and of acute manic episodes associated with bipolar disorder (bipolar mania) and for treatment of bipolar depression. In 2009, quetiapine XR was approved as adjunctive treatment of major depressive disorder.
Quetiapine received its initial indication from the FDA for treatment of schizophrenia in 1997. In 2004, it received its second indication for the treatment of mania-associated bipolar disorder. In 2007 and 2008, studies were conducted on quetiapine’s efficacy in treating generalized anxiety disorder and major depression.
Patent protection for the product ended in 2012; however, in a number of regions, the long-acting version remained under patent until 2017.
In April 2010, the US Department of Justice fined Astra-Zeneca $520 million for the company’s aggressive marketing of Seroquel for off-label uses. According to the Department of Justice, “the company recruited doctors to serve as authors of articles that were ghostwritten by medical literature companies and about studies the doctors in question did not conduct. AstraZeneca then used those studies and articles as the basis for promotional messages about unapproved uses of Seroquel.”
Multiple lawsuits have been filed in relation to quetiapine’s side-effects, in particular, diabetes.
Approximately 10,000 lawsuits have been filed against AstraZeneca, alleging that quetiapine caused problems ranging from slurred speech and chronic insomnia to deaths.
In 2004, a young man named Dan Markingson committed suicide in a controversial Seroquel clinical trial at the University of Minnesota while under an involuntary commitment order. A group of University of Minnesota bioethicists charged that the trial involved an alarming number of ethical violations.
Nurofen Plus Tampering Case
In August 2011, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) issued a class-4 drug alert following reports that some batches of Nurofen plus contained Seroquel XL tablets instead.
Following the issue of the Class-4 Drug Alert, Reckitt Benckiser (UK) Ltd received further reports of rogue blister strips in cartons of two additional batches of Nurofen Plus tablets. One of the new batches contained Seroquel XL 50 mg tablets and one contained the Pfizer product Neurontin 100 mg capsules.
Following discussions with the MHRA’s Defective Medicines Report Centre (DMRC), Reckitt Benckiser (UK) Ltd decided to recall all remaining unexpired stock of Nurofen Plus tablets in any pack size, leading to a Class-1 Drug Alert. The contamination was later traced to in-store tampering by a customer.