It is characterized by a person’s efforts, conscious or unconscious, to avoid dealing with a stressor in order to protect oneself from the difficulties the stressor presents. Avoidance coping can lead to substance abuse, social withdrawal, and other forms of escapism. High levels of avoidance behaviours may lead to a diagnosis of avoidant personality disorder, though not everyone who displays such behaviours meets the definition of having this disorder. Avoidance coping is also a symptom of post-traumatic stress disorder (PTSD) and related to symptoms of depression and anxiety. Additionally, avoidance coping is part of the approach-avoidance conflict theory introduced by psychologist Kurt Lewin.
Literature on coping often classifies coping strategies into two broad categories: approach/active coping and avoidance/passive coping. Approach coping includes behaviours that attempt to reduce stress by alleviating the problem directly, and avoidance coping includes behaviours that reduce stress by distancing oneself from the problem. Traditionally, approach coping has been seen as the healthiest and most beneficial way to reduce stress, while avoidance coping has been associated with negative personality traits, potentially harmful activities, and generally poorer outcomes. However, avoidance coping can reduce stress when nothing can be done to address the stressor.
Avoidance coping is measured via a self-reported questionnaire. Initially, the Multidimensional Experiential Avoidance Questionnaire (MEAQ) was used, which is a 62-item questionnaire that assesses experiential avoidance, and thus avoidance coping, by measuring how many avoidant behaviours a person exhibits and how strongly they agree with each statement on a scale of 1-6. Today, the Brief Experiential Avoidance Questionnaire (BEAQ) is used instead, containing 15 of the original 62 items from the MEAQ.
Both active-cognitive and active-behavioural coping are used as replacement techniques for avoidance coping. Active-cognitive coping includes changing one’s attitude towards a stressful event and looking for any positive impacts. Active-behavioural coping refers taking positive actions after finding out more about the situation.
It may alternatively be classified as a tricyclic antidepressant (TCA), specifically a secondary amine. In terms of its chemistry and pharmacology, maprotiline is closely related to other secondary amine TCAs like nortriptyline and protriptyline, and has similar effects to them.
Maprotiline was developed by Ciba (now operated by Novartis). It was patented in 1966 and was first described in the literature in 1969. The drug was introduced for medical use in 1974. Generics are now widely available. It was introduced after most of the other TCAs but was the first TeCA to be developed and marketed, with the TeCAs mianserin and amoxapine following shortly thereafter and mirtazapine being introduced later on.
Maprotiline is used in the treatment of depression, such as depression associated with agitation or anxiety and has similar efficacy to the antidepressant drug moclobemide.
Treatment of depression of all forms and severities (endogenous, psychotic, involutional, and neurotic) especially for depression associated with agitation or anxiety.
Treatment of the depressive phase in bipolar depression.
For the symptomatic relief of anxiety, tension or insomnia.
The use of maprotiline in the treatment of enuresis in paediatric patients has so far not been systematically explored and its use is not recommended. Safety and effectiveness in the paediatric population in general have not been established. Anyone considering the use of maprotiline in a child or adolescent must balance the potential risks with the clinical need. In general, lower dosages are recommended for patients over 60 years of age. Dosages of 50 mg to 75 mg daily are usually satisfactory as maintenance therapy for elderly patients who do not tolerate higher amounts.
Coated Tablets, 10 mg, 25 mg, 50 mg, and 75 mg.
Injectable concentrate, 25 mg.
Maprotiline may worsen psychotic conditions like schizophrenia and should be given with caution. The antipsychotic treatment should be continued. Patients with bipolar affective disorder should not receive antidepressants whilst in a manic phase, as antidepressants can worsen mania.
Hypersensitivity to maprotiline or to other TCAs and TeCAs.
Hypertrophy of the prostate gland with urine hesitancy.
Closed angle glaucoma.
Special Caution Needed
Concomitant treatment with a MAO inhibitor.
Serious impairment of liver and kidney function.
Epilepsy and other conditions that lower the seizure threshold (active brain tumours, alcohol withdrawal, other medications).
Serious cardiovascular conditions (arrhythmias, heart insufficience, state after myocardial infarction etc.).
Treatment of patients under age 18.
Same as other antidepressants, maprotiline increased the risk compared to placebo of suicidal thinking and behaviour (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of maprotiline or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behaviour. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Maprotiline is not approved for use in paediatric patients.
Pregnancy and Lactation
Reproduction studies have been performed in female laboratory rabbits, mice, and rats at doses up to 1.3, 7, and 9 times the maximum daily human dose respectively and have revealed no evidence of impaired fertility or harm to the foetus due to maprotiline. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Maprotiline is excreted in breast milk. At steady-state, the concentrations in milk correspond closely to the concentrations in whole blood. Caution should be exercised when maprotiline hydrochloride is administered to a nursing woman.
The side-effect profile is comparable to other TCAs and TeCAS and many of the following are due to anticholinergic (which are less prominent than those of most TCAs) and antihistamine effects. Most often seen are:
Dry mouth (and complications of long-term uncontrolled dry mouth such as dental caries).
Nausea (rare, incidence of ~2%) and vomiting.
Increased appetite and weight gain.
Orthostatic hypotension, hypertension, sinus tachycardia, heart-block, arrhythmias and other cardiac effects.
Sexual dysfunction in men: impotence, priapism, delayed ejaculation, anejaculation, decreased libido.
Sexual dysfunction in women: decreased libido, vaginal dryness, painful sexual intercourse, anorgasmia.
Allergic skin reactions such as rash or urticaria (more often than with other antidepressants).
Rarely, severe skin reactions such as erythema multiforme can occur.
Induction of hypomania or mania in patients suffering from underlying bipolar affective disorder.
Seizures (at high doses).
Rare haematological complications: leukopenia and agranulocytosis (dangerous fall in white blood cells).
Maprotiline causes a strong initial sedation (first 2 to 3 weeks of therapy) and is therefore indicated to treat agitated patients or those with suicidal risks. It causes anticholinergic side effects (dry mouth, constipation, confusion, tachycardia) with a lower incidence than amitriptyline. Originally, the manufacturer claimed that maprotiline is better tolerated than other TCAs and TeCAs. However, seizures, leukopenia and skin reactions occur more often with maprotiline than with comparable drugs like amitriptyline.
Maprotiline has no known potential for abuse and psychological dependence.
Withdrawal symptoms frequently seen when treatment with maprotiline is stopped abruptly (agitation, anxiety, insomnia, sometimes activation of mania or rebound depression) are not indicative of addiction and can be avoided by reducing the daily dose of maprotiline gradually by approximately 25% each week. If treatment has to be stopped at once due to medical reasons, the use of a benzodiazepine (e.g. lorazepam, clonazepam, or alprazolam) for a maximum of 4 weeks as needed will usually suppress withdrawal symptoms.
Maprotiline has a wide range of possible interactions. Some are typical for TCAs and TeCAs, others are caused by specific metabolic effects (e.g. high plasma-protein-binding) of maprotiline:
Irreversible MAO-inhibitors: agitation, delirium, coma, hyperpyrexia (high fever), seizures and severe changes in blood pressure.
Treatment-resistant and hospitalised patients may be treated concomitantly with an MAO-inhibitor, if they are closely monitored and if the initial dose of the MAO-Inhibitor is low.
Increased Drug Actions
Other antidepressants, barbiturates, narcotics, sedating antihistamines, anticonvulsive drugs, alcohol, resulting in increased central depression.
Anticholinergics (antiparkinsonian agents, TCAs and TeCAs) – resulting in increased anticholinergic action (dry mouth, constipation etc.).
Sympathomimetics (also those used in local anaesthetics like noradrenaline):
Clonidine: antihypertensive effects decreased and risk of (massive) rebound hypertension.
Other Types of Interaction
Drugs, which induce certain enzymes in the liver, e.g. barbiturates, phenytoin, carbamazepine and oral anti-conceptive drugs, enhance the elimination of maprotiline and decrease its antidepressant effects.
Additionally the blood-concentrations of phenytoin or carbamazepine may be increased, leading to a higher incidents of side effects.
The concomitant use of maprotiline and neuroleptics can lead to increased maprotiline blood-levels and to seizures.
Combining maprotiline and thioridazine could induce severe arrhythmias.
Additionally, increased blood-levels of Maprotiline are possible, if certain beta-blocking agents (e.g. Propranolol) are given concomitantly.
Maprotiline may amplify the actions of coumarin-type anticoagulants (e.g. warfarin, phenprocoumon).
The plasma-prothrombin-activity must be assessed closely in order to avoid overt bleedings.
Maprotiline can increase the actions of oral antidiabetic drugs (sulfonylureas) and Insulin.
Diabetic patients should have regular assessments of their blood-glucose-levels.
The concomitant application with fluoxetine or fluvoxamine may lead to significantly increased plasma-levels of maprotiline with a high incidence of maprotiline side effects.
Due to the long half-lives of fluoxetine and fluvoxamine this effect may persist.
Maprotiline exhibits strong effects as a norepinephrine reuptake inhibitor with only weak actions the reuptake of serotonin and dopamine. It is also a strong antagonist of the H1 receptor, a moderate antagonist of the 5-HT2 and α1-adrenergic receptors, and a weak antagonist of the D2 and muscarinic acetylcholine receptors. Maprotiline has also more recently been identified as a potent antagonist of the 5-HT7 receptor, with this action potentially playing an important role in its antidepressant effectiveness. The drug is a strong antihistamine, but unlike most TCAs, has minimal anticholinergic effects.
The pharmacological profile of maprotiline explains its antidepressant, sedative, anxiolytic, and sympathomimetic activities. In accordance to the pharmacological characteristics it is used in the treatment of depression, such as depression associated with agitation or anxiety. Additionally, it shows strong antagonism against reserpine-induced effects in animal studies, as do the other ‘classical’ antidepressants. Although maprotiline behaves in most regards as a ‘first-generation antidepressant’ it is commonly referred to as ‘second-generation antidepressant’.
The postulated mechanism of maprotiline is that it acts primarily by potentiation of central adrenergic synapses by blocking reuptake of norepinephrine at nerve endings. This pharmacological action is thought to be primarily responsible for the drug’s antidepressant and anxiolytic effects. It is a strong norepinephrine reuptake inhibitor with only weak effects on serotonin and dopamine reuptake. At higher doses however, maprotiline increases serotonergic transmission and increases the level of serotonin available.
After oral use absorption is good. It binds to plasma proteins 80-90%. Maximal plasma concentration is reached 6 hours after use. The mean time to peak is 12 hours. The terminal half-life of averages 51 hours.
Maprotiline is a tetracyclic compound and is grouped with the TeCAs. Its chemical name is N-methyl-9,10-ethanoanthracen-9(10H)-propylamine. The drug has a dibenzobicyclo[2.2.2]octadiene (9,10-dihydro-9,10-ethanoanthracene) ring system; that is, a tricyclic anthracene ring system with an ethylene bridge across the central ring. This results in it having a unique three-dimensional central ring (a bicyclo[2.2.2]octane or 1,4-endoethylenecyclohexane ring) and being a tetracyclic rather than a tricyclic compound. However, it could also or alternatively be considered to be a tricyclic and hence a TCA. In addition to its heterocyclic ring system, maprotiline has an alkylamine side chain attached similarly to other TCAs (but notably unlike other TeCAs). In terms of the side chain, it is a secondary amine, and its chemical structure, aside from the ethylene link in the central ring, is similar to that of secondary amine TCAs like nortriptyline and protriptyline. In accordance, the pharmacology of maprotiline is very similar to that of secondary amine TCAs.
Maprotiline is very similar in structure to the anxiolytic, sedative, and muscle relaxant drug benzoctamine (Tacitin). The only structural difference between the two compounds is in the length of their side chain. However, this modification results in considerable differences in their pharmacological and therapeutic effects.
Society and Culture
Maprotiline is the English and French generic name of the drug and its INN, USAN, BAN, and DCF, while maprotiline hydrochloride is its USAN, USP, BANM and JAN. Its generic name in Spanish and Italian and its DCIT are maprotilina, in German is maprotilin, and in Latin is maprotilinum. The methanesulfonate (mesylate) salt is known unofficially as maprotiline methanesulfonate.
Maprotiline is marketed throughout the world mainly under the brand name Ludiomil. It is also available under a variety of other brand names including Deprilept, Maprolu, and Psymion among others.
CBT Toolbox for Children and Adolescents: Over 220 Worksheets & Exercises for Trauma, ADHD, Autism, Anxiety, Depression & Conduct Disorders.
Author(s): Lisa Phifer.
Edition: First (1st).
Publisher: PESI Publishing & Media.
Type(s): Spiral-bound, Paperback and Kindle.
The CBT Toolbox for Children and Adolescents gives you the resources to help the children in your life handle their daily obstacles with ease. Inside this workbook you’ll find hundreds of worksheets, exercises, and activities to help treat:
Written by clinicians and teachers with decades of experience working with kids, these practical and easy-to-use therapy tools are vital to teaching children how to cope with and overcome their deepest struggles. Step-by-step, you’ll see how the best strategies from cognitive behavioural therapy are adapted for children.
It is also effective in treating anxiety and panic disorder. The drug is also used to treat bedwetting. Imipramine is taken by mouth.
Common side effects of imipramine include dry mouth, drowsiness, dizziness, low blood pressure, rapid heart rate, urinary retention, and electrocardiogram changes. Overdose of the medication can result in death. Imipramine appears to work by increasing levels of serotonin and norepinephrine and by blocking certain serotonin, adrenergic, histamine, and cholinergic receptors.
Imipramine was discovered in 1951 and was introduced for medical use in 1957. It was the first TCA to be marketed. Imipramine and the other TCAs have decreased in use in recent decades, due to the introduction of the selective serotonin reuptake inhibitors (SSRIs), which have fewer side effects and are safer in overdose.
The parent compound of imipramine, 10,11-dihydro-5H-dibenz[b,f]azepine (dibenzazepine), was first synthesized in 1899, but no pharmacological assessment of this compound or any substituted derivatives was undertaken until the late 1940s. Imipramine was first synthesized in 1951, as an antihistamine. The antipsychotic effects of chlorpromazine were discovered in 1952, and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia. The medication was tested in several hundred patients with psychosis, but showed little effectiveness. However, imipramine was serendipitously found to possess antidepressant effects in the mid-1950s following a case report of symptom improvement in a woman with severe depression who had been treated with it. This was followed by similar observations in other patients and further clinical research. Subsequently, imipramine was introduced for the treatment of depression in Europe in 1958 and in the United States in 1959. Along with the discovery and introduction of the monoamine oxidase inhibitor iproniazid as an antidepressant around the same time, imipramine resulted in the establishment of monoaminergic drugs as antidepressants.
In the late 1950s, imipramine was the first TCA to be developed (by Ciba). At the first international congress of neuropharmacology in Rome, September 1958 Dr Freyhan from the University of Pennsylvania discussed as one of the first clinicians the effects of imipramine in a group of 46 patients, most of them diagnosed as “depressive psychosis”. The patients were selected for this study based on symptoms such as depressive apathy, kinetic retardation and feelings of hopelessness and despair. In 30% of all patients, he reported optimal results, and in around 20%, failure. The side effects noted were atropine-like, and most patients suffered from dizziness. Imipramine was first tried against psychotic disorders such as schizophrenia, but proved ineffective. As an antidepressant, it did well in clinical studies and it is known to work well in even the most severe cases of depression. It is not surprising, therefore, that imipramine may cause a high rate of manic and hypomanic reactions in hospitalised patients with pre-existing bipolar disorder, with one study showing that up to 25% of such patients maintained on Imipramine switched into mania or hypomania. Such powerful antidepressant properties have made it favourable in the treatment of treatment-resistant depression.
Before the advent of SSRIs, its sometimes intolerable side-effect profile was considered more tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released TCAs. Since the 1990s, it has no longer been used as commonly, but is sometimes still prescribed as a second-line treatment for treating major depression . It has also seen limited use in the treatment of migraines, ADHD, and post-concussive syndrome. Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome. In paediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis.
Imipramine is used in the treatment of depression and certain anxiety disorders. It is similar in efficacy to the antidepressant drug moclobemide. It has also been used to treat nocturnal enuresis because of its ability to shorten the time of delta wave stage sleep, where wetting occurs. In veterinary medicine, imipramine is used with xylazine to induce pharmacologic ejaculation in stallions. Blood levels between 150-250 ng/mL of imipramine plus its metabolite desipramine generally correspond to antidepressant efficacy.
Imipramine is available in the form of oral tablets and capsules.
Combining it with alcohol consumption causes excessive drowsiness. It may be unsafe during pregnancy.
Those listed in italics below denote common side effects.
Imipramine affects numerous neurotransmitter systems known to be involved in the aetiology of depression, anxiety, attention-deficit hyperactivity disorder (ADHD), enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.
The mechanisms of imipramine’s actions include, but are not limited to, effects on:
Serotonin: very strong reuptake inhibition.
Norepinephrine: strong reuptake inhibition.
Desipramine has more affinity to norepinephrine transporter than imipramine.
Imipramine blocks D2 receptors.
Imipramine, and its metabolite desipramine, have no appreciable affinity for the dopamine transporter (Ki = 8,500 and >10,000 nM, respectively).
Imipramine is an anticholinergic, specifically an antagonist of the muscarinic acetylcholine receptors.
Thus, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the “dementing” effects of anticholinergics increases the potential of imipramine to cause hallucinations, confusion and delirium in this population.
Imipramine antagonises adrenergic receptors, thus sometimes causing orthostatic hypotension.
Activity on sigma receptors is present, but it is very weak (Ki = 520 nM) and it is about half that of amitriptyline (Ki = 300 nM).
Imipramine is an antagonist of the histamine H1 receptors.
BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis.
It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours.
Chronic imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promoter, and also reduced expression of hippocampal HDAC5.
Within the body, imipramine is converted into desipramine (desmethylimipramine) as a metabolite.
Imipramine 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 desipramine (N-desmethylimipramine), clomipramine (3-chloroimipramine), trimipramine (2′-methylimipramine or β-methylimipramine), and lofepramine (N-(4-chlorobenzoylmethyl)desipramine). Imipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of imipramine is 3-(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 C19H24N2 with a molecular weight of 280.407 g/mol. The drug is used commercially mostly as the hydrochloride salt; the embonate (pamoate) salt is used for intramuscular administration and the free base form is not used. The CAS Registry Number of the free base is 50-49-7, of the hydrochloride is 113-52-0, and of the embonate is 10075-24-8.
Society and Culture
Imipramine is the English and French generic name of the drug and its INN, BAN, and DCF, while imipramine hydrochloride is its USAN, USP, BANM, and JAN. Its generic name in Spanish and Italian and its DCIT are imipramina, in German is imipramin, and in Latin is imipraminum. The embonate salt is known as imipramine pamoate.
Imipramine is marketed throughout the world mainly under the brand name Tofranil. Imipramine pamoate is marketed under the brand name Tofranil-PM for intramuscular injection.
Imipramine is available for medical use widely throughout the world, including in the United States, the United Kingdom, elsewhere in Europe, Brazil, South Africa, Australia, and New Zealand.
Lofepramine, sold under the brand names Gamanil, Lomont, and Tymelyt among others, is a tricyclic antidepressant (TCA) which is used to treat depression.
The TCAs are so named as they share the common property of having three rings in their chemical structure. Like most TCAs lofepramine is believed to work in relieving depression by increasing concentrations of the neurotransmitters norepinephrine and serotonin in the synapse, by inhibiting their reuptake. It is usually considered a third-generation TCA, as unlike the first- and second-generation TCAs it is relatively safe in overdose and has milder and less frequent side effects.
Lofepramine is not available in the United States, Canada, Australia or New Zealand, although it is available in Ireland, Japan, South Africa and the United Kingdom, among other countries.
Lofepramine was developed by Leo Läkemedel AB. It first appeared in the literature in 1969 and was patented in 1970. The drug was first introduced for the treatment of depression in either 1980 or 1983.
In the United Kingdom, lofepramine is licensed for the treatment of depression which is its primary use in medicine.
Lofepramine is an efficacious antidepressant with about 64% patients responding to it.
To be used with caution, or not at all, for people with the following conditions:
Impaired kidney or liver function.
Narrow angle glaucoma.
In the immediate recovery period after myocardial infarction.
In arrhythmias (particularly heart block).
In severe liver and/or severe renal impairment.
And in those being treated with amiodarone or terfenadine.
Pregnancy and Lactation
Lofepramine use during pregnancy is advised against unless the benefits clearly outweigh the risks. This is because its safety during pregnancy has not been established and animal studies have shown some potential for harm if used during pregnancy. If used during the third trimester of pregnancy it can cause insufficient breathing to meet oxygen requirements, agitation and withdrawal symptoms in the infant. Likewise its use by breastfeeding women is advised against, except when the benefits clearly outweigh the risks, due to the fact it is excreted in the breast milk and may therefore adversely affect the infant. Although the amount secreted in breast milk is likely too small to be harmful.
The most common adverse effects (occurring in at least 1% of those taking the drug) include agitation, anxiety, confusion, dizziness, irritability, abnormal sensations, like pins and needles, without a physical cause, sleep disturbances (e.g. sleeplessness) and a drop in blood pressure upon standing up. Less frequent side effects include movement disorders (like tremors), precipitation of angle closure glaucoma and the potentially fatal side effects paralytic ileus and neuroleptic malignant syndrome.
Dropout incidence due to side effects is about 20%.
Side effects with unknown frequency include (but are not limited to):
Effects on the heart:
Abnormal heart rhythm.
Sudden cardiac death.
High heart rate.
Abnormal blood cell counts.
Blood sugar changes.
Low blood sodium levels.
Breast enlargement, including in males.
Spontaneous breast milk secretion that is unrelated to breastfeeding or pregnancy.
Effects on the skin:
Increased light sensitivity.
Mental / neurologic effects:
Difficulty emptying the bladder.
Difficulty talking due to difficulties in moving the required muscles.
Ringing in the ears.
Sexual dysfunction, such as impotence.
If abruptly stopped after regular use it can cause withdrawal effects such as sleeplessness, irritability and excessive sweating.
Compared to other TCAs, lofepramine is considered to be less toxic in overdose. Its treatment is mostly a matter of trying to reduce absorption of the drug, if possible, using gastric lavage and monitoring for adverse effects on the heart.
Lofepramine is known to interact with:
Alcohol. Increased sedative effect.
Altretamine. Risk of severe drop in blood pressure upon standing.
Analgesics (painkillers). Increased risk of ventricular arrhythmias.
Anticoagulants (blood thinners). Lofepramine may inhibit the metabolism of certain anticoagulants leading to a potentially increased risk of bleeding.
Anticonvulsants. Possibly reduce the anticonvulsant effect of antiepileptics by lowering the seizure threshold.
Antihistamines. Possible increase of antimuscarinic (potentially increasing risk of paralytic ileus, among other effects) and sedative effects.
Antimuscarinics. Possible increase of antimuscarinic side-effects.
Anxiolytics and hypnotics. Increased sedative effect.
Apraclonidine. Avoidance advised by manufacturer of apraclonidine.
Brimonidine. Avoidance advised by manufacturer of brimonidine.
Clonidine. Lofepramine may reduce the antihypertensive effects of clonidine.
Digoxin. May increase risk of irregular heart rate.
Disulfiram. May require a reduction of lofepramine dose.
Diuretics. Increased risk of reduced blood pressure on standing.
Cimetidine, diltiazem, verapamil. May increase concentration of lofepramine in the blood plasma.
Hydralazine. Enhanced hypotensive effect.
Monoamine oxidase inhibitors (MAOIs). Advised not to be started until at least 2 weeks after stopping MAOIs. MAOIs are advised not to be started until at least 1-2 weeks after stopping TCAs like lofepramine.
Moclobemide. Moclobemide is advised not to be started until at least one week after treatment with TCAs is discontinued.
Nitrates. Could possibly reduce the effects of sublingual tablets of nitrates (failure to dissolve under tongue owing to dry mouth).
Rifampicin. May accelerate lofepramine metabolism thereby decreasing plasma concentrations of lofepramine.
Ritonavir. May increase lofepramine concentration in the blood plasma.
Thyroid hormones. Effects on the heart of lofepramine may be exacerbated.
Lofepramine is a strong inhibitor of norepinephrine reuptake and a moderate inhibitor of serotonin reuptake. It is a weak-intermediate level antagonist of the muscarinic acetylcholine receptors.
Lofepramine has been said to be a prodrug of desipramine, although there is also evidence against this notion.
Lofepramine is extensively metabolised, via cleavage of the p-chlorophenacyl group, to the TCA, desipramine, in humans. However, it is unlikely this property plays a substantial role in its overall effects as lofepramine exhibits lower toxicity and anticholinergic side effects relative to desipramine while retaining equivalent antidepressant efficacy. The p-chlorophenacyl group is metabolised to p-chlorobenzoic acid which is then conjugated with glycine and excreted in the urine. The desipramine metabolite is partly secreted in the faeces. Other routes of metabolism include hydroxylation, glucuronidation, N-dealkylation and N-oxidation.
Lofepramine 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, clomipramine, and trimipramine. Lofepramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine. Unlike other tertiary amine TCAs, lofepramine has a bulky 4-chlorobenzoylmethyl substituent on its amine instead of a methyl group. Although lofepramine is technically a tertiary amine, it acts in large part as a prodrug of desipramine, and is more similar to secondary amine TCAs in its effects. Other secondary amine TCAs besides desipramine include nortriptyline and protriptyline. The chemical name of lofepramine is N-(4-chlorobenzoylmethyl)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine and its free base form has a chemical formula of C26H27ClN2O with a molecular weight of 418.958 g/mol. The drug is used commercially mostly as the hydrochloride salt; the free base form is not used. The CAS Registry Number of the free base is 23047-25-8 and of the hydrochloride is 26786-32-3.
Society and Culture
Lofepramine is the generic name of the drug and its INN and BAN, while lofepramine hydrochloride is its USAN, BANM, and JAN. Its generic name in French and its DCF are lofépramine, in Spanish and Italian and its DCIT are lofepramina, in German is lofepramin, and in Latin is lofepraminum.
Brand names of lofepramine include Amplit, Deftan, Deprimil, Emdalen, Gamanil, Gamonil, Lomont, Tymelet, and Tymelyt.
In the United Kingdom, lofepramine is marketed (as the hydrochloride salt) in the form of 70 mg tablets and 70 mg/5 mL oral suspension.
A formulation containing lofepramine and the amino acid phenylalanine is under investigation as a treatment for fatigue as of 2015.
Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression.
It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or “second-generation” TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.
Trimipramine was developed by Rhône-Poulenc. It was patented in 1959 and first appeared in the literature in 1961. The drug was first introduced for medical use in 1966, in Europe. It was not introduced in the United States until later in 1979 or 1980.
Trimipramine’s primary use in medicine is in the treatment of major depressive disorder, especially where sedation is helpful due to its prominent sedative effects. The drug is also an effective anxiolytic, and can be used in the treatment of anxiety. In addition to depression and anxiety, trimipramine is effective in the treatment of insomnia, and unlike most other hypnotics, does not alter the normal sleep architecture. In particular, it does not suppress REM sleep, and dreams are said to “brighten” during treatment. Trimipramine also has some weak antipsychotic effects with a profile of activity described as similar to that of clozapine, and may be useful in the treatment of psychotic symptoms such as in delusional depression or schizophrenia.
Recent myocardial infarction.
Any degree of heart block or other cardiac arrhythmias.
Severe liver disease.
Hypersensitivity to trimipramine or to any of the excipients.
The side effects of trimipramine have been said to be similar to those of other tertiary amine TCAs, with a preponderance of anticholinergic and sedative effects. However, trimipramine has also been said to be associated with a different side effect profile compared to other TCAs and in general with fewer side effects, chiefly due to its lack of norepinephrine reuptake inhibition and relatively lower anticholinergic effects (although it is still a potent anticholinergic). Somnolence is the most common side effect of the drug. Dry mouth is the most common anticholinergic side effect, but others like constipation, urinary retention, and blurred vision are also present.
It is described as being associated with minimal or no orthostatic hypotension, at least in comparison to clomipramine, in spite of its potent and comparable activity as an alpha-1 blocker. However, it has also been said to have a rate of orthostatic hypotension similar to that of other TCAs. Trimipramine is said to be less epileptogenic than other TCAs, although seizures have still been reported in association with it. It is also less cardiotoxic than other TCAs and cardiotoxicity is said to be minimal, with a “very favourable profile”.
List of Side Effects
Common adverse effects include:
Especially common with trimipramine compared to the other TCAs.
Anticholinergic effects including:
Urinary hesitancy or retention.
Reduced GI motility.
Tachycardia (high heart rate).
Anticholinergic delirium (particularly in the elderly and in Parkinson’s disease).
Sexual dysfunction including impotence, loss of libido and other sexual adverse effects.
Adverse effects with an unknown incidence includes:
Extrapyramidal side effects (e.g. parkinsonism, dystonia, etc.).
Increased liver function tests.
Rare adverse effects include:
Syndrome of inappropriate secretion of antidiuretic hormone.
Trimipramine should not be given with sympathomimetic agents such as epinephrine (adrenaline), ephedrine, isoprenaline, norepinephrine (noradrenaline), phenylephrine and phenylpropanolamine.
Barbiturates may increase the rate of metabolism. Trimipramine should be administered with care in patients receiving therapy for hyperthyrodism.
Heavy exposure to any tricyclic antidepressants was associated with an elevated rate ratio for breast cancer 11–15 years later. However, on tests done on Drosophila melanogaster, nongenotoxic TCAs (amitriptyline, maprotiline, nortriptyline, and protriptyline), and genotoxic TCAs (amoxapine, clomipramine, desipramine, doxepin, imipramine, and trimipramine) were identified.
The mechanism of action of trimipramine in terms of its antidepressant effects differs from that of other TCAs and is not fully clear. The mechanism of action of its anxiolytic effects is similarly unclear. Trimipramine is a very weak reuptake inhibitor of serotonin, norepinephrine, and dopamine (see below), and unlike most other TCAs, has been claimed to be devoid of clinically significant monoamine reuptake inhibition. The effects of the drug are thought to be mainly due to receptor antagonism as follows:
Very strong: H1.
Strong: 5-HT2A, α1-adrenergic.
Moderate: D2, mACh.
Weak: 5-HT2C, D1, α2-adrenergic.
In spite of its atypical nature and different profile of activity, trimipramine has been shown in head-to-head clinical studies to possess equivalent effectiveness to other antidepressants, including but not limited to other TCAs (e.g. amitriptyline, imipramine, doxepin, amineptine), tetracyclic antidepressants (TeCAs) (e.g. maprotiline), monoamine oxidase inhibitors (MAOIs) (e.g. phenelzine, isocarboxazid), and selective serotonin reuptake inhibitors (e.g. fluoxetine). In addition, trimipramine has been found to possess greater anxiolytic effects than other TCAs such as amitriptyline and doxepin in head-to-head comparisons. Indeed, its prominent anxiolytic effects have been said to distinguish it from most other TCAs. The atypicality of trimipramine in relation to its lack of monoamine reuptake inhibition is described as challenging the monoamine hypothesis of depression.
The major metabolite of trimipramine, desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants.
Monoamine Reuptake Inhibition
Studies have generally found only very weak inhibition of serotonin and norepinephrine reuptake with trimipramine, and the drug has been described by various authors as devoid of monoamine reuptake inhibition. Richelson & Pfenning (1984) found a relatively high Ki for the NET of 510 nM in rat brain synaptosomes and Tatsumi et al. (1997) found a relatively high KD of 149 nM for the SERT in human HEK293 cells, but other authors and a more recent study with an improved design have not had the same findings. In the most recent study, by Haenisch et al. (2011), the researchers suggested that the discrepant findings from the Tatsumi et al. study were due to methodological differences, in particular the use of radioligand binding in isolated membranes (KD) to study interactions as opposed to actual functional reuptake inhibition (IC50).
Trimipramine is extensively metabolized, so its metabolites may contribute to its pharmacology, including potentially to monoamine reuptake inhibition. In what was the only study to date to have assessed the activity profiles of the metabolites of trimipramine, Haenisch et al. (2011) assayed desmethyltrimipramine, 2-hydroxytrimipramine, and trimipramine-N-oxide in addition to trimipramine and found that these metabolites showed IC50 values for the SERT, NET, and DAT similar to those of trimipramine (see table to the right). Like other secondary amine TCAs, desmethyltrimipramine was slightly more potent than trimipramine in its norepinephrine reuptake inhibition but less potent in its inhibition of serotonin reuptake. However, desmethyltrimipramine still showed only very weak inhibition of the NET.
Therapeutic concentrations of trimipramine are between 0.5 and 1.2 μM (150-350 ng/mL) and hence significant monoamine reuptake inhibition would not be expected with it or its metabolites. However, these concentrations are nearly 2-fold higher if the active metabolites of trimipramine are also considered, and studies of other TCAs have found that they cross the blood-brain barrier and accumulate in the brain to levels of up to 10-fold those in the periphery. As such, trimipramine and its metabolites might at least partially inhibit reuptake of serotonin and/or norepinephrine, though not of dopamine, at therapeutic concentrations, and this could be hypothesized to contribute at least in part to its antidepressant effects. This is relevant as Haenisch et al. has stated that these are the only actions known at present which could explain or at least contribute to the antidepressant effects of trimipramine. That said, blockade of the 5-HT2A, 5-HT2C, and α2-adrenergic receptors, as with mirtazapine, has also been implicated in antidepressant effects.
In any case, there is also clinical and animal evidence that trimipramine does not inhibit the reuptake of monoamines. Unlike other TCAs, it does not downregulate β3-adrenergic receptors, which is likely the reason that it does not cause orthostatic hypotension. It can be safely combined with MAOIs apparently without risk of serotonin syndrome or hypertensive crisis. Indeed, in rabbits, whereas hyperpyrexia (a symptom of serotonin syndrome) occurs with imipramine and an MAOI and to a lesser extent with amitriptyline and an MAOI, it does not occur at all with trimipramine and an MAOI, likely due to trimipramine’s lack of serotonin reuptake inhibition.
Trimipramine is a very potent antihistamine; it has the third highest affinity for the H1 receptor (Ki = 0.27 nM) after mirtazapine (Ki = 0.14 nM) and doxepin (Ki = 0.24 nM) among the TCAs and tetracyclic antidepressants (TeCAs). The TeCA mianserin (Ki = 0.40) and the TCA amitriptyline (Ki = 1.0) are also very potent H1 receptor antagonists, whereas other TCAs and TeCAs are less potent. These TCAs and TeCAs, including trimipramine, are far more potent than the standard antihistamine diphenhydramine (approximately 800 times for doxepin and 250 times for trimipramine), and are among the most potent antihistamines available.
Trimipramine is also an antagonist of the H2 receptor with lower potency and has been found to be effective in the treatment of duodenal ulcers.
As a Hypnotic
Blockade of the H1 receptor is responsible for the sedative effects of trimipramine and other TCAs and their effectiveness in the treatment of insomnia.
Most antidepressants suppress REM sleep, in parallel with their alleviation of depressive symptoms (although suppression of REM sleep is not required for antidepressant effects). This includes TCAs (e.g. amitriptyline, nortriptyline), TeCAs (e.g. mianserin, maprotiline), MAOIs (e.g. clorgiline, pargyline), and SSRIs (e.g. fluoxetine, zimelidine, indalpine). Trimipramine is unique in that it is an exception and produces antidepressant effects without compromising or otherwise affecting REM sleep. Even long-term treatment with trimipramine for up to 2 years has not been found to suppress REM sleep. In addition, trimipramine has been found to decrease nocturnal cortisol levels to normal and to normalize cortisol response in depressed patients; hence, it normalizes the hypothalamic-pituitary-adrenal axis, whereas imipramine and other antidepressants tend to increase nocturnal cortisol secretion.
In clinical studies, trimipramine has been found in doses of 50 to 200 mg/day to significantly increase sleep efficiency and total sleep time and to decrease waking time for up to 3 weeks in patients with insomnia. It also improved subjectively perceived sleep quality and well-being during daytime. Monitoring of patients upon discontinuation of trimipramine found that it did not cause rebound insomnia or worsening of sleep quality in subjective evaluations of sleep, although objective measurements found total sleep time below baseline in a subset of patients during trimipramine withdrawal.
Trimipramine is a weak but significant antagonist of the dopamine D1 and D2 receptors, and also binds to the D4 receptor (Ki = 275 nM). Its affinities for various monoamine receptors including the D2 and 5-HT2A receptors closely resemble those of the atypical antipsychotic clozapine. In accordance, high doses of trimipramine have been found to have antipsychotic effects in schizophrenic patients, notably without causing extrapyramidal symptoms, and trimipramine has recently been found to be effective in reducing psychotic symptoms in patients with delusional depression. The lack of extrapyramidal symptoms with trimipramine may be related to its affinity for the D4 receptor, these both being properties it shares with clozapine. Unlike other TCAs, but reminiscent of antipsychotics, trimipramine has been found to markedly increase plasma prolactin levels (a marker of D2 receptor antagonism) at a dose of 75 mg/day and to increase nocturnal prolactin secretion at doses of 75 and 200 mg/day. These findings are suggestive of important antidopaminergic actions of trimipramine.
Unlike various other TCAs, trimipramine shows marked antagonism of presynaptic dopamine autoreceptors, potentially resulting in increased dopaminergic neurotransmission. This effect has also been observed with low-potency tricyclic antipsychotics like thioridazine and chlorprothixene. Notably, these two antipsychotics have been claimed many times to also possess antidepressant effects. As such, blockade of inhibitory dopamine autoreceptors and hence facilitation of dopaminergic signalling could be involved in the antidepressant effects of trimipramine. However, other authors have attributed the claimed antidepressant effects of antipsychotics like the two previously mentioned to α2-adrenergic receptor antagonism, although trimipramine specifically has only weak affinity for this receptor. Aside from antidepressant effects, low doses of antipsychotics have been found to increase REM sleep, and so dopamine autoreceptor antagonism could be involved in the unique effects of trimipramine in terms of REM sleep and sleep architecture.
The time to peak concentrations following a dose is 2 to 4 hours. The typical antidepressant therapeutic range of trimipramine concentrations is 150 to 300 ng/mL. The terminal half-life of trimipramine has been variously reported to be as little as 8 hours (in plasma) and as long as 24 hours. In any case, the terminal half-life of trimipramine is described as shorter than that of other TCAs, which makes it ideal for use in the treatment of insomnia.
Trimipramine is a racemic compound with two enantiomers. CYP2C19 is responsible for the demethylation of (D)- and (L)-trimipramine to (D)- (L)-desmethyltrimipramine, respectively, and CYP2D6 is responsible for the 2-hydroxylation of (D)- and (L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively. CYP2D6 also metabolises (L)-trimipramine into (L)-2-hydroxytrimipramine.
Trimipramine 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 clomipramine. Trimipramine is a derivative of imipramine with a methyl group added to its side chain and is also known as 2′-methylimipramine or β-methylimipramine. The tri- prefix in its name may allude to the fact that its side chain features three methyl groups. Trimipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desmethyltrimipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), and doxepin. The chemical name of trimipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine and its free base form has a chemical formula of C20H26N2 with a molecular weight of 294.434 g/mol. The drug is used commercially as the maleate salt. The CAS Registry Number of the free base is 739-71-9 and of the maleate is 521-78-8.
Society and Culture
Trimipramine is the generic name of the drug and its INN, USAN, BAN, and DCF, while trimipramine maleate is its USAN, USP, BANM, and JAN. Its generic name in Latin is trimipraminum, in German is trimipramin, and in Spanish is trimipramina.
Trimipramine is marketed throughout the world mainly under the brand name Surmontil. Other notable brand names of trimipramine have included Herphonal, Rhotrimine, Sapilent, Stangyl, and Tydamine.
Trimipramine is no longer marketed in Australia, though it was previously.
It acts as a relatively selective norepinephrine reuptake inhibitor (SNRI), though it does also have other activities such as weak serotonin reuptake inhibitory, α1-blocking, antihistamine, and anticholinergic effects. The drug is not considered a first-line treatment for depression since the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants, which have fewer side effects and are safer in overdose.
Desipramine was developed by Geigy. It first appeared in the literature in 1959 and was patented in 1962. The drug was first introduced for the treatment of depression in 1963 or 1964.
Desipramine is primarily used for the treatment of depression. It may also be useful to treat symptoms of attention-deficit hyperactivity disorder (ADHD). Evidence of benefit is only in the short term, and with concerns of side effects its overall usefulness is not clear. Desipramine at very low doses is also used to help reduce the pain associated with functional dyspepsia. It has also been tried, albeit with little evidence of effectiveness, in the treatment of cocaine dependence. Evidence for usefulness in neuropathic pain is also poor.
Desipramine tends to be less sedating than other TCAs and tends to produce fewer anticholinergic effects such as dry mouth, constipation, urinary retention, blurred vision, and cognitive or memory impairments.
Desipramine is particularly toxic in cases of overdose, compared to other antidepressants. Any overdose or suspected overdose of desipramine is considered to be a medical emergency and can result in death without prompt medical intervention.
Desipramine is a very potent and relatively selective norepinephrine reuptake inhibitor (NRI), which is thought to enhance noradrenergic neurotransmission Based on one study, it has the highest affinity for the norepinephrine transporter (NET) of any other TCA, and is said to be the most noradrenergic and the most selective for the NET of the TCAs. The observed effectiveness of desipramine in the treatment of ADHD was the basis for the development of the selective NRI atomoxetine and its use in ADHD.
Desipramine has the weakest antihistamine and anticholinergic effects of the TCAs. It tends to be slightly activating/stimulating rather than sedating, unlike most others TCAs. Whereas other TCAs are useful for treating insomnia, desipramine can cause insomnia as a side effect due to its activating properties. The drug is also not associated with weight gain, in contrast to many other TCAs. Secondary amine TCAs like desipramine and nortriptyline have a lower risk of orthostatic hypotension than other TCAs, although desipramine can still cause moderate orthostatic hypotension.
Desipramine is the major metabolite of imipramine and lofepramine.
Desipramine 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 (N-methyldesipramine), clomipramine, trimipramine, and lofepramine (N-(4-chlorobenzoylmethyl)desipramine). Desipramine is a secondary amine TCA, with its N-methylated parent imipramine being a tertiary amine. Other secondary amine TCAs include nortriptyline and protriptyline. The chemical name of desipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine and its free base form has a chemical formula of C18H22N2 with a molecular weight of 266.381 g/mol. The drug is used commercially mostly as the hydrochloride salt; the dibudinate salt is or has been used for intramuscular injection in Argentina (brand name Nebril) and the free base form is not used. The CAS Registry Number of the free base is 50-47-5, of the hydrochloride is 58-28-6, and of the dibudinate is 62265-06-9.
Society and Culture
Desipramine is the generic name of the drug and its INN and BAN, while desipramine hydrochloride is its USAN, USP, BAN, and JAN. Its generic name in French and its DCF are désipramine, in Spanish and Italian and its DCIT are desipramina, in German is desipramin, and in Latin is desipraminum.
Desipramine is or has been marketed throughout the world under a variety of brand names, including Irene, Nebril, Norpramin, Pertofran, Pertofrane, Pertrofran, and Petylyl among others.
The diathesis-stress model, also known as the vulnerability-stress model, is a psychological theory that attempts to explain a disorder, or its trajectory, as the result of an interaction between a predispositional vulnerability, the diathesis, and a stress caused by life experiences. The term diathesis derives from the Greek term (διάθεσις) for a predisposition, or sensibility. A diathesis can take the form of genetic, psychological, biological, or situational factors. A large range of differences exists among individuals’ vulnerabilities to the development of a disorder.
The diathesis, or predisposition, interacts with the individual’s subsequent stress response. Stress is a life event or series of events that disrupts a person’s psychological equilibrium and may catalyse the development of a disorder. Thus the diathesis-stress model serves to explore how biological or genetic traits (diatheses) interact with environmental influences (stressors) to produce disorders such as depression, anxiety, or schizophrenia. The diathesis-stress model asserts that if the combination of the predisposition and the stress exceeds a threshold, the person will develop a disorder. The use of the term diathesis in medicine and in the specialty of psychiatry dates back to the 1800s; however, the diathesis-stress model was not introduced and used to describe the development of psychopathology until it was applied to explaining schizophrenia in the 1960s by Paul Meehl.
The diathesis-stress model is used in many fields of psychology, specifically for studying the development of psychopathology. It is useful for the purposes of understanding the interplay of nature and nurture in the susceptibility to psychological disorders throughout the lifespan. Diathesis-stress models can also assist in determining who will develop a disorder and who will not. For example, in the context of depression, the diathesis-stress model can help explain why Person A may become depressed while Person B does not, even when exposed to the same stressors. More recently, the diathesis-stress model has been used to explain why some individuals are more at risk for developing a disorder than others. For example, children who have a family history of depression are generally more vulnerable to developing a depressive disorder themselves. A child who has a family history of depression and who has been exposed to a particular stressor, such as exclusion or rejection by his or her peers, would be more likely to develop depression than a child with a family history of depression that has an otherwise positive social network of peers. The diathesis-stress model has also served as useful in explaining other poor (but non-clinical) developmental outcomes.
Protective factors, such as positive social networks or high self-esteem, can counteract the effects of stressors and prevent or curb the effects of disorder. Many psychological disorders have a window of vulnerability, during which time an individual is more likely to develop disorder than others. Diathesis-stress models are often conceptualised as multi-causal developmental models, which propose that multiple risk factors over the course of development interact with stressors and protective factors contributing to normal development or psychopathology. The differential susceptibility hypothesis is a recent theory that has stemmed from the diathesis-stress model.
The term diathesis is synonymous with vulnerability, and variants such as “vulnerability-stress” are common within psychology. A vulnerability makes it more or less likely that an individual will succumb to the development of psychopathology if a certain stress is encountered. Diatheses are considered inherent within the individual and are typically conceptualised as being stable, but not unchangeable, over the lifespan. They are also often considered latent (i.e. dormant), because they are harder to recognise unless provoked by stressors.
Diatheses are understood to include genetic, biological, physiological, cognitive, and personality-related factors. Some examples of diatheses include genetic factors, such as abnormalities in some genes or variations in multiple genes that interact to increase vulnerability. Other diatheses include early life experiences such as the loss of a parent, or high neuroticism. Diatheses can also be conceptualised as situational factors, such as low socio-economic status or having a parent with depression.
Stress can be conceptualised as a life event that disrupts the equilibrium of a person’s life. For instance, a person may be vulnerable to become depressed, but will not develop depression unless they are exposed to a specific stress, which may trigger a depressive disorder. Stressors can take the form of a discrete event, such the divorce of parents or a death in the family, or can be more chronic factors such as having a long-term illness, or ongoing marital problems. Stresses can also be related to more daily hassles such as school assignment deadlines. This also parallels the popular (and engineering) usage of stress, but note that some literature defines stress as the response to stressors, especially where usage in biology influences neuroscience.
It has been long recognised that psychological stress plays a significant role in understanding how psychopathology develops in individuals. However, psychologists have also identified that not all individuals who are stressed, or go through stressful life events, develop a psychological disorder. To understand this, theorists and researchers explored other factors that affect the development of a disorder and proposed that some individuals under stress develop a disorder and others do not. As such, some individuals are more vulnerable than others to develop a disorder once stress has been introduced. This led to the formulation of the diathesis-stress model.
Sensory processing sensitivity (SPS) is a temperamental or personality trait involving “an increased sensitivity of the central nervous system and a deeper cognitive processing of physical, social and emotional stimuli”. The trait is characterised by “a tendency to ‘pause to check’ in novel situations, greater sensitivity to subtle stimuli, and the engagement of deeper cognitive processing strategies for employing coping actions, all of which is driven by heightened emotional reactivity, both positive and negative”.
Sensory processing sensitivity captures sensitivity to environment in a heritable, evolutionary-conserved trait, associated with increased information processing in the brain. Moderating sensitivity to environments in a for-better-and-for-worse fashion. Interaction with negative experiences increases risk for psychopathology. Whereas interaction with positive experiences (including interventions), increases positive outcomes. Mast cells are long-lived tissue-resident cells with an important role in many inflammatory settings including host defence to parasitic infection and in allergic reactions. Stress is known to be a mast cell activator.
There is evidence that children exposed to prenatal stress may experience resilience driven by epigenome-wide interactions.” Early life stress interactions with the epigenome show potential mechanisms driving vulnerability towards psychiatric illness. ancestral stress alters lifetime mental health trajectories via epigenetic regulation.
Carriers of congenital adrenal hyperplasia have a predeposition to stress, due to the unique nature of this gene. True rates of prevalence are not known but common genetic variants of the human Steroid 21-Hydroxylase Gene (CYP21A2) are related to differences in circulating hormone levels in the population.
Psychological distress is a known feature of generalised joint hypermobility (gJHM), as well as of its most common syndromic presentation, namely Ehlers-Danlos syndrome, hypermobility type (a.k.a. joint hypermobility syndrome – JHS/EDS-HT), and significantly contributes to the quality of life of affected individuals. Interestingly, in addition to the confirmation of a tight link between anxiety and gJHM, preliminary connections with depression, attention deficit (and hyperactivity) disorder, autism spectrum disorders, and obsessive-compulsive personality disorder were also found.
Protective factors, while not an inherent component of the diathesis-stress model, are of importance when considering the interaction of diatheses and stress. Protective factors can mitigate or provide a buffer against the effects of major stressors by providing an individual with developmentally adaptive outlets to deal with stress. Examples of protective factors include a positive parent-child attachment relationship, a supportive peer network, and individual social and emotional competence.
Throughout the Lifespan
Many models of psychopathology generally suggest that all people have some level of vulnerability towards certain mental disorders, but posit a large range of individual differences in the point at which a person will develop a certain disorder. For example, an individual with personality traits that tend to promote relationships such as extroversion and agreeableness may engender strong social support, which may later serve as a protective factor when experiencing stressors or losses that may delay or prevent the development of depression. Conversely, an individual who finds it difficult to develop and maintain supportive relationships may be more vulnerable to developing depression following a job loss because they do not have protective social support. An individual’s threshold is determined by the interaction of diatheses and stress.
Windows of vulnerability for developing specific psychopathologies are believed to exist at different points of the lifespan. Moreover, different diatheses and stressors are implicated in different disorders. For example, breakups and other severe or traumatic life stressors are implicated in the development of depression. Stressful events can also trigger the manic phase of bipolar disorder and stressful events can then prevent recovery and trigger relapse. Having a genetic disposition for becoming addicted and later engaging in binge drinking in college are implicated in the development of alcoholism. A family history of schizophrenia combined with the stressor of being raised in a dysfunctional family raises the risk of developing schizophrenia.
Diathesis-stress models are often conceptualised as multi-causal developmental models, which propose that multiple risk factors over the course of development interact with stressors and protective factors contributing to normal development or psychopathology. For example, a child with a family history of depression likely has a genetic vulnerability to depressive disorder. This child has also been exposed to environmental factors associated with parental depression that increase their vulnerability to developing depression as well. Protective factors, such as strong peer network, involvement in extracurricular activities, and a positive relationship with the non-depressed parent, interact with the child’s vulnerabilities in determining the progression to psychopathology versus normative development.
Some theories have branched from the diathesis-stress model, such as the differential susceptibility hypothesis, which extends the model to include a vulnerability to positive environments as well as negative environments or stress. A person could have a biological vulnerability that when combined with a stressor could lead to psychopathology (diathesis-stress model); but that same person with a biological vulnerability, if exposed to a particularly positive environment, could have better outcomes than a person without the vulnerability.
Depression is a symptom of some physical diseases; a side effect of some drugs and medical treatments; and a symptom of some mood disorders such as major depressive disorder or dysthymia. Physical causes are ruled out with a clinical assessment of depression that measures vitamins, minerals, electrolytes, and hormones. Management of depression may involve a number of different therapies: medications, behaviour therapy, psychotherapy, and medical devices.
Though psychiatric medication is the most frequently prescribed therapy for major depression, psychotherapy may be effective, either alone or in combination with medication. Combining psychotherapy and antidepressants may provide a “slight advantage”, but antidepressants alone or psychotherapy alone are not significantly different from other treatments, or “active intervention controls”. Given an accurate diagnosis of major depressive disorder, in general the type of treatment (psychotherapy and/or antidepressants, alternate or other treatments, or active intervention) is “less important than getting depressed patients involved in an active therapeutic program.”
Psychotherapy is the treatment of choice in those under the age of 18, with medication offered only in conjunction with the former and generally not as a first line agent. The possibility of depression, substance misuse or other mental health problems in the parents should be considered and, if present and if it may help the child, the parent should be treated in parallel with the child.
Psychotherapy and Behaviour Therapy
There are a number of different psychotherapies for depression which are provided to individuals or groups by psychotherapists, psychiatrists, psychologists, clinical social workers, counsellors or psychiatric nurses. With more chronic forms of depression, the most effective treatment is often considered to be a combination of medication and psychotherapy. Psychotherapy is the treatment of choice in people under 18. A meta-analysis examined the effectiveness of psychotherapy for depression across ages from younger than 13 years to older than 75 years. It summarizes results from 366 trials included 36,702 patients. It found that the best results were for young adults, with an average effect size of g=.98 (95% CI, 0.79-1.16). The effects were smallest for young children (<13 years), g = .35 (95% CI, 0.15-0.55), and second largest in the oldest group, g = .97 (95% CI, 0.42-1.52). The study was not able to compare the different types of therapy to each other. Most of the studies with children used therapies originally developed with adults, which may have reduced the effectiveness. The greater benefits with young adults might be due to a large number of studies including college students, who might have an easier time learning therapy skills and techniques. Most of the studies in children were done in the USA, whereas in older age groups, more balanced numbers of studies came from Europe and other parts of the world as well.
As the most studied form of psychotherapy for depression, cognitive behavioural therapy (CBT) is thought to work by teaching clients to learn a set of cognitive and behavioural skills, which they can employ on their own. Earlier research suggested that cognitive behavioural therapy was not as effective as antidepressant medication in the treatment of depression; however, more recent research suggests that it can perform as well as antidepressants in treating patients with moderate to severe depression. Beck’s treatment manual, Cognitive therapy of depression, has undergone the most research and accumulated the most evidence for its use. However, a number of other CBT manuals also have evidence to support their effectiveness with depression.
The effect of psychotherapy on patient and clinician rated improvement as well as on revision rates have declined steadily from the 1970s.
A systematic review of data comparing low-intensity CBT (such as guided self-help by means of written materials and limited professional support, and website-based interventions) with usual care found that patients who initially had more severe depression benefited from low-intensity interventions at least as much as less-depressed patients.
For the treatment of adolescent depression, one published study found that CBT without medication performed no better than a placebo, and significantly worse than the antidepressant fluoxetine. However, the same article reported that CBT and fluoxetine outperformed treatment with only fluoxetine. Combining fluoxetine with CBT appeared to bring no additional benefit in two different studies or, at the most, only marginal benefit, in a fourth study.
Behaviour therapy for depression is sometimes referred to as behavioural activation. Studies exist showing behavioural activation to be superior to CBT. In addition, behavioural activation appears to take less time and lead to longer lasting change. Two well-researched treatment manuals include Social skills training for depression and Behavioural activation treatment for depression.
Emotionally focused therapy, founded by Sue Johnson and Les Greenberg in 1985, treats depression by identifying and processing underlying emotions. The treatment manual, Facilitating emotional change, outlines treatment techniques.
Acceptance and commitment therapy (ACT), a mindfulness form of CBT, which has its roots in behaviour analysis, also demonstrates that it is effective in treating depression, and can be more helpful than traditional CBT, especially where depression is accompanied by anxiety and where it is resistant to traditional CBT.
A review of four studies on the effectiveness of mindfulness-based cognitive therapy (MBCT), a recently developed class-based program designed to prevent relapse, suggests that MBCT may have an additive effect when provided with the usual care in patients who have had three or more depressive episodes, although the usual care did not include antidepressant treatment or any psychotherapy, and the improvement observed may have reflected non-specific or placebo effects. Of note, although Mindfulness-based cognitive therapy for depression prevented relapse of future depressive episodes, there is no research on whether it can cause the remission of a current depressive episode.
Interpersonal psychotherapy (IPT) focuses on the social and interpersonal triggers that may cause depression. There is evidence that it is an effective treatment for depression. Here, the therapy takes a fairly structured course (often 12 sessions, as in the original research versions) as in the case with CBT; however, the focus is on relationships with others. Unlike family therapy, IPT is an individual format, so it is possible to work on interpersonal themes even if other family members do not come to the session. Therapy can be used to help a person develop or improve interpersonal skills in order to allow him or her to communicate more effectively and reduce stress. In a meta-analysis of 16 studies and 4,356 patients, the average improvement in depressive symptoms was an effect size of d = 0.63 (95% CI, 0.36 to 0.90). IPT combined with pharmacotherapy was more effective in preventing relapse than pharmacotherapy alone, number needed to treat = 7.63.
Psychoanalysis, a school of thought founded by Sigmund Freud that emphasizes the resolution of unconscious mental conflicts, is used by its practitioners to treat clients presenting with major depression. A more widely practiced technique, called psychodynamic psychotherapy, is loosely based on psychoanalysis and has an additional social and interpersonal focus. In a meta-analysis of three controlled trials, psychodynamic psychotherapy was found to be as effective as medication for mild to moderate depression.
Shared decision making is an approach whereby patients and clinicians freely share important evidence when tasked with decision making and where patients are guided to consider the best available options to make an informed decision. The principles are well documented, but there is a gap in that it’s hard to apply them in routine clinical practice. The steps have been simplified into five steps. The first step is seeking patient participation in that the health practitioner is tasked with communicating existing choices and therefore inviting them to the decision making process. The next step involves assisting the patient to explore and compare the treatment options by a critical analysis of the risks and benefits. The third step involves the assessment of the patient’s values and what they prefer taking to account what is of paramount urgency to the patient. Step 4 involves decision making where the patient and the practitioner make a conclusive decision on the best option and arrange for subsequent follow up meetings. Finally, the fifth step involves the analysis of the patient’s decision’. Five steps for you and your patients to work together to make the best possible health care decisions. The step involves monitoring of the degree of implementation, overcoming of barriers of decision implantation consequently the decisions need to be revisited and optimised thus ensuring the decision has a positive impact on health outcomes its success relies on the ability of the health practitioner to create a good interpersonal relationship with the patient.
Depression still remains a major problem in the US whereby statistics have it that 16 million people were affected in the year 2017. The depression is multifactorial and has been on the increase due to societal pressure, genetic association and increase in use of drugs. incorporation of nursing in management of depression may seem important in that nursing holds a pivotal role in health care delivery where they are the health practitioners that have been trained to be versatile from clinical to psychological care. Their incorporation in shared decision making in treating depression may be important as nurses are known to have the best interpersonal relationship with the patients thus a better collaborative model can be achieved due to this fact. With this in mind, the nurses may serve to administer drugs in management, prepare and maintain the patient’s records, interaction with other care staff to achieve optimum care, and organising therapy sessions. In a study another study concerning shared decision-making interventions for people with mental health conditions there were no overt benefits that were discovered and the called for further research in this area. Another study found that it is important to begin the dissemination and implementation of SDM as they proved that it has benefits in healthcare especially in mental health care and has received social and government support and however transitioning to SDM has proven to be an uphill task. It has been suggested that SDM is of importance in demonstrating patient preferences in decision making when there is no clear approach to treatment. In addition, numerous tools can be used to make the decision making the process easier these include the Controlled Preferences Scale that informs clinicians on how to actively involve patients
Commentators suggest that providers need to embrace shared decision making by making sure that patients participate actively in their management thus enabling the success of the model.
To find the most effective pharmaceutical drug treatment, the dosages of medications must often be adjusted, different combinations of antidepressants tried, or antidepressants changed. Norepinephrine reuptake inhibitor (NRIs) can be used as antidepressants. Selective serotonin reuptake inhibitors (SSRIs), such as sertraline (Zoloft, Lustral), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac), paroxetine (Seroxat), and citalopram, are the primary medications considered, due to their relatively mild side effects and broad effect on the symptoms of depression and anxiety, as well as reduced risk in overdose, compared to their older tricyclic alternatives. Those who do not respond to the first SSRI tried can be switched to another. If sexual dysfunction is present prior to the onset of depression, SSRIs should be avoided. Another popular option is to switch to the atypical antidepressant bupropion (Wellbutrin) or to add bupropion to the existing therapy; this strategy is possibly more effective. It is not uncommon for SSRIs to cause or worsen insomnia; the sedating noradrenergic and specific serotonergic antidepressant (NaSSA) antidepressant mirtazapine (Zispin, Remeron) can be used in such cases. CBT for Insomnia can also help to alleviate the insomnia without additional medication. Venlafaxine (Effexor) from the SNRI class may be moderately more effective than SSRIs; however, it is not recommended as a first-line treatment because of the higher rate of side effects, and its use is specifically discouraged in children and adolescents. Fluoxetine is the only antidepressant recommended for people under the age of 18, though, if a child or adolescent patient is intolerant to fluoxetine, another SSRI may be considered. Evidence of effectiveness of SSRIs in those with depression complicated by dementia is lacking.
Tricyclic antidepressants (TCAs) have more side effects than SSRIs (but less sexual dysfunctions) and are usually reserved for the treatment of inpatients, for whom the tricyclic antidepressant amitriptyline, in particular, appears to be more effective. A different class of antidepressants, the monoamine oxidase inhibitors, have historically been plagued by questionable efficacy (although early studies used dosages now considered too low) and life-threatening adverse effects. They are still used only rarely, although newer agents of this class (RIMA), with a better side effect profile, have been developed.
In older patients TCAs and SSRIs are of the same efficacy. However, there are differences between TCA related antidepressants and classical TCAs in terms of side effect profiles and withdrawal when compared to SSRIs.
There is evidence a prominent side-effect of antidepressants, emotional blunting, is confused with a symptom of depression itself. The cited study, according to Professor Linda Gask was: ‘funded by a pharmaceutical company (Servier) and two of its authors are employees of that company’, which may bias the results. The study authors’ note: “emotional blunting is reported by nearly half of depressed patients on antidepressants and that it appears to be common to all monoaminergic antidepressants not only SSRIs”. Additionally, they note: “The OQuESA scores are highly correlated with the HAD depression score; emotional blunting cannot be described simply as a side-effect of antidepressant, but also as a symptom of depression…More emotional blunting is associated with a poorer quality of remission…”
Acetylcarnitine levels were lower in depressed patients than controls and in rats it causes rapid antidepressant effects through epigenetic mechanisms. A systematic review and meta-analysis of 12 randomised controlled trials found “supplementation significantly decreases depressive symptoms compared with placebo/no intervention, while offering a comparable effect with that of established antidepressant agents with fewer adverse effects.”
A 2012 cross-sectional study found an association between zinc deficiency and depressive symptoms among women, but not men, and a 2013 meta-analysis of 17 observational studies found that blood zinc concentrations were lower in depressed subjects than in control subjects. A 2012 meta-analysis found that zinc supplementation as an adjunct to antidepressant drug treatment significantly lowered depressive symptom scores of depressed patients. The potential mechanisms underlying the association between low serum zinc and depression remain unclear, but may involve the regulation of neurotransmitter, endocrine and neurogenesis pathways. Zinc supplementation has been reported to improve symptoms of ADHD and depression. A 2013 review found that zinc supplementation may be an effective treatment in major depression.
Many studies have found an association between magnesium intake and depression. Magnesium was lower in serum of depressed patients than controls. One trial found magnesium chloride to be effective for depression in seniors with type 2 diabetes while another trial found magnesium citrate decreased depression in patients with fibromyalgia. One negative trial used magnesium oxide, which is poorly absorbed. A randomised, open-label study found that consumption of magnesium chloride for 6 weeks resulted in a clinically significant net improvement in depression, and that effects were observed within 2 weeks.
Physicians often add a medication with a different mode of action to bolster the effect of an antidepressant in cases of treatment resistance; a 2002 large community study of 244,859 depressed Veterans Administration patients found that 22% had received a second agent, most commonly a second antidepressant. Lithium has been used to augment antidepressant therapy in those who have failed to respond to antidepressants alone. Furthermore, lithium dramatically decreases the suicide risk in recurrent depression. Addition of atypical antipsychotics when the patient has not responded to an antidepressant is also known to increase the effectiveness of antidepressant drugs, albeit at the cost of more frequent and potentially serious side effects. There is some evidence for the addition of a thyroid hormone, triiodothyronine, in patients with normal thyroid function. Stephen M. Stahl, renowned academician in psychopharmacology, has stated resorting to a dynamic psychostimulant, in particular, d-amphetamine is the “classical augmentation strategy for treatment-refractory depression”. However, the use of stimulants in cases of treatment-resistant depression is relatively controversial.
Efficacy of Medication and Psychotherapy
Antidepressants are statistically superior to placebo but their overall effect is low-to-moderate. In that respect they often did not exceed the National Institute for Health and Clinical Excellence (NICE) criteria for a “clinically significant” effect. In particular, the effect size was very small for moderate depression but increased with severity, reaching “clinical significance” for very severe depression. These results were consistent with the earlier clinical studies in which only patients with severe depression benefited from either psychotherapy or treatment with an antidepressant, imipramine, more than from the placebo treatment. Despite obtaining similar results, the authors argued about their interpretation. One author concluded that there “seems little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed to provide benefit.” The other author agreed that “antidepressant ‘glass’ is far from full” but disagreed “that it is completely empty”. He pointed out that the first-line alternative to medication is psychotherapy, which does not have superior efficacy.
Antidepressants in general are as effective as psychotherapy for major depression, and this conclusion holds true for both severe and mild forms of MDD. In contrast, medication gives better results for dysthymia. The subgroup of SSRIs may be slightly more efficacious than psychotherapy. On the other hand, significantly more patients drop off from the antidepressant treatment than from psychotherapy, likely because of the side effects of antidepressants. Successful psychotherapy appears to prevent the recurrence of depression even after it has been terminated or replaced by occasional “booster” sessions. The same degree of prevention can be achieved by continuing antidepressant treatment.
Two studies suggest that the combination of psychotherapy and medication is the most effective way to treat depression in adolescents. Both TADS (Treatment of Adolescents with Depression Study) and TORDIA (Treatment of Resistant Depression in Adolescents) showed very similar results. TADS resulted in 71% of their teen subjects having “much” or “very much” improvement in mood over the 61% with medication alone and 43% with CBT alone. Similarly, TORDIA showed a 55% improvement with CBT and drugs versus a 41% with drug therapy alone. However, a more recent meta-analysis of 34 trials of 14 drugs used with children and adolescents found that only fluoxetine produced significant benefit compared to placebo, with a medium sized effect (standardize mean difference = .5).
The risk factors for treatment resistant depression are: the duration of the episode of depression, severity of the episode, if bipolar, lack of improvement in symptoms within the first couple of treatment weeks, anxious or avoidant and borderline comorbidity and old age. Treatment resistant depression is best handled with a combination of conventional antidepressant together with atypical antipsychotics. Another approach is to try different antidepressants. It is inconclusive which approach is superior. Treatment resistant depression can be misdiagnosed if subtherapeutic doses of antidepressants is the case, patient nonadherence, intolerable adverse effects or their thyroid disease or other conditions is misdiagnosed as depression.
Clinical and experimental studies have reported antidepressant activity of chromium particularly in atypical depression, characterised by increased appetite and carbohydrate craving.
Essential Fatty Acids
A 2015 Cochrane Collaboration review found insufficient evidence with which to determine if omega-3 fatty acid has any effect on depression. A 2016 review found that if trials with formulations containing mostly eicosapentaenoic acid (EPA) are separated from trials using formulations containing docosahexaenoic acid (DHA), it appeared that EPA may have an effect while DHA may not, but there was insufficient evidence to be sure.
The amino acid creatine, commonly used as a supplement to improve the performance of bodybuilders, has been studied for its potential antidepressant properties. A double-blinded, placebo-controlled trial focusing on women with major depressive disorder found that daily creatine supplementation adjunctive to escitalopram was more effective than escitalopram alone. Studies on mice have found that the antidepressant effects of creatine can be blocked by drugs that act against dopamine receptors, suggesting that the drug acts on dopamine pathways.
Dopamine Receptor Agonist
Some research suggests dopamine receptor agonist may be effective in treating depression, however studies are few and results are preliminary.
Inositol, an alcohol sugar found in fruits, beans grains and nuts may have antidepressant effects in high doses. Inositol may exert its effects by altering intracellular signalling.
Research on the antidepressant effects of ketamine infusions at subanaesthetic doses has consistently shown rapid (4 to 72 hours) responses from single doses, with substantial improvement in mood in the majority of patients and remission in some. However, these effects are often short-lived, and attempts to prolong the antidepressant effect with repeated doses and extended (“maintenance”) treatment have resulted in only modest success.
A systematic review and meta-analysis of 5 studies found that N-Acetylcysteine reduces depressive symptoms more than placebo and has good tolerability. N-Acetylecysteine may exert benefits as a precursor to the antioxidant glutathione, thus modulating glutamatergic, neurotropic, and inflammatory pathways.
St John’s Wort
A 2008 Cochrane Collaboration meta-analysis concluded that:
“The available evidence suggests that the hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; c) and have fewer side effects than standard antidepressants. The association of country of origin and precision with effects sizes complicates the interpretation.”
The United States National Centre for Complementary and Integrative Health advice is that “St. John’s wort may help some types of depression, similar to treatment with standard prescription antidepressants, but the evidence is not definitive.” and warns that “Combining St. John’s wort with certain antidepressants can lead to a potentially life-threatening increase of serotonin, a brain chemical targeted by antidepressants. St. John’s wort can also limit the effectiveness of many prescription medicines.”
A 2011 review reported Rhodiola rosea “is an adaptogen plant that can be especially helpful in treating asthenic or lethargic depression, and may be combined with conventional antidepressants to alleviate some of their common side effects.” A 6 week double-blind, placebo-controlled, randomised study with 89 patients with mild to moderate depression found that R. rosea statistically significantly reduced depression symptoms, and no side effects were reported.
A 2013 meta-analysis found that saffron supplementation significantly reduced depression symptoms compared to placebo, and both saffron supplementation and the antidepressant groups were similarly effective in reducing depression symptoms. A 2015 meta-analysis supported the “efficacy of saffron as compared to placebo in improving the following conditions: depressive symptoms (compared to anti-depressants and placebo), premenstrual symptoms, and sexual dysfunction. In addition, saffron use was also effective in reducing excessive snacking behavior.” The antidepressant effect of saffron stigma extracts may be mediated via its components safranal and crocin: “crocin may act via the uptake inhibition of dopamine and norepinephrine, and safranal via serotonin.” Therapeutic doses of saffron exhibits no significant toxicity in both clinical and experimental investigations.
S-Adenosyl methionine (SAMe) is available as a prescription antidepressant in Europe and an over-the-counter dietary supplement in the US. Evidence from 16 clinical trials with a small number of subjects, reviewed in 1994 and 1996 suggested it to be more effective than placebo and as effective as standard antidepressant medication for the treatment of major depression.
Tryptophan and 5-HTP
The amino acid tryptophan is converted into 5-hydroxytryptophan (5-HTP) which is subsequently converted into the neurotransmitter serotonin. Since serotonin deficiency has been recognized as a possible cause of depression, it has been suggested that consumption of tryptophan or 5-HTP may therefore improve depression symptoms by increasing the level of serotonin in the brain. 5-HTP and tryptophan are sold over the counter in North America, but requires a prescription in Europe. The use of 5-HTP instead of tryptophan bypasses the conversion of tryptophan into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin, and 5-HTP easily crosses the blood–brain barrier unlike tryptophan, which requires a transporter.
Small studies have been performed using 5-HTP and tryptophan as adjunctive therapy in addition to standard treatment for depression. While some studies had positive results, they were criticised for having methodological flaws, and a more recent study did not find sustained benefit from their use. The safety of these medications has not been well studied. Due to the lack of high quality studies, preliminary nature of studies showing effectiveness, the lack of adequate study on their safety, and reports of Eosinophilia-myalgia syndrome from contaminated tryptophan in 1989 and 1990, the use of tryptophan and 5-HTP is not highly recommended or thought to be clinically useful.
A variety of medical devices are in use or under consideration for treatment of depression including devices that offer electroconvulsive therapy, vagus nerve stimulation, repetitive transcranial magnetic stimulation, and cranial electrotherapy stimulation. The use of such devices in the United States requires approval by the US Food and Drug Administration (FDA) after field trials. In 2010 an FDA advisory panel considered the question of how such field trials should be managed. Factors considered were whether drugs had been effective, how many different drugs had been tried, and what tolerance for suicides should be in field trials.
Electroconvulsive therapy (ECT) is a standard psychiatric treatment in which seizures are electrically induced in patients to provide relief from psychiatric illnesses. ECT is used with informed consent as a last line of intervention for major depressive disorder. Among the elderly, who often experience depression, the efficacy of ECT is difficult to determine due to the lack of trials comparing ECT to other treatments.
A round of ECT is effective for about 50% of people with treatment-resistant major depressive disorder, whether it is unipolar or bipolar. Follow-up treatment is still poorly studied, but about half of people who respond, relapse with twelve months.
Aside from effects in the brain, the general physical risks of ECT are similar to those of brief general anaesthesia. Immediately following treatment, the most common adverse effects are confusion and memory loss. ECT is considered one of the least harmful treatment options available for severely depressed pregnant women.
A usual course of ECT involves multiple administrations, typically given two or three times per week until the patient is no longer suffering symptoms ECT is administered under anaesthetic with a muscle relaxant. Electroconvulsive therapy can differ in its application in three ways: electrode placement, frequency of treatments, and the electrical waveform of the stimulus. These three forms of application have significant differences in both adverse side effects and symptom remission. After treatment, drug therapy is usually continued, and some patients receive maintenance ECT.
ECT appears to work in the short term via an anticonvulsant effect mostly in the frontal lobes, and longer term via neurotrophic effects primarily in the medial temporal lobe.
Deep Brain Stimulation
The support for the use of deep brain stimulation in treatment-resistant depression comes from a handful of case studies, and this treatment is still in a very early investigational stage. In this technique electrodes are implanted in a specific region of the brain, which is then continuously stimulated. A March 2010 systematic review found that “about half the patients did show dramatic improvement” and that adverse events were “generally trivial” given the younger psychiatric patient population than with movements disorders. Deep brain stimulation is available on an experimental basis only in the United States; no systems are approved by the FDA for this use. It is available in Australia.
Repetitive Transcranial Magnetic Stimulation
Transcranial magnetic stimulation (TMS) or deep transcranial magnetic stimulation is a non-invasive method used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator, or “coil” is placed near the head of the person receiving the treatment. The coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. The coil is connected to a pulse generator, or stimulator, that delivers electric current to the coil.
TMS was approved by the FDA for treatment-resistant major depressive disorder in 2008 and as of 2014 clinical evidence supports this use. The American Psychiatric Association, the Canadian Network for Mood and Anxiety Disorders, and the Royal Australia and New Zealand College of Psychiatrists have endorsed rTMS for trMDD.
Vagus Nerve Stimulation
Vagus nerve stimulation (VNS) uses an implanted electrode and generator to deliver electrical pulses to the vagus nerve, one of the primary nerves emanating from the brain. It is an approved therapy for treatment-resistant depression in the EU and US and is sometimes used as an adjunct to existing antidepressant treatment. The support for this method comes mainly from open-label trials, which indicate that several months may be required to see a benefit. The only large double-blind trial conducted lasted only 10 weeks and yielded inconclusive results; VNS failed to show superiority over a sham treatment on the primary efficacy outcome, but the results were more favourable for one of the secondary outcomes. The authors concluded “This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.”
Cranial Electrotherapy Stimulation
A 2014 Cochrane review found insufficient evidence to determine whether or not Cranial electrotherapy stimulation with alternating current is safe and effective for treating depression.
Transcranial Direct Current Stimulation
A 2016 meta-analysis of transcranial direct current stimulation (tDCS) reported some efficacy of tDCS in the treatment of acute depressive disorder with moderate effect size, and low efficacy in treatment-resistant depression, and that use of 2 mA current strength over 20 minutes per day over a short time span can be considered safe.
Bright Light Therapy
A meta-analysis of bright light therapy commissioned by the American Psychiatric Association found a significant reduction in depression symptom severity associated with bright light treatment. Benefit was found for both seasonal affective disorder and for non-seasonal depression, with effect sizes similar to those for conventional antidepressants. For non-seasonal depression, adding light therapy to the standard antidepressant treatment was not effective. A meta-analysis of light therapy for non-seasonal depression conducted by Cochrane Collaboration, studied a different set of trials, where light was used mostly in combination with antidepressants or wake therapy. A moderate statistically significant effect of light therapy was found, with response significantly better than control treatment in high-quality studies, in studies that applied morning light treatment, and with patients who respond to total or partial sleep deprivation. Both analyses noted poor quality of most studies and their small size, and urged caution in the interpretation of their results. The short 1-2 weeks duration of most trials makes it unclear whether the effect of light therapy could be sustained in the longer term.
The 2013 Cochrane Collaboration review on physical exercise for depression noted that, based upon limited evidence, it is moderately more effective than a control intervention and comparable to psychological or antidepressant drug therapies. Smaller effects were seen in more methodologically rigorous studies. Three subsequent 2014 systematic reviews that included the Cochrane review in their analysis concluded with similar findings: one indicated that physical exercise is effective as an adjunct treatment with antidepressant medication; the other two indicated that physical exercise has marked antidepressant effects and recommended the inclusion of physical activity as an adjunct treatment for mild-moderate depression and mental illness in general. These studies also found smaller effect sizes in more methodologically rigorous studies. All four systematic reviews called for more research in order to determine the efficacy or optimal exercise intensity, duration, and modality. The evidence for brain-derived neurotrophic factor (BDNF) in mediating some of the neurobiological effects of physical exercise was noted in one review which hypothesized that increased BDNF signalling is responsible for the antidepressant effect.
Mindfulness meditation programs may help improve symptoms of depression, but they are no better than active treatments such as medication, exercise, and other behavioural therapies.
A 2009 review found that 3 to 10 sessions of music therapy resulted in a noticeable improvement in depressive symptoms, with still greater improvement after 16 to 51 sessions.
Depression is sometimes associated with insomnia – (difficulty in falling asleep, early waking, or waking in the middle of the night). The combination of these two results, depression and insomnia, will only worsen the situation. Hence, good sleep hygiene is important to help break this vicious circle. It would include measures such as regular sleep routines, avoidance of stimulants such as caffeine and management of sleeping disorders such as sleep apnoea.
Quitting smoking cigarettes is associated with reduced depression and anxiety, with the effect “equal or larger than” those of antidepressant treatments.
Total/Partial Sleep Deprivation
Sleep deprivation (skipping a night’s sleep) has been found to improve symptoms of depression in 40-60% of patients. Partial sleep deprivation in the second half of the night may be as effective as an all night sleep deprivation session. Improvement may last for weeks, though the majority (50-80%) relapse after recovery sleep. Shifting or reduction of sleep time, light therapy, antidepressant drugs, and lithium have been found to potentially stabilise sleep deprivation treatment effects.
Shared care, when primary and specialty physicians have joint management of an individual’s health care, has been shown to alleviate depression outcomes.