Tag: Depression

What is Behavioural Activation?

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Introduction

Behavioural activation (BA) is a third generation behaviour therapy for treating depression.

It is one functional analytic psychotherapy which are based on a Skinnerian psychological model of behaviour change, generally referred to as applied behaviour analysis. This area is also a part of what is called clinical behaviour analysis (CBA) and makes up one of the most effective practices in the professional practice of behaviour analysis. The technique can also be used from a cognitive-behaviour therapy (CBT) framework.

Overview

The Beck Institute describes BA as “getting clients more active and involved in life by scheduling activities that have the potential to improve their mood.”

Theoretical Underpinnings

Behavioural activation emerged from a component analysis of cognitive behavioural therapy. This analysis found that any cognitive component added little to the overall treatment of depression. The behavioural component had existed as a stand-alone treatment in the early work of Peter Lewinsohn and thus a group of behaviourists decided that it might be more efficient to pursue a purer behavioural treatment for the disorder. The theory holds that not enough environmental reinforcement or too much environmental punishment can contribute to depression. The goal of the intervention is to increase environmental reinforcement and reduce punishment.

The theoretical underpinnings of behavioural activation for depression is Charles Ferster’s functional analysis of depression. Ferster’s basic model has been strengthened by further development in the study of reinforcement principles which led to the matching law and continuing theoretical advances in the possible functions of depression, as well as a look at behaviour analysis of child development in order to determine long-term patterns which may lead to dysthymia.

Methods

One behavioural activation approach to depression was as follows: participants were asked to create a hierarchy of reinforcing activities which were then rank-ordered by difficulty; participants tracked their own goals along with clinicians who used a token economy to reinforce success in moving through the hierarchy of activities; participants were measured before and after by the Beck Depression Inventory (BDI) and a great effect on their depression was found as a result of their treatment. This was then compared to a control group who did not receive the same treatment. The results of those who received behavioural activation treatment were markedly superior to those of the persons in the control group. Multiple clinics have since piloted and developed the treatment.

Another behavioural activation approach utilised a different methodology: clients are asked to develop an understanding of the relationship between actions and emotions, with actions being seen as the cause of emotions. An hourly self-monitoring chart is created to track activities and the impact on the mood they create for a full week. A rating scale from 1 to 10 is used for each mood change per hour. The goal is to identify depression loops. A depression loop is when a temporary coping method reduces the overall depression, such as the temporary relief provided by alcohol or other drugs, escape or avoidance or rumination. When patterns of dysfunctional responding, or loops, are identified alternative coping responses are attempted to break the loop. This method is described with the acronym “TRAP” (Trigger, Response, Avoidance Pattern) which is to be replaced with a “TRAC” (Trigger, Response, Alternate Coping response). Particular attention is given to rumination, which is provided with its own acronym RCA (Rumination Cues Action). Rumination is identified as a particularly common avoidance behaviour which worsens mood. The client is to evaluate the rumination in terms of it having improved the thing being ruminated about, providing understanding, and its emotional effects on the client. Attending to experience is suggested as an alternative to rumination as well as other possible distracting or mood improving actions.

The general program is described with the acronym ACTION (Assess behaviour/mood, Choose alternate responses, Try out those alternate responses, Integrate these alternatives, Observe results and (Now) evaluate). The goal being the understanding of the relationship between actions and emotional consequences and a systematic replacement of dysfunctional patterns with adaptive ones. Additionally, focus is given to quality sleep, and improving social functioning.

Research Support

Depression

Reviews of behavioural activation studies for depression found that it has a robust effect and that policy makers should consider it an effective treatment. A large-scale treatment study found behavioural activation to be more effective than cognitive therapy and on par with medication for treating depression. A meta-analysis study comprising 34 Randomised Control Trials found that while Behavioural Activation treatment of adults with depression showed significantly greater beneficial effect compared with control participants, compared to participants treated with CT/CBT, at post treatment there were no statistically significant differences between treatment groups. A 2009 meta-analysis showed a medium post-treatment effect size compared to psychotherapy and other treatments.

Anxiety

A 2006 study of behavioural activation being applied to anxiety appeared to give promising results. One study found it to be effective with fibromyalgia-related pain anxiety.

In the Context of Third Generation Behaviour Therapies

Behavioural activation comes under the heading clinical behaviour analysis or what is often termed third generation behaviour therapy. Other behaviour therapies are acceptance and commitment therapy (ACT), as well as dialectical behaviour therapy (DBT) and functional analytic psychotherapy (FAP). Behavioural activation owes its basis to Charles Ferster’s Functional Analysis of Depression (1973) which developed B.F. Skinner’s idea of depression, within his analysis of motivation, as a lack of reinforcement.

Professional Organisations

The Association for Behaviour Analysis International has a special interest group for practitioner issues, behavioural counselling, and clinical behaviour analysis. The association has larger special interest groups for behavioural medicine. It also serves as the core intellectual home for behaviour analysts.

The Association for Behavioural and Cognitive Therapies (ABCT) also has an interest group in behaviour analysis, which focuses on clinical behaviour analysis.

Doctoral level behaviour analysts who are psychologists belong to the American Psychological Association’s division 25 -Behaviour analysis. APA offers a diplomate in behavioural psychology.

BA in Virtual Reality

Due to a lack of access to trained providers, physical constraints or financial reasons, many patients are not able to attend BA therapy. Researchers are trying to overcome these challenges by providing BA via Virtual Reality. The idea of the concept is to enable especially elderly adults to participate in engaging activities that they would not attend it without VR. Possibly, the so-called “BA-inspired VR protocols” will mitigate the lower mood, life satisfaction, and likelihood of depressions.

What is Metacognitive Training?

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Introduction

Metacognitive training, (MCT), is an approach for treating the symptoms of psychosis in schizophrenia, especially delusions, which has been adapted for other disorders such as depression, obsessive-compulsive disorder and borderline personality disorder over the years (see below and external links for free download).

It was developed by Steffen Moritz and Todd Woodward. The intervention is based on the theoretical principles of cognitive behavioural therapy (CBT), but focuses in particular on problematic thinking styles (cognitive biases) that are associated with the development and maintenance of positive symptoms, e.g. overconfidence in errors and jumping to conclusions. Metacognitive training exists as a group training (MCT) and as an individualized intervention (MCT+).

Refer to Metacognitive Therapy.

Background

Metacognition can be defined as “thinking about thinking”. Over the course of the training, cognitive biases subserving positive symptoms are identified and corrected. The current empirical evidence assumes a connection between certain cognitive biases, such as jumping to conclusions, and the development and maintenance of psychosis. Accordingly, correcting these problematic/unhelpful thinking styles should lead to a reduction of symptoms.

Intervention

In eight training units (modules) and two additional modules, examples of “cognitive traps”, which can promote the development and maintenance of the positive symptoms of schizophrenia, are presented to patients in a playful way. Patients are instructed to critically reflect on their thought patterns, which may contribute to problematic behaviours, and to implement the contents of the training in everyday life. MCT deals with the following problematic styles of thinking: monocausal attributions, jumping to conclusions, inflexibility, problems in social cognition, overconfidence for memory errors and depressive thought patterns. The additional modules deal with stigma and low self-esteem. Individualised metacognitive training (MCT+) targets the same symptoms and cognitive biases as the group training, but is more flexible in that it allows discussion of individualised topics. The treatment materials for the group training can be obtained free of charge in over 30 languages from the website.

Efficacy

A recent meta-analysis found significant improvements for positive symptoms and delusions, as well as the acceptance of the training. These findings have been replicated in 2018 and 2019. An older meta-analysis based on a smaller number of studies found a small effect, which reached significance when newer studies were considered. Individual studies provide evidence for the long-term effectiveness of the approach beyond the immediate treatment period. MCT is recommended as an evidence-based treatment by the Royal Australian and New Zealand College of Psychiatrists as well as the German Association for Psychiatry, Psychotherapy and Psychosomatics.

Adaptations to other Disorders

Since its introduction, MCT has been adapted to other mental disorders. Empirical studies have been carried out for borderline personality disorder, obsessive-compulsive disorder (self-help approach), depression, bipolar disorders, and problem gambling.

Links (External)

What is Avoidance Coping?

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Introduction

In psychology, avoidance coping is a coping mechanism and form of experiential avoidance.

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.

Measurement

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.

Treatment

Cognitive behavioural and psychoanalytic therapy are used to help those coping by avoidance to acknowledge, comprehend, and express their emotions. Acceptance and commitment therapy, a behavioural therapy that focuses on breaking down avoidance coping and showing it to be an unhealthy method for dealing with traumatic experiences, is also sometimes used.

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.

What is Maprotiline?

Published on by Andrew Marshall3 Comments

Introduction

Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression.

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.

Brief History

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.

Medical Uses

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.
  • Panic disorder.
  • Neuropathic pain.
  • 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.[8][9]

Available Forms

  • Coated Tablets, 10 mg, 25 mg, 50 mg, and 75 mg.
  • Injectable concentrate, 25 mg.

Contraindications

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.

Absolute

  • 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.

Suicidal Patients

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.

Side Effects

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:

  • Dizziness.
  • Drowsiness.
  • Somnolence.
  • Fatigue.
  • Dry mouth (and complications of long-term uncontrolled dry mouth such as dental caries).
  • Constipation.
  • Vertigo.
  • 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.
  • Photosensitivity.
  • Agitation, confusion.
  • Induction of hypomania or mania in patients suffering from underlying bipolar affective disorder.
  • Psychotic symptoms.
  • Tremor.
  • Extrapyramidal symptoms.
  • Headache.
  • Seizures (at high doses).
  • Rare haematological complications: leukopenia and agranulocytosis (dangerous fall in white blood cells).
  • Fever.
  • Urinary retention.

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

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.

Interactions

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):
    • Sympathomimetic effects increased (increased blood pressure, pulse rate, paleness of skin etc.)
  • Nitrates and anti-hypertensives (e.g. beta-blockers), increased antihypertensive action with pronounced fall in blood pressure.

Decreased Drug Actions

  • Guanethidine, Reserpine, Guanfacine : antihypertensive effects decreased.
  • 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.

Pharmacology

Pharmacodynamics

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.

Pharmacokinetics

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.

Chemistry

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

Generic Names

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.

Brand Names

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.

Book: CBT Toolbox for Children and Adolescents

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Book Title:

CBT Toolbox for Children and Adolescents: Over 220 Worksheets & Exercises for Trauma, ADHD, Autism, Anxiety, Depression & Conduct Disorders.

Author(s): Lisa Phifer.

Year: 2017.

Edition: First (1st).

Publisher: PESI Publishing & Media.

Type(s): Spiral-bound, Paperback and Kindle.

Synopsis:

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:

  • Trauma.
  • ADHD.
  • Autism.
  • Anxiety.
  • Depression.
  • Conduct Disorders.

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.

What is Imipramine?

Published on by Andrew Marshall10 Comments

Introduction

Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression.

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.

Brief History

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.

Medical Uses

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.

Available Forms

Imipramine is available in the form of oral tablets and capsules.

Contraindications

Combining it with alcohol consumption causes excessive drowsiness. It may be unsafe during pregnancy.

Side Effects

Those listed in italics below denote common side effects.

  • Central nervous system: dizziness, drowsiness, confusion, seizures, headache, anxiety, tremors, stimulation, weakness, insomnia, nightmares, extrapyramidal symptoms in geriatric patients, increased psychiatric symptoms, paraesthesia.
  • Cardiovascular: orthostatic hypotension, ECG changes, tachycardia, hypertension, palpitations, dysrhythmias
  • Eyes, ears, nose and throat: blurred vision, tinnitus, mydriasis.
  • Gastrointestinal: dry mouth, nausea, vomiting, paralytic ileus, increased appetite, cramps, epigastric distress, jaundice, hepatitis, stomatitis, constipation, taste change.
  • Genitourinary: urinary retention.
  • Hematological: agranulocytosis, thrombocytopenia, eosinophilia, leukopenia.
  • Skin: rash, urticaria, diaphoresis, pruritus, photosensitivity.

Overdose

Refer to Tricyclic Antidepressant Overdose.

Pharmacology

Pharmacodynamics

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.
  • Dopamine:
    • 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).
  • Acetylcholine:
    • 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.
  • Epinephrine:
    • Imipramine antagonises adrenergic receptors, thus sometimes causing orthostatic hypotension.
  • Sigma receptor:
    • 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).
  • Histamine:
    • Imipramine is an antagonist of the histamine H1 receptors.
  • BDNF:
    • 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.

Pharmacokinetics

Within the body, imipramine is converted into desipramine (desmethylimipramine) as a metabolite.

Chemistry

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

Generic Names

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.

Brand Names

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.

Availability

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.

What is Lofepramine?

Published on by Andrew MarshallLeave a comment

Introduction

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.

Brief History

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.

Depression

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.

Contraindications

To be used with caution, or not at all, for people with the following conditions:

  • Heart disease.
  • Impaired kidney or liver function.
  • Narrow angle glaucoma.
  • In the immediate recovery period after myocardial infarction.
  • In arrhythmias (particularly heart block).
  • Mania.
  • 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.

Side Effects

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):

  • Digestive effects:
    • Constipation.
    • Diarrhoea.
    • Dry mouth.
    • Nausea.
    • Taste disturbances.
    • Vomiting.
  • Effects on the heart:
    • Arrhythmia.
    • ECG changes.
    • Abnormal heart rhythm.
    • Heart block.
    • Sudden cardiac death.
    • High heart rate.
  • Blood abnormalities:
    • Abnormal blood cell counts.
    • Blood sugar changes.
    • Low blood sodium levels.
  • Breast effects:
    • Breast enlargement, including in males.
    • Spontaneous breast milk secretion that is unrelated to breastfeeding or pregnancy.
  • Effects on the skin:
    • Abnormal sweating.
    • Hair loss.
    • Hives.
    • Increased light sensitivity.
    • Itching.
    • Rash.
  • Mental / neurologic effects:
    • Delusions.
    • Hallucinations.
    • Headache.
    • Hypomania/mania.
    • Seizures.
    • Suicidal behaviour.
  • Other effects:
    • Appetite changes.
    • Blurred vision.
    • Difficulty emptying the bladder.
    • Difficulty talking due to difficulties in moving the required muscles.
    • Liver problems.
    • Ringing in the ears.
    • Sexual dysfunction, such as impotence.
    • Swelling.
    • Weight changes.

Withdrawal

If abruptly stopped after regular use it can cause withdrawal effects such as sleeplessness, irritability and excessive sweating.

Overdose

Refer to Tricyclic Antidepressant Overdose.

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.

Interactions

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.
  • Diazoxide. Enhanced hypotensive (blood pressure-lowering) effect.
  • 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.
  • Sodium nitroprusside. Enhanced hypotensive effect.
  • Thyroid hormones. Effects on the heart of lofepramine may be exacerbated.

Pharmacology

Pharmacodynamics

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.

Pharmacokinetics

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.

Chemistry

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

Generic Names

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

Brand names of lofepramine include Amplit, Deftan, Deprimil, Emdalen, Gamanil, Gamonil, Lomont, Tymelet, and Tymelyt.

Availability

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.

Research

Fatigue

A formulation containing lofepramine and the amino acid phenylalanine is under investigation as a treatment for fatigue as of 2015.

What is Trimipramine?

Published on by Andrew Marshall3 Comments

Introduction

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.

Brief History

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.

Medical Uses

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.

Contraindications

Contraindications include:

  • Recent myocardial infarction.
  • Any degree of heart block or other cardiac arrhythmias.
  • Mania.
  • Severe liver disease.
  • During breastfeeding.
  • Hypersensitivity to trimipramine or to any of the excipients.

Side Effects

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:

  • Sedation:
    • Especially common with trimipramine compared to the other TCAs.
  • Anticholinergic effects including:
    • Dry mouth.
    • Blurred vision.
    • Mydriasis.
    • Decreased lacrimation.
    • Constipation.
    • Urinary hesitancy or retention.
    • Reduced GI motility.
    • Tachycardia (high heart rate).
    • Anticholinergic delirium (particularly in the elderly and in Parkinson’s disease).
  • Weight gain.
  • Orthostatic hypotension.
  • Sexual dysfunction including impotence, loss of libido and other sexual adverse effects.
  • Tremor.
  • Dizziness.
  • Sweating.
  • Anxiety.
  • Insomnia.
  • Agitation.
  • Rash.

Adverse effects with an unknown incidence includes:

  • Confusion.
  • Nausea.
  • Vomiting.
  • Extrapyramidal side effects (e.g. parkinsonism, dystonia, etc.).
  • Tinnitus.
  • Paraesthesia.
  • ECG changes.
  • Increased liver function tests.

Rare adverse effects include:

  • Seizures.
  • Syndrome of inappropriate secretion of antidiuretic hormone.
  • Blood dyscrasias including:
    • Agranulocytosis.
    • Thrombocytopenia.
    • Eosinophilia.
    • Leukopenia.
  • Myocardial infarction.
  • Heart block.
  • QTc interval prolongation.
  • Sudden cardiac death.
  • Depression worsening.
  • Suicidal ideation.

Overdose

Refer to Tricyclic Antidepressant Overdose.

Compared to other TCAs, trimipramine is relatively safe in overdose, although it is more dangerous than the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) but less dangerous than bupropion in cases of overdose.

Interactions

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.

Genotoxicity

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.

Pharmacology

Pharmacodynamics

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.

Antihistamine Activity

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.

Antidopaminergic Activity

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.

Pharmacokinetics

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.

Chemistry

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

Generic Names

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.

Brand Names

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.

Availability

Trimipramine is no longer marketed in Australia, though it was previously.

What is Desipramine

Published on by Andrew Marshall7 Comments

Introduction

Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression.

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.

Refer to Demexiptiline and Depramine (not to be confused with).

Brief History

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.

Medical Uses

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.

Side Effects

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.

Overdose

Refer to Tricyclic Antidepressant Overdose.

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.

Pharmacology

Pharmacodynamics

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.

Pharmacokinetics

Desipramine is the major metabolite of imipramine and lofepramine.

Chemistry

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

Generic Names

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.

Brand Names

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.