What is Olanzapine/Fluoxetine?

Introduction

Olanzapine/fluoxetine (trade name Symbyax, created by Eli Lilly and Company) is a fixed-dose combination medication containing olanzapine (Zyprexa), an atypical antipsychotic, and fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI). Olanzapine/fluoxetine is primarily used to treat the depressive episodes of bipolar I disorder as well as treatment-resistant depression.

Medical Uses

Olanzapine/fluoxetine was approved by the US Food and Drug Administration (FDA) to treat the depressive episodes of bipolar I disorder in 2003. In 2009, it was granted approval for the treatment of treatment-resistant depression.

Olanzapine/fluoxetine, or other antidepressant/antipsychotic combinations, are sometimes prescribed off-label for anxiety disorders, eating disorders, obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD).

Side Effects

Possible side effects of olanzapine/fluoxetine include all those of the two component drugs: olanzapine (side effects) and fluoxetine (side effects). Common side effects include suicidal thoughts, increased appetite, weight gain, drowsiness, fatigue, dry mouth, swelling, tremor, blurred vision, and difficulty concentrating.

Olanzapine/fluoxetine could produce a severe allergic reaction and should not be used if the patient has previously experienced an allergic reaction to either fluoxetine or olanzapine.

Olanzapine is correlated with an increase in blood sugar. Patients with diabetes, or those at risk for developing it, require careful monitoring.

In rare cases, olanzapine/fluoxetine may cause neuroleptic malignant syndrome.

Like other SSRIs, olanzapine/fluoxetine carries a boxed warning stating that it could increase the risk of suicidal thoughts and behaviours in patients aged 24 and under. The warning also states that olanzapine/fluoxetine may increase the risk of death in elderly patients with dementia-related psychosis.

What is Lormetazepam?

Introduction

Lormetazepam, sold under the brand name Noctamid among others, is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative and temazepam analogue. It possesses hypnotic, anxiolytic, anticonvulsant, sedative, and skeletal muscle relaxant properties.

It was patented in 1961 and came into medical use in 1980. Lormetazepam is not approved for sale in the United States or Canada. It is licensed in the UK as 0.5 and 1 mg tablets for short-term treatment (2-4 weeks) of moderately severe insomnia. It is licensed in the Netherlands as 1 and 2 mg tablets, under the brand names Loramet and Noctamid and as generic, available from several manufacturers. It is sold in Poland as Noctofer. A Dutch analysis stated that lormetazepam could be suitable to be included in drug prescribing formularies, although zolpidem, zopiclone, and temazepam appear better.

Medical Uses

Lormetazepam is considered a hypnotic benzodiazepine and is officially indicated for moderate to severe insomnia. Lormetazepam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or falling asleep. Hypnotics should only be used on a short-term basis or, in those with chronic insomnia, on an occasional basis.

Side Effects

Side effects of lormetazepam are similar to those of other hypnotic benzodiazepines and can for the most part be regarded as a class effect. In a sleep study, 1 mg lormetazepam increased total sleep time, reduced wakefulness, but did not alter REM sleep. However, at 2 mg doses, there were significant increases in stage 3 sleep and reductions in REM sleep. Rebound effects have been reported after chronic use including rebound REM. In one clinical trial with patients who had prior experience with older hypnotics temazepam and nitrazepam, most preferred lormetazepam due to less heavy sedation, amnesia, and residual effects. Some side effects, including drowsiness, amnesia, and respiratory depression, are increased when lormetazepam is combined with other drugs with similar effects, e.g. alcohol and nonbenzodiazepine drugs.

Although lormetazepam has been associated with adversely affecting immediate and delayed recall memory functions, studies have shown that lormetazepam’s amnesic properties may be lesser compared to other hypnotic benzodiazepines. For example, in a 1984 study comparing the amnesic effects of lormetazepam to temazepam and flurazepam showed that amnesia was smallest after lormetazepam and greatest after temazepam, which had produced greater amnesia than both lormetazepam and flurazepam by a significant margin.

Side effects of lormetazepam include:

  • Somnolence.
  • Paradoxical increase in aggression.
  • Lightheadedness.
  • Confusion.
  • Muscle weakness.
  • Ataxia (particularly in the elderly).
  • Anterograde amnesia.
  • Headache.
  • Vertigo.
  • Hypotension.
  • Salivation changes.
  • Gastro-intestinal disturbances.
  • Visual disturbances.
  • Dysarthria.
  • Tremor.
  • Changes in libido.
  • Incontinence.
  • Urinary retention.
  • Blood disorders and jaundice.
  • Skin reactions.
  • Dependence and withdrawal reactions.

Residual “hangover” effects after nighttime administration of lormetazepam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may impair the ability of users to drive safely and increase risks of falls and hip fractures.

Benzodiazepines require special precaution if used during pregnancy, in children, in alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders. Lormetazepam may be unsuitable for the elderly due to residual effects on memory and body sway which may result in falls. Lormetazepam causes impaired driving skills, thus caution is required in individuals who drive or operate machinery.

Tolerance, Dependence, and Withdrawal

The risks of tolerance, dependence, and withdrawal are very low when the drug is used for 2-4 weeks only, and lormetazepam is generally a safe and effective drug when used for no longer than 2-4 weeks. Some sleep disturbance in the form of rebound insomnia can, however, occur even after short-term usage of 7 days. Those with a history of addiction may be at increased risk of problems of tolerance and dependence especially those with a past history of dependency on sedative hypnotic drugs.

Lormetazepam as with other benzodiazepines is generally only recommended for short-term use (2-4 weeks) due to tolerance and loss of efficacy. Tolerance to and loss of the sedative effects of benzodiazepine hypnotics can occur within 14 days of regular use. Some studies however suggest such treatments retain their effectiveness in the long term – such a lack of consistency in the findings of many studies could be due to the variation of responses to benzodiazepine treatment.

Dependence is the medical term for addiction. Dependence can either be psychological and/or physical. Psychological dependence can manifest itself as a reliance on a drug to cope with everyday life or in the form of craving. Physical dependence occurs due to physiological adaptations occurring as the body attempts to overcome the drugs effects which is known as tolerance and the continuing need to take the drug to avoid or suppress withdrawal symptoms which can sometimes resemble the original condition being treated. When the dose or the drug is discontinued withdrawal symptoms typically occur. Lormetazepam as with all other benzodiazepines produces both physical and psychological dependence but the main problem of concern is physical dependence which appears in the form of the benzodiazepine withdrawal syndrome after the dosage is reduced or the drug is stopped completely. The dependence induced by lormetazepam is related to changes in the sensitivity of the GABA-BZD receptor complex.

Withdrawal symptoms which can occur from stopping benzodiazepines such as lormetazepam can include:

  • Rebound insomnia and nightmares.
  • Anxiety, panic attacks, and agoraphobia.
  • Clinical depression.
  • Malaise.
  • Lack of concentration.
  • Abdominal discomfort.
  • Depersonalisation and feelings of unreality.
  • Emotional lability.
  • Cognitive impairment.
  • Tinnitus.
  • Paraesthesiae, tingling, numbness, and pain.
  • Muscle pain, weakness, tension, painful tremor, shaking attacks, jerks, blepharospasm.
  • Excitability, jumpiness, and restlessness.
  • Stiffness.
  • Sweats.

Abrupt or over rapid withdrawal from high doses can provoke:

Withdrawal symptoms typically subside after 4-8 weeks but in approximately 10-15% of individuals symptoms can persist for many months and in rare cases years. Some “Withdrawal Symptoms” can emerge despite a constant dosage with the body needing extra dosage in order to feel normal. This is sometimes associated with dosage escalation.

Lormetazepam has a short to intermediate half-life of approximately 10-12 hours. Shorter acting benzodiazepine compounds are generally associated with a more intense and immediate withdrawal reaction compared to longer acting benzodiazepines. For this reason it is generally recommended to cross from lormetazepam to an equivalent dose of diazepam to gradually taper the dosage.

Pharmacology

The bioavailability of lormetazepam was found to be 80%.

Lormetazepam and other benzodiazepine drugs act as positive modulators at the GABAA benzodiazepine receptor complex. Lormetazepam binds to the benzodiazepine receptor which in turn enhances the effect of the GABAA receptor producing its therapeutic effects as well as adverse effects. When lormetazepam binds to the benzodiazepine receptor sites in sufficient quantities it produces sedation which is used clinically as a therapeutic treatment for insomnia. Lormetazepam alters the brain electrical activity which has been studied via EEG readings. Lormetazepam appears to be more selective in the type of benzodiazepine receptor it binds to showing a higher affinity for the omega 1 receptor which is responsible for sedation. Changes in EEG can therefore be used to measure the sedative sleep promoting properties of lormetazepam.

Trade Names

Trade names include Aldosomnil, Dilamet, Ergocalm, Loramet, Loretam, Metatop, Minias, Noctamid, Noctamide, Noctofer, Nocton, Pronoctan, Sedaben, and Stilaze.

Stereochemistry

Lormetazepam has a stereocenter and two enantiomers. Medications are racemates.

What is Fluphenazine?

Introduction

Fluphenazine, sold under the brand names Prolixin among others, is a high-potency typical antipsychotic medication.

It is used in the treatment of chronic psychoses such as schizophrenia, and appears to be about equal in effectiveness to low-potency antipsychotics like chlorpromazine. It is given by mouth, injection into a muscle, or just under the skin. There is also a long acting injectable version that may last for up to four weeks. Fluphenazine decanoate, the depot injection form of fluphenazine, should not be used by people with severe depression.

Common side effects include movement problems, sleepiness, depression and increased weight. Serious side effects may include neuroleptic malignant syndrome, low white blood cell levels, and the potentially permanent movement disorder tardive dyskinesia. In older people with psychosis as a result of dementia it may increase the risk of dying. It may also increase prolactin levels which may result in milk production, enlarged breasts in males, impotence, and the absence of menstrual periods. It is unclear if it is safe for use in pregnancy.

Fluphenazine is a typical antipsychotic of the phenothiazine class. Its mechanism of action is not entirely clear but believed to be related to its ability to block dopamine receptors. In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal.

Fluphenazine came into use in 1959. The injectable form is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. It was discontinued in Australia around mid 2017.

Brief History

Fluphenazine came into use in 1959.

Medical Use

A 2018 Cochrane review found that fluphenazine was an imperfect treatment and other inexpensive drugs less associated with side effects may be an equally effective choice for people with schizophrenia.

Side Effects

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Pharmacology

Pharmacodynamics

Fluphenazine acts primarily by blocking post-synaptic D2 receptors in the basal ganglia, cortical and limbic system. It also blocks alpha-1 adrenergic receptors, muscarinic-1 receptors, and histamine-1 receptors.

Availability

The injectable form is on the World Health Organisation’s List of Essential Medicines, the safest and most effective medicines needed in a health system. It is available as a generic medication. It was discontinued in Australia around mid 2017.

Other Animals

In horses, it is sometimes given by injection as an anxiety-relieving medication, though there are many negative common side effects and it is forbidden by many equestrian competition organisations.

What is Flurazepam?

Introduction

Flurazepam (marketed under the brand names Dalmane and Dalmadorm) is a drug which is a benzodiazepine derivative.

It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It produces a metabolite with a long half-life, which may stay in the bloodstream for days. Flurazepam was patented in 1968 and came into medical use the same year. Flurazepam, developed by Roche Pharmaceuticals was one of the first benzo hypnotics (sleeping pills) to be marketed.

Medical Uses

Flurazepam is officially indicated for mild to moderate insomnia and as such it is used for short-term treatment of patients with mild to moderate insomnia such as difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Flurazepam is a long-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep, though benzodiazepines with intermediate half-lives such as loprazolam, lormetazepam, and temazepam are also indicated for patients with difficulty maintaining sleep.

Flurazepam was temporarily unavailable in the United States when its sole producer, Mylan Pharmaceuticals, discontinued making it in January 2019. In October of 2019, the US Food and Drug Administration (FDA) informed pharmacies that they could expect to be resupplied by manufacturers in early to mid December 2019. As of this date, Flurazepam is now again available in the United States.

Side Effects

The most common adverse effects are dizziness, drowsiness, light-headedness, and ataxia. Flurazepam has abuse potential and should never be used with alcoholic beverages or any other substance that can cause drowsiness. Addictive and possibly fatal results may occur. Flurazepam users should only take this drug strictly as prescribed, and should only be taken directly before the user plans on sleeping a full night. Next day drowsiness is common and may increase during the initial phase of treatment as accumulation occurs until steady-state plasma levels are attained.

A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking hypnotic drugs compared to those taking a placebo.

In September 2020, the FDA required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Tolerance, Dependence and Withdrawal

Refer to Benzodiazepine Withdrawal Syndrome.

A review paper found that long-term use of flurazepam is associated with drug tolerance, drug dependence, rebound insomnia and central nervous system (CNS) related adverse effects. Flurazepam is best used for a short time period and at the lowest possible dose to avoid complications associated with long-term use. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality. Flurazepam and other benzodiazepines such as fosazepam, and nitrazepam lost some of their effect after seven days administration in psychogeriatric patients. Flurazepam shares cross tolerance with barbiturates and barbiturates can easily be substituted by flurazepam in those who are habituated to barbiturate sedative hypnotics.

After discontinuation of flurazepam a rebound effect or benzodiazepine withdrawal syndrome may occur about four days after discontinuation of medication.

Contraindications and Special Caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.

Elderly

Flurazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments. An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilised. Compared with the benzodiazepines including flurazepam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy in elderly persons. Tolerability in elderly patients, however, is improved marginally in that benzodiazepines have moderately higher risks of falls, memory problems, and disinhibition (“paradoxical agitation”) when compared to non-benzodiazepine sedatives. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Chronic use of sedative-hypnotic drugs for the management of insomnia does not have an evidence base and has been discouraged due to concerns including potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of sedative hypnotics has been determined to be no better than placebo after 3 months of therapy and worse than placebo after 6 months of therapy.

Pharmacology

Flurazepam is a “classical” benzodiazepine; some other classical benzodiazepines include diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam, and clorazepate. Flurazepam generates an active metabolite, N-desalkylflurazepam, with a very long elimination half-life. Flurazepam could be therefore unsuitable as a sleeping medication for some individuals due to next-day sedation; however, this same effect may also provide next-day anxiety relief. Residual ‘hangover’ effects after nighttime administration of flurazepam, such as sleepiness, impaired psychomotor and cognitive functions, may persist into the next day, which may impair the ability of users to drive safely and increase risks of falls and hip fractures.

Flurazepam is lipophilic, is metabolised hepatically via oxidative pathways. The main pharmacological effect of flurazepam is to increase the effect of GABA at the GABAA receptor via binding to the benzodiazepine site on the GABAA receptor causing an increase influx of chloride ions into the GABAA neuron.

Flurazepam is contraindicated in pregnancy. It is recommended to withdraw flurazepam during breast feeding, as flurazepam is excreted in breast milk.

Society and Culture

Drug Misuse

Refer to Benzodiazepine Use Disorder.

Flurazepam is a drug with potential for misuse. Two types of drug misuse can occur, either recreational misuse where the drug is taken to achieve a high, or when the drug is continued long term against medical advice.

Flurazepam is a Schedule IV drug under the Convention on Psychotropic Substances.

What is Dialectical Behaviour Therapy?

Introduction

Dialectical behaviour therapy (DBT) is an evidence-based psychotherapy that began with efforts to treat personality disorders, ADHD, and interpersonal conflicts.

There is evidence that DBT can be useful in treating mood disorders, suicidal ideation, and for change in behavioural patterns such as self-harm and substance use. DBT evolved into a process in which the therapist and client work with acceptance and change-oriented strategies, and ultimately balance and synthesize them, in a manner comparable to the philosophical dialectical process of hypothesis and antithesis, followed by synthesis.

This approach was developed by Marsha M. Linehan, a psychology researcher at the University of Washington, to help people increase their emotional and cognitive regulation by learning about the triggers that lead to reactive states and helping to assess which coping skills to apply in the sequence of events, thoughts, feelings, and behaviours to help avoid undesired reactions.

Linehan developed DBT as a modified form of cognitive behavioural therapy (CBT) in the late 1980s to treat people with borderline personality disorder (BPD) and chronically suicidal individuals. Research on its effectiveness in treating other conditions has been fruitful; DBT has been used by practitioners to treat people with depression, drug and alcohol problems, post-traumatic stress disorder (PTSD), traumatic brain injuries (TBI), binge-eating disorder, and mood disorders. Research indicates DBT might help patients with symptoms and behaviours associated with spectrum mood disorders, including self-injury. Work also suggests its effectiveness with sexual-abuse survivors and chemical dependency.

DBT combines standard cognitive-behavioural techniques for emotion regulation and reality-testing with concepts of distress tolerance, acceptance, and mindful awareness largely derived from contemplative meditative practice. DBT is based upon the biosocial theory of mental illness and is the first therapy that has been experimentally demonstrated to be generally effective in treating BPD. The first randomised clinical trial of DBT showed reduced rates of suicidal gestures, psychiatric hospitalisations, and treatment drop-outs when compared to treatment as usual. A meta-analysis found that DBT reached moderate effects in individuals with borderline personality disorder.

Overview

DBT is considered part of the “third wave” of cognitive-behavioural therapy, and DBT adapts CBT to assist patients to deal with stress.

This approach was developed by Marsha M. Linehan, a psychology researcher at the University of Washington, to help people increase their emotional and cognitive regulation by learning about the triggers that lead to reactive states and helping to assess which coping skills to apply in the sequence of events, thoughts, feelings, and behaviours to help avoid undesired reactions.

Linehan developed DBT as a modified form of cognitive behavioural therapy (CBT) in the late 1980s to treat people with borderline personality disorder (BPD) and chronically suicidal individuals. Research on its effectiveness in treating other conditions has been fruitful; DBT has been used by practitioners to treat people with depression, drug and alcohol problems, post-traumatic stress disorder (PTSD), traumatic brain injuries (TBI), binge-eating disorder, and mood disorders. Research indicates DBT might help patients with symptoms and behaviours associated with spectrum mood disorders, including self-injury. Recent work also suggests its effectiveness with sexual-abuse survivors and chemical dependency.

DBT strives to have the patient view the therapist as an ally rather than an adversary in the treatment of psychological issues. Accordingly, the therapist aims to accept and validate the client’s feelings at any given time, while, nonetheless, informing the client that some feelings and behaviours are maladaptive, and showing them better alternatives. DBT focuses on the client acquiring new skills and changing their behaviours, with the ultimate goal of achieving a “life worth living”, as defined by the patient.

In DBT’s biosocial theory of BPD, clients have a biological predisposition for emotional dysregulation, and their social environment validates maladaptive behaviour.

DBT skills training alone is being used to address treatment goals in some clinical settings, and the broader goal of emotion regulation that is seen in DBT has allowed it to be used in new settings, for example, supporting parenting.

Four Modules

Mindfulness

Mindfulness is one of the core ideas behind all elements of DBT. It is considered a foundation for the other skills taught in DBT, because it helps individuals accept and tolerate the powerful emotions they may feel when challenging their habits or exposing themselves to upsetting situations.

The concept of mindfulness and the meditative exercises used to teach it are derived from traditional contemplative religious practice, though the version taught in DBT does not involve any religious or metaphysical concepts. Within DBT it is the capacity to pay attention, nonjudgmentally, to the present moment; about living in the moment, experiencing one’s emotions and senses fully, yet with perspective. The practice of mindfulness can also be intended to make people more aware of their environments through their five senses: touch, smell, sight, taste, and sound. Mindfulness relies heavily on the principle of acceptance, sometimes referred to as “radical acceptance”. Acceptance skills rely on the patient’s ability to view situations with no judgment, and to accept situations and their accompanying emotions. This causes less distress overall, which can result in reduced discomfort and symptomology.

Acceptance and Change

The first few sessions of DBT introduce the dialectic of acceptance and change. The patient must first become comfortable with the idea of therapy; once the patient and therapist have established a trusting relationship, DBT techniques can flourish. An essential part of learning acceptance is to first grasp the idea of radical acceptance: radical acceptance embraces the idea that one should face situations, both positive and negative, without judgment. Acceptance also incorporates mindfulness and emotional regulation skills, which depend on the idea of radical acceptance. These skills, specifically, are what set DBT apart from other therapies.

Often, after a patient becomes familiar with the idea of acceptance, they will accompany it with change. DBT has five specific states of change which the therapist will review with the patient:

  • Precontemplation is the first stage, in which the patient is completely unaware of their problem.
  • In the second stage, contemplation, the patient realises the reality of their illness: this is not an action, but a realisation.
  • It is not until the third stage, preparation, that the patient is likely to take action, and prepares to move forward. This could be as simple as researching or contacting therapists.
  • Finally, in stage 4, the patient takes action and receives treatment.
  • In the final stage, maintenance, the patient must strengthen their change in order to prevent relapse.

After grasping acceptance and change, a patient can fully advance to mindfulness techniques.

There are six mindfulness skills used in DBT to bring the client closer to achieving a “wise mind”, the synthesis of the rational mind and emotion mind: three “what” skills (observe, describe, participate) and three “how” skills (nonjudgementally, one-mindfully, effectively).

Distress Tolerance

Many current approaches to mental health treatment focus on changing distressing events and circumstances such as dealing with the death of a loved one, loss of a job, serious illness, terrorist attacks and other traumatic events. They have paid little attention to accepting, finding meaning for, and tolerating distress. This task has generally been tackled by person-centred, psychodynamic, psychoanalytic, gestalt, or narrative therapies, along with religious and spiritual communities and leaders. Dialectical behaviour therapy emphasizes learning to bear pain skilfully. This module outlines healthy coping behaviours intended to replace harmful ones, such as distractions, improving the moment, self-soothing, and practicing acceptance of what is.

Distress tolerance skills constitute a natural development from DBT mindfulness skills. They have to do with the ability to accept, in a non-evaluative and non-judgemental fashion, both oneself and the current situation. Since this is a non-judgmental stance, this means that it is not one of approval or resignation. The goal is to become capable of calmly recognizing negative situations and their impact, rather than becoming overwhelmed or hiding from them. This allows individuals to make wise decisions about whether and how to take action, rather than falling into the intense, desperate, and often destructive emotional reactions that are part of borderline personality disorder.

Emotion Regulation

Individuals with borderline personality disorder and suicidal individuals are frequently emotionally intense and labile. They can be angry, intensely frustrated, depressed, or anxious. This suggests that these clients might benefit from help in learning to regulate their emotions. DBT skills for emotion regulation include:

  • Identify and label emotions.
  • Identify obstacles to changing emotions.
  • Reduce vulnerability to emotion mind.
  • Increase positive emotional events.
  • Increase mindfulness to current emotions.
  • Take opposite action.
  • Apply distress tolerance techniques.

Emotional regulation skills are based on the theory that intense emotions are a conditioned response to troublesome experiences, the conditioned stimulus, and therefore, are required to alter the patient’s conditioned response. These skills can be categorised into four modules: understanding and naming emotions, changing unwanted emotions, reducing vulnerability, and managing extreme conditions:

  • Learning how to understand and name emotions:
    • The patient focuses on recognising their feelings.
    • This segment relates directly to mindfulness, which also exposes a patient to their emotions.
  • Changing unwanted emotions:
    • The therapist emphasizes the use of opposite-reactions, fact-checking, and problem solving to regulate emotions.
    • While using opposite-reactions, the patient targets distressing feelings by responding with the opposite emotion.
  • Reducing vulnerability:
    • The patient learns to accumulate positive emotions and to plan coping mechanisms in advance, in order to better handle difficult experiences in the future.
  • Managing extreme conditions:
    • The patient focuses on incorporating their use of mindfulness skills to their current emotions, to remain stable and alert in a crisis.

Interpersonal Effectiveness

The three interpersonal skills focused on in DBT include self-respect, treating others “with care, interest, validation, and respect”, and assertiveness. The dialectic involved in healthy relationships involves balancing the needs of others with the needs of the self, while maintaining one’s self-respect

Tools

Specially formatted diary cards can be used to track relevant emotions and behaviours. Diary cards are most useful when they are filled out daily. The diary card is used to find the treatment priorities that guide the agenda of each therapy session. Both the client and therapist can use the diary card to see what has improved, gotten worse, or stayed the same.

Chain Analysis

Chain analysis is a form of functional analysis of behaviour but with increased focus on sequential events that form the behaviour chain. It has strong roots in behavioural psychology in particular applied behaviour analysis concept of chaining. A growing body of research supports the use of behaviour chain analysis with multiple populations.

Efficacy

Borderline Personality Disorder

DBT is the therapy that has been studied the most for treatment of borderline personality disorder, and there have been enough studies done to conclude that DBT is helpful in treating borderline personality disorder. A 2009 Canadian study compared the treatment of borderline personality disorder with dialectical behaviour therapy against general psychiatric management. A total of 180 adults, 90 in each group, were admitted to the study and treated for an average of 41 weeks. Statistically significant decreases in suicidal events and non-suicidal self-injurious events were seen overall (48% reduction, p=0.03; and 77% reduction, p=0.01; respectively). No statistically-significant difference between groups were seen for these episodes (p=.64). Emergency department visits decreased by 67% (p<0.0001) and emergency department visits for suicidal behaviour by 65% (p<0.0001), but there was also no statistically significant difference between groups.

Depression

A Duke University pilot study compared treatment of depression by antidepressant medication to treatment by antidepressants and dialectical behaviour therapy. A total of 34 chronically depressed individuals over age 60 were treated for 28 weeks. Six months after treatment, statistically-significant differences were noted in remission rates between groups, with a greater percentage of patients treated with antidepressants and dialectical behaviour therapy in remission.

Complex Post-Traumatic Stress Disorder (CPTSD)

Exposure to complex trauma, or the experience of traumatic events, can lead to the development of complex post-traumatic stress disorder (CPTSD) in an individual. CPTSD is a concept which divides the psychological community. The American Psychological Association (APA) does not recognise it in the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, the manual used by providers to diagnose, treat and discuss mental illness), though some practitioners argue that CPTSD is separate from post-traumatic stress disorder (PTSD).

CPTSD is similar to PTSD in that its symptomatology is pervasive and includes cognitive, emotional, and biological domains, among others. CPTSD differs from PTSD in that it is believed to originate in childhood interpersonal trauma, or chronic childhood stress, and that the most common precedents are sexual traumas. Currently, the prevalence rate for CPTSD is an estimated 0.5%, while PTSD’s is 1.5%. Numerous definitions for CPTSD exist. Different versions are contributed by the World Health Organisation (WHO), The International Society for Traumatic Stress Studies (ISTSS), and individual clinicians and researchers.

Most definitions revolve around criteria for PTSD with the addition of several other domains. While The APA may not recognise CPTSD, the WHO has recognized this syndrome in its 11th edition of the International Classification of Diseases (ICD-11). The WHO defines CPTSD as a disorder following a single or multiple events which cause the individual to feel stressed or trapped, characterised by low self-esteem, interpersonal deficits, and deficits in affect regulation. These deficits in affect regulation, among other symptoms are a reason why CPTSD is sometimes compared with borderline personality disorder (BPD).

Similarities between CPTSD and Borderline Personality Disorder

In addition to affect dysregulation, case studies reveal that patients with CPTSD can also exhibit splitting, mood swings, and fears of abandonment. Like patients with borderline personality disorder, patients with CPTSD were traumatised frequently and/or early in their development and never learned proper coping mechanisms. These individuals may use avoidance, substances, dissociation, and other maladaptive behaviours to cope. Thus, treatment for CPTSD involves stabilising and teaching successful coping behaviours, affect regulation, and creating and maintaining interpersonal connections. In addition to sharing symptom presentations, CPTSD and BPD can share neurophysiological similarities, for example, abnormal volume of the amygdala (emotional memory), hippocampus (memory), anterior cingulate cortex (emotion), and orbital prefrontal cortex (personality). Another shared characteristic between CPTSD and BPD is the possibility for dissociation. Further research is needed to determine the reliability of dissociation as a hallmark of CPTSD, however it is a possible symptom. Because of the two disorders’ shared symptomatology and physiological correlates, psychologists began hypothesising that a treatment which was effective for one disorder may be effective for the other as well.

DBT as a Treatment for CPTSD

DBT’s use of acceptance and goal orientation as an approach to behaviour change can help to instil empowerment and engage individuals in the therapeutic process. The focus on the future and change can help to prevent the individual from becoming overwhelmed by their history of trauma. This is a risk especially with CPTSD, as multiple traumas are common within this diagnosis. Generally, care providers address a client’s suicidality before moving on to other aspects of treatment. Because PTSD can make an individual more likely to experience suicidal ideation, DBT can be an option to stabilize suicidality and aid in other treatment modalities.

Some critics argue that while DBT can be used to treat CPTSD, it is not significantly more effective than standard PTSD treatments. Further, this argument posits that DBT decreases self-injurious behaviours (such as cutting or burning) and increases interpersonal functioning but neglects core CPTSD symptoms such as impulsivity, cognitive schemas (repetitive, negative thoughts), and emotions such as guilt and shame. The ISTSS reports that CPTSD requires treatment which differs from typical PTSD treatment, using a multiphase model of recovery, rather than focusing on traumatic memories. The recommended multiphase model consists of establishing safety, distress tolerance, and social relations.

Because DBT has four modules which generally align with these guidelines (Mindfulness, Distress Tolerance, Affect Regulation, Interpersonal Skills) it is a treatment option. Other critiques of DBT discuss the time required for the therapy to be effective. Individuals seeking DBT may not be able to commit to the individual and group sessions required, or their insurance may not cover every session.

A study co-authored by Linehan found that among women receiving outpatient care for BPD and who had attempted suicide in the previous year, 56% additionally met criteria for PTSD. Because of the correlation between borderline personality disorder traits and trauma, some settings began using DBT as a treatment for traumatic symptoms. Some providers opt to combine DBT with other PTSD interventions, such as prolonged exposure therapy (PE) (repeated, detailed description of the trauma in a psychotherapy session) or cognitive processing therapy (CPT) (psychotherapy which addresses cognitive schemas related to traumatic memories).

For example, a regimen which combined PE and DBT would include teaching mindfulness skills and distress tolerance skills, then implementing PE. The individual with the disorder would then be taught acceptance of a trauma’s occurrence and how it may continue to affect them throughout their lives. Participants in clinical trials such as these exhibited a decrease in symptoms, and throughout the 12-week trial, no self-injurious or suicidal behaviours were reported.

Another argument which supports the use of DBT as a treatment for trauma hinges upon PTSD symptoms such as emotion regulation and distress. Some PTSD treatments such as exposure therapy may not be suitable for individuals whose distress tolerance and/or emotion regulation is low. Biosocial theory posits that emotion dysregulation is caused by an individual’s heightened emotional sensitivity combined with environmental factors (such as invalidation of emotions, continued abuse/trauma), and tendency to ruminate (repeatedly think about a negative event and how the outcome could have been changed).

An individual who has these features is likely to use maladaptive coping behaviours. DBT can be appropriate in these cases because it teaches appropriate coping skills and allows the individuals to develop some degree of self-sufficiency. The first three modules of DBT increase distress tolerance and emotion regulation skills in the individual, paving the way for work on symptoms such as intrusions, self-esteem deficiency, and interpersonal relations.

Noteworthy is that DBT has often been modified based on the population being treated. For example, in veteran populations DBT is modified to include exposure exercises and accommodate the presence of traumatic brain injury (TBI), and insurance coverage (i.e. shortening treatment). Populations with comorbid BPD may need to spend longer in the “Establishing Safety” phase. In adolescent populations, the skills training aspect of DBT has elicited significant improvement in emotion regulation and ability to express emotion appropriately. In populations with comorbid substance use, adaptations may be made on a case-by-case basis.

For example, a provider may wish to incorporate elements of motivational interviewing (psychotherapy which uses empowerment to inspire behaviour change). The degree of substance use should also be considered. For some individuals, substance use is the only coping behaviour they know, and as such the provider may seek to implement skills training before target substance reduction. Inversely, a client’s substance use may be interfering with attendance or other treatment compliance and the provider may choose to address the substance use before implementing DBT for the trauma.

What is Desvenlafaxine?

Introduction

Desvenlafaxine, sold under the brand name Pristiq among others, is a medication used to treat depression.

It is recommended that the need for further treatment be occasionally reassessed. It may be less effective than its parent compound venlafaxine, although some studies have found comparable efficacy. It is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class and is taken by mouth.

Common side effects include dizziness, trouble sleeping, increased sweating, constipation, sleepiness, anxiety, and sexual problems. Serious side effects may include suicide in those under the age of 25, serotonin syndrome, bleeding, mania, and high blood pressure. A withdrawal syndrome may occur if the dose is rapidly decreased. It is unclear if use during pregnancy or breastfeeding is safe.

Desvenlafaxine was approved for medical use in the United States in 2008. In Europe its application for use was denied in 2009. In 2017, it was the 235th most commonly prescribed medication in the United States, with more than two million prescriptions.

Medical Uses

Desvenlafaxine is primarily used as a treatment for major depressive disorder. Use has only been studied up to 8 weeks. It may be less effective than venlafaxine, although some studies have found comparable efficacy with a lower rate of nausea.

Doses of 50-400 mg/day appear effective for major depressive disorder, although no additional benefit was demonstrated at doses greater than 50 mg/day, and adverse events and discontinuations were more frequent at higher doses.

Desvenlafaxine improves the HAM-D17 score and measures of well being such as the Sheehan Disability Scale (SDS) and 5-item World Health Organisation Well-Being Index (WHO-5).

Adverse Effects

Frequency of adverse effects:

  • Very common adverse effects include:
    • Nausea.
    • Headache.
    • Dizziness.
    • Dry mouth.
    • Hyperhidrosis.
    • Diarrhoea.
    • Insomnia.
    • Constipation.
    • Fatigue.
  • Common adverse effects include:
    • Tremor.
    • Blurred vision.
    • Mydriasis.
    • Decreased appetite.
    • Sexual dysfunction.
    • Insomnia.
    • Anxiety.
    • Elevated cholesterol and triglycerides.
    • Proteinuria.
    • Vertigo.
    • Feeling jittery.
    • Asthenia.
    • Nervousness.
    • Hot flush.
    • Irritability.
    • Abnormal dreams.
    • Urinary hesitation.
    • Yawning.
    • Rash.
  • Uncommon adverse effects include:
  • Rare adverse effects include:
    • Hyponatraemia (low blood sodium).
    • Seizures.
    • Extrapyramidal side effects.
    • Hallucinations.
    • Angioedema.
    • Photosensitivity reaction.
    • Stevens-Johnson syndrome.
  • Common however unknown intensity of adverse effects include:
    • Abnormal bleeding (gastrointestinal bleeds).
    • Narrow-angle glaucoma.
    • Mania.
    • Interstitial lung disease.
    • Eosinophilic pneumonia.
    • Hypertension.
    • Suicidal behaviour and thoughts.
    • Serotonin syndrome.

Pharmacology

Desvenlafaxine is a synthetic form of the isolated major active metabolite of venlafaxine, and is categorised as a serotonin-norepinephrine reuptake inhibitor (SNRI). When most normal metabolisers take venlafaxine, approximately 70% of the dose is metabolised into desvenlafaxine, so the effects of the two drugs are expected to be very similar. It works by blocking the “reuptake” transporters for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline). It is approximately 10 times more potent at inhibiting serotonin uptake than norepinephrine uptake.

Approval Status

United States

Wyeth announced on 23 January 2007 that it received an approvable letter from the Food and Drug Administration (FDA) for desvenlafaxine. Final approval to sell the drug was contingent on a number of things, including:

  • A satisfactory FDA inspection of Wyeth’s Guayama, Puerto Rico facility, where the drug is to be manufactured;
  • Several postmarketing surveillance commitments, and follow-up studies on low-dose use, relapse, and use in children;
  • Clarity by Wyeth around the company’s product education plan for physicians and patients;
  • Approval of desvenlafaxine’s proprietary name, Pristiq.

The FDA approved the drug for antidepressant use in February 2008, and was to be available in US pharmacies in May 2008.

In March 2017, the generic form of the drug was made available in the US.

Canada

On 04 February 2009, Health Canada approved use of desvenlafaxine for treatment of depression.

European Union

In 2009, an application to market desvenlafaxine for major depressive disorder in the European Union was declined. In 2012, Pfizer received authorization in Spain to market desvenlafaxine for the disorder but it is not being sold.

Australia

Desvenlafaxine is classified as a schedule 4 (prescription only) drug in Australia. It was listed on the PBS (Pharmaceutical Benefits Scheme) in 2008 for the treatment of major depressive disorders.

What is Clinical Behaviour Analysis?

Introduction

Clinical behaviour analysis (CBA; a third-generation behaviour therapy) is the clinical application of behaviour analysis (ABA). CBA represents a movement in behaviour therapy away from methodological behaviourism and back toward radical behaviourism and the use of functional analytic models of verbal behaviour – particularly, relational frame theory (RFT).

Current Models

CBA therapies include acceptance and commitment therapy (ACT), behavioural medicine (such as behavioural gerontology and paediatric feeding therapy), community reinforcement approach and family training (CRAFT), exposure therapies/desensitisation (such as systematic desensitisation), functional analytic psychotherapy (FAP, such as behavioural activation (BA) and integrative behavioural couples therapy), and voucher-based contingency management.

Acceptance and Commitment Therapy

Acceptance and commitment therapy is probably the most well-researched of all the third-generation behaviour therapy models. Its development co-occurred with that of relational frame theory, with several researchers such as Steven C Hayes being involved with both. ACT has been argued to be based on relational frame theory, although this is a matter of some debate within the community. Originally this approach was referred to as comprehensive distancing. Every practitioner mixes acceptance with a commitment to one’s values. These ingredients become enmeshed into the treatment in different ways which leads to ACT being either more on the mindfulness side or more on the behaviour-changing side. ACT has, as of May 2021, been evaluated in over 600 randomised clinical trials for a variety of client problems. Overall, when compared to other active treatments designed or known to be helpful, the effect size for ACT is a Cohen’s d of around 0.6, which is considered a medium effect size.

Behavioural Activation

Behavioural activation emerged from a component analysis of cognitive behaviour therapy. This research found no additive effect for the cognitive component. Behavioural activation is based on a matching law model of reinforcement. A recent review of the research supports the notion that the use of behavioural activation is clinically important for the treatment of depression.

Community Reinforcement Approach and Family Training

Community reinforcement approach and family training (CRAFT) is a model developed by Robert Meyer and based on the community reinforcement approach (CRA) first developed by Nathan Azrin and Hunt. The model focuses on the use of functional behavioural assessment to reduce drinking behaviour. CRAFT combines CRA with family therapy.

Functional Analytic Psychotherapy

Functional analytic psychotherapy is based on a functional analysis of the therapeutic relationship. It places a greater emphasis on the therapeutic context and returns to the use of in-session reinforcement. The basic FAP analysis utilises what is called the clinically relevant behaviour (CRB1), which is the client’s presenting problem as presented in-session. Client in-session actions that improve their CRB1s are referred to as CRB2s. Client statements, or verbal behaviour, about CRBs are referred to as CRB3s. In general, 40 years of research supports the idea that in-session reinforcement of behaviour can lead to behavioural change.

Integrative Behavioural Couples Therapy

Integrative behavioural couples therapy developed from dissatisfaction with traditional behavioural couples therapy. Integrative behavioural couples therapy looks to Skinner (1966) for the difference between contingency shaped and rule-governed behaviour. It couples this analysis with a thorough functional assessment of the couples relationship. Recent efforts have used radical behavioural concepts to interpret a number of clinical phenomena including forgiveness.

Clinical Formulation

As with all behaviour therapy, clinical behaviour analysis relies on a functional analysis of problem behaviour. Depending on the clinical model this analysis draws on B.F Skinner’s model of Verbal Behaviour or relational frame theory.

Professional Organisations

The Association for Behaviour Analysis International has a special interest group in clinical behaviour analysis ABA:I. ABA:I 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.

The Association for Contextual Behavioural Science is devoted to third-generation therapies and basic research on derived relational responding and relational frame theory.

What is Behavioural Activation?

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 Agomelatine?

Introduction

Agomelatine is an atypical antidepressant used to treat major depressive disorder.

One review found that it is as effective as other antidepressants with similar discontinuation rates overall but less discontinuations due to side effects. Another review also found it was similarly effective to many other antidepressants.

Common side effects include weight gain, fatigue, liver problems, nausea, headaches, and anxiety. Due to potential liver problems ongoing blood tests are recommended. Its use is not recommended in people with dementia or over the age of 75. There is tentative evidence that it may have fewer side effects than some other antidepressants. It works by stimulating melatonin receptors and blocking serotonin receptors.

Agomelatine was approved for medical use in Europe in 2009 and Australia in 2010. Its use is not approved in the United States and efforts to get approval were ended in 2011. It was developed by the pharmaceutical company Servier.

Brief History

Agomelatine was discovered and developed by the European pharmaceutical company Servier Laboratories Ltd. Servier continued to develop the drug and conduct phase III trials in the European Union.

In March 2005, Servier submitted agomelatine to the European Medicines Agency (EMA) under the trade names Valdoxan and Thymanax. On 27 July 2006, the Committee for Medical Products for Human Use (CHMP) of the EMA recommended a refusal of the marketing authorisation. The major concern was that efficacy had not been sufficiently shown, while there were no special concerns about side effects. In September 2007, Servier submitted a new marketing application to the EMA.

In March 2006, Servier announced it had sold the rights to market agomelatine in the United States to Novartis. It was undergoing several phase III clinical trials in the US, and until October 2011 Novartis listed the drug as scheduled for submission to the FDA no earlier than 2012. However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available.

It received approval from the European Medicines Agency (EMA) for marketing in the European Union in February 2009 and approval from the Therapeutic Goods Administration (TGA) for marketing in Australia in August 2010.

Medical Uses

Major Depressive Disorder

Agomelatine is used for the treatment of major depressive episodes in adults in Europe. Ten placebo controlled trials have been performed to investigate the short term efficacy of agomelatine in major depressive disorder. At the end of treatment, significant efficacy was demonstrated in six of the ten short-term double-blind placebo-controlled studies. Two were considered “failed” trials, as comparators of established efficacy failed to differentiate from placebo. Efficacy was also observed in more severely depressed patients in all positive placebo-controlled studies. The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study. One meta-analysis found agomelatine to be as effective as standard antidepressants.

A meta-analysis found that agomelatine is effective in treating severe depression. Its antidepressant effect is greater for more severe depression. In people with a greater baseline score (>30 on HAMD17 scale), the agomelatine-placebo difference was of 4.53 points. Controlled studies in humans have shown that agomelatine is at least as effective as the SSRI antidepressants paroxetine, sertraline, escitalopram, and fluoxetine in the treatment of major depression. A 2018 meta-study comparing 21 antidepressants found agomelatine was one of the more tolerable, yet effective antidepressants.

However, the body of research on agomelatine has been substantially affected by publication bias, prompting analyses which take into account both published and unpublished studies. These have confirmed that agomelatine is approximately as effective as more commonly used antidepressants (e.g. SSRIs), but some qualified this as “marginally clinically relevant”, being only slightly above placebo. According to a 2013 review, agomelatine did not seem to provide an advantage in efficacy over other antidepressants for the acute-phase treatment of major depression.

Use in Special Populations

It is not recommended in Europe for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. However, a study reported in September, 2020, showed greater efficacy vs. placebo for agomelatine 25mg per day in youth age 7-18 years. Only limited data is available on use in elderly people ≥ 75 years old with major depressive episodes.

It is not recommended during pregnancy or breastfeeding.

Contraindications

Agomelatine is contraindicated in patients with kidney or liver impairment. According to information disclosed by Servier in 2012, guidelines for the follow-up of patients treated with Valdoxan have been modified in concert with the European Medicines Agency. As some patients may experience increased levels of liver enzymes in their blood during treatment with Valdoxan, doctors have to run laboratory tests to check that the liver is working properly at the initiation of the treatment and then periodically during treatment, and subsequently decide whether to pursue the treatment or not. No relevant modification in agomelatine pharmacokinetic parameters in patients with severe renal impairment has been observed. However, only limited clinical data on its use in depressed patients with severe or moderate renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing agomelatine to these patients.

Adverse Effects

Agomelatine does not alter daytime vigilance and memory in healthy volunteers. In depressed patients, treatment with the drug increased slow wave sleep without modification of REM (Rapid Eye Movement) sleep amount or REM latency. Agomelatine also induced an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients.

Agomelatine appears to cause fewer sexual side effects and discontinuation effects than paroxetine.

  • Common (1-10% incidence) adverse effects include:
    • Hyperhidrosis (excess sweating that is not proportionate to the ambient temperature).
    • Abdominal pain.
    • Nausea.
    • Vomiting.
    • Diarrhoea.
    • Constipation.
    • Back pain.
    • Fatigue.
    • Increased ALAT and ASAT (liver enzymes).
    • Headache.
    • Dizziness.
    • Somnolence.
    • Insomnia.
    • Migraine.
    • Anxiety.
  • Uncommon (0.1-1%) adverse effects include:
    • Paraesthesia (abnormal sensations [e.g. itching, burning, tingling, etc.] due to malfunctioning of the peripheral nerves).
    • Blurred vision.
    • Eczema.
    • Pruritus (itching).
    • Urticaria.
    • Agitation.
    • Irritability.
    • Restlessness.
    • Aggression.
    • Nightmares.
    • Abnormal dreams.
  • Rare (0.01-0.1%) adverse effects include:
    • Mania.
    • Hypomania.
    • Suicidal ideation.
    • Suicidal behaviour.
    • Hallucinations.
    • Steatohepatitis.
    • Increased GGT and/or alkaline phosphatase.
    • Liver failure.
    • Jaundice.
    • Erythematous rash.
    • Face oedema and angioedema.
    • Weight gain or loss, which tends to be less significant than with SSRIs.

Dependence and Withdrawal

No dosage tapering is needed on treatment discontinuation. Agomelatine has no abuse potential as measured in healthy volunteer studies.

Overdose

Agomelatine is expected to be relatively safe in overdose.

Interactions

Agomelatine is a substrate of CYP1A2, CYP2C9 and CYP2C19. Inhibitors of these enzymes, e.g. the SSRI antidepressant fluvoxamine, reduce its clearance and can therefore lead to an increase in agomelatine exposure. There is also the potential for agomelatine to interact with alcohol to increase the risk of hepatotoxicity.

Pharmacology

Pharmacodynamics

Agomelatine is a melatonin receptor agonist (MT1 (Ki 0.1 nM) and MT2 (Ki = 0.12 nM)) and serotonin 5-HT2C (Ki = 631 nM) and 5-HT2B receptor (Ki = 660 nM) antagonist. Binding studies indicate that it has no effect on monoamine uptake and no affinity for adrenergic, histamine, cholinergic, dopamine, and benzodiazepine receptors, nor other serotonin receptors.

Agomelatine resynchronizes circadian rhythms in animal models of delayed sleep phase syndrome. By antagonising 5-HT2C, it disinhibits/increases noradrenaline and dopamine release specifically in the frontal cortex. Therefore, it is sometimes classified as a norepinephrine-dopamine disinhibitor. It has no influence on the extracellular levels of serotonin. Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset.

Antagonism of 5-HT2B is an antidepressant property agomelatine shares with several atypical antipsychotics, such as aripiprazole, which are themselves used as atypical antidepressants. 5-HT2B antagonists are currently being investigated for their usefulness in reducing cardiotoxicity of drugs as well as being effective in reducing headache. Hence this particular receptor antagonism of agomelatine is useful for its antidepressant effectiveness as well as reducing the drug’s adverse effects.

Chemistry

Structure

The chemical structure of agomelatine is very similar to that of melatonin. Where melatonin has an indole ring system, agomelatine has a naphthalene bioisostere instead.

Research

Agomelatine is under development by Servier for the treatment of generalised anxiety disorder and has reached phase III clinical trials for this indication, but in August 2017, Servier communicated that development for this indication is suspended.

Agomelatine is also studied for its effects on sleep regulation. Studies report various improvements in general quality of sleep metrics, as well as benefits in circadian rhythm disorders. It has been found more effective than placebo in the treatment of generalised anxiety disorder. A 2019 review suggested no recommendations of agomelatine in support of, or against, its use to treat individuals with seasonal affective disorder.