What are Expressive Therapies?

Introduction

The expressive therapies are the use of the creative arts as a form of therapy, including the distinct disciplines expressive arts therapy and the creative arts therapies (art therapy, dance/movement therapy, drama therapy, music therapy, writing therapy, poetry therapy, and psychodrama).

Unlike traditional arts expression, the process of creation is emphasized rather than the final product. The expressive therapies are based on the assumption that people can heal through the various forms of creative expression. Expressive therapists share the belief that through creative expression and the tapping of the imagination, people can examine their body, feelings, emotions, and thought process.

Brief History

Margaret Namburg, Edith Kramer, Hanna Kwiatkowska and Elinor Ulman have been credited with being the pioneers of the field of sensory art therapy. While all of these scientists made significant contributions, Margaret Namburg has been hailed the “Mother of Art Therapy”. Her work focused on the use of art, mainly as a psychoanalytic diagnostic tool. It followed closely other psychoanalytic practices of the time, and was viewed as the communication of unconscious ideas and emotions that were being expressed by the patient.

Modern Approaches

Today’s art therapy is broken down into three different approaches:

ApproachOutline
PsychodynamicThe psychodynamic approach uses terms such as “transference” and defence mechanism to describe why individuals express the art in the way they do, and why this is an expression of the subconscious.
HumanisticThe humanistic approach is more of a positive psychology approach, and is defined by an optimistic view of humans, and how expression through their art allows them to take control over these emotions.
Learning and DevelopmentThe learning and developmental approach focuses on the art therapy as a method to assist children who have emotional and developmental disabilities.

Definition and Credentialing

Expressive arts therapy is the practice of using imagery, storytelling, dance, music, drama, poetry, movement, horticulture, dreamwork, and visual arts together, in an integrated way, to foster human growth, development, and healing. Expressive arts therapy is its own distinct therapeutic discipline, an inter-modal discipline where the therapist and client move freely between drawing, dancing, music, drama, and poetry.

According to the National Organisation for Arts in Health (NOAH), what distinguishes the six creative arts therapies – art, dance/movement, drama, music and poetry therapy as well as psychodrama – from expressive arts therapy is that expressive arts therapy interventions are designed to include more than one of the “expressive” art forms (art, dance, drama, music, poetry), whereas creative arts therapists, such as art, dance/movement, drama, music, poetry and psychodrama therapists, are often intensively trained and educated to use only one modality in their practice. However, NOAH also acknowledged that the terms “are often used interchangeably in the field”, and that in any case all such professionals should collaborate closely. 

The International Expressive Arts Therapy Association (IEATA) is the responsible organisation handling the credentialing of expressive arts therapists.

The National Coalition of Creative Arts Therapies Association (NCCATA) connects all six modalities of the creative arts therapies. However, each modality of the creative arts therapies has its own national association that regulates professional credentials, establishes educational standards and hosts annual conferences for the purpose of exchanging new ideas and research.

Education

Each national association of the different modalities of expressive therapies sets its own educational standards. In the United States, there are a fair number of colleges that offer approved programmes in compliance with the national associations’ credentialing requirements.

There are 37 universities for music therapy, 34 universities for art therapy, seven universities for dance/movement therapy, and five universities for drama therapy, as well as 5 universities for expressive arts therapy, that have approved master’s degree programmes in the United States. In addition, the American Music Therapy Association (AMTA) has 75 undergraduate music therapy programmes approved. Once finished with an academic degree, potential therapists have to apply for credentialing at the responsible national association.

Creative Arts Therapies Modalities

There are six creative arts therapy modalities, recognised by the NCCATA, including art therapy, dance therapy, drama therapy, music therapy, poetry therapy and psychodrama. In some areas, the terms Creative Arts Therapy and Creative Arts Therapist may only be used by those who are properly licensed, as is the case in the State of New York.

Art Therapy

Created in the 1940s, Art therapy consists of the combination of psychotherapy and art. The creative process as well as the created art piece serves as a foundation for self-exploration, understanding, acceptance and eventually healing and personal growth. The creative act in therapy therefore can be seen as a means of re-experiencing inner conflict connected to resolution. The four main types are expression, imagination, active participation, and mind-body connection. Assisting in those with depression, breast cancer, and asthma, art therapy can be done at any age and does not require and skill set. Art Therapy has undergone extensive research which revealed that it decreases anxiety, increases self-concept and quality of life, and reduces negative thoughts. With two main goals in mind, Art Therapy strives to enhance personal and relational goals for those in need. Self-esteem, social skills, and cognitive functions are also said to be an area of importance. A certified art therapist is essential in order for the therapy to ensure improvement, however common art therapy using even a friend to discuss trauma can be enough to help someone.

Dance/Movement Therapy

Like other creative arts therapy modalities, dance/movement therapy is based on the assumption that “mind, body and spirit are inseparable and interconnected” (ADTA). Movement is the primary tool of intervention in a therapy session, but dance/movement therapy also uses the art of play in therapy. Like other creative art therapies it uses primarily nonverbal communication. Dance and movement therapy has shown to be the most beneficial in those who enjoy exercises that involve less talking an expression through movements.

Drama Therapy

Drama therapy refers to the combination of the two disciplines drama/theatre and psychotherapy. Drama Therapy, as a hybrid of both disciplines, uses theatre techniques to treat individuals with mental health, cognitive, and developmental disorders. Through the art of play and pretend, patients gain perspective in therapy to their life experiences, which in the field is referred to as “aesthetic distance”.

Music Therapy

Music Therapy is the use of music, music-making, or other music-related interventions within a therapeutic relationship. Music therapy is a broad field with many areas and populations to specialize in. A holistic practice, music therapy can address emotional/psychological, cognitive, communication, motor, sensory, pain, social, behavioural, end of life, and even spiritual needs. This is due in part to music being processed in many areas of the brain. Music therapy helps patients “communicate, process difficult experiences, and improve motor or cognitive functioning” (Jenni Rook, MT-BC, LCPC, 2016). When used as psychotherapy, at its core, music therapy may use music as a symbolic representation and expression of the psychological world of the individual.

Music Therapy also benefits a variety of disorders, like cardiac and mental disorders. It aids those who suffer from depression, anxiety, autism, substance abuse, and Alzheimer’s. In cases where a person is suffering from mental disorders, music relieves stress, improves self-esteem, etc. Evidence has shown that people who have used Music Therapy in the past have improved in several aspects of life that do not concern just those suffering from mental illness. In music therapy people may improve their singing which may then impact their ability to speak. Therefore, it can change several aspects of life, not just those of helping mental illness.

Poetry Therapy

Poetry therapy (also referred to using the broader term bibliotherapy) stands out from other creative arts therapies, which are all based on the assumption of the existence of a language that functions without words. Poetry therapy, however, is the use of the written word to bring healing and personal growth.

Psychodrama

Psychodrama is a distinct form of psychotherapy developed by Jacob L. Moreno in the early 20th century. Moreno, a trained psychoanalyst himself, had the goal of creating a more effective, action-based form of psychoanalysis as developed by Sigmund Freud and Carl Jung. He developed a clear three phase structure (warm up, action, sharing) to his therapy as well as multiple intervention-methods that are still used by psychodrama therapists today.

Although related, psychodrama and drama therapy describe different modalities within the field of creative arts therapies. Whereas psychodrama uses real-life experience of the patients in therapy to “practice new and more effective roles and behaviors” (ASGPP), drama therapy lets the patients explore more fictional stories, such as improvised scenes, myths or fairy tales.

Benefits

BenefitOutline
Self-DiscoveryThis discovery often leads to a relief of emotional tension caused by past events, and can be used as a coping mechanism.
EmpowermentArt therapy gives individuals the ability to articulate their fears and stresses in a non-conventional way, and often leads to sense of control over these emotions.
Stress ReliefEffective for stress relief by itself, but can provide even better results if paired with other relaxation devices such as guided imagery.
Physical Pain Relief and RehabilitationArt therapy has been shown to help decrease pain in patients who are recovering from illness and injury. It has also been used in patients who are chronically or terminally ill, to provide relief and pain control.

Empirical Evidence

Ball (2002)

Ball conducted long-term research on five children who were considered to be severely emotionally disturbed. These children participated in 50 art therapy sessions, and the results suggested that the art therapy was successful, and the children showed marked progress in their treatment over the course of the 50 sessions.

Pifalo (2006)

In this study, 41 girls or young women who had been sexually abused were given structured group art therapy for eight weeks, and were measured before treatment using the Briere’s Trauma Symptom Checklist for Children (TSCC). They were given the test again after the treatment, and for 9 out of 10 of the girls, a statistically significant reduction in scores on the test were observed.

Bar-Sela, Atid, Danos, Gabay & Epelbaum (2007)

This study worked with 60 adults who had cancer. These adults attended weekly individual art therapy, in addition to watercolour painting classes. After just four sessions, the experimental group saw marked and significant improvement in depression and fatigue, as measured by the Hospital Anxiety and Depression Scale and a brief fatigue inventory. While they showed a decrease in depression, there was no significant difference in the levels of anxiety of the patients.

Gusak (2006)

In this study, the researcher worked with 29 incarcerated men. The men attended eight sessions of group art therapy, and were tested before and after the treatment using the Beck Depression Inventory Short Form. After the eight sessions, all of the men showed significant improvement in the symptoms of depression and their score on the Beck Depression Inventory reflected these improvements.

Bulfone et al. (2009)

In this study Bulfone et al. utilised music therapy as their treatment. 60 women who had been diagnosed with stage 1 or 2 breast cancer were randomly assigned to a control or experimental group. The control group received standard assistance before chemotherapy, while the experimental group had the chance to listen to music before the chemotherapy began. The results showed that the anxiety levels of the experimental group were significantly lower than those of the control group, and also showed a significantly lower level of depression.

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What is Climazolam?

Introduction

Climazolam was introduced under licence as a veterinary medicine by the Swiss Pharmaceutical company Gräub under the tradename Climasol.

Background

Climazolam is a benzodiazepine, specifically an imidazobenzodiazepine derivative developed by Hoffman-LaRoche.

It is similar in structure to midazolam and diclazepam and is used in veterinary medicine for anaesthetising animals.

What is Midazolam?

Introduction

Midazolam, sold under the brand name Versed, among others, is a benzodiazepine medication used for anaesthesia, procedural sedation, trouble sleeping, and severe agitation.

It works by inducing sleepiness, decreasing anxiety, and causing a loss of ability to create new memories. It is important to note that this drug does not cause an individual to become unconscious, merely be sedated. It is also useful for the treatment of seizures. Midazolam can be given by mouth, intravenously, by injection into a muscle, by spraying into the nose, or through the cheek. When given intravenously, it typically begins working within five minutes; when injected into a muscle, it can take fifteen minutes to begin working. Effects last between one and six hours.

Side effects can include a decrease in efforts to breathe, low blood pressure, and sleepiness. Tolerance to its effects and withdrawal syndrome may occur following long-term use. Paradoxical effects, such as increased activity, can occur especially in children and older people. There is evidence of risk when used during pregnancy but no evidence of harm with a single dose during breastfeeding. It belongs to the benzodiazepine class of drugs and works by increasing the activity of the GABA neurotransmitter in the brain.

Midazolam was patented in 1974 and came into medical use in 1982. It is on the World Health Organisation’s List of Essential Medicines. Midazolam is available as a generic medication. In many countries, it is a controlled substance.

Brief History

Midazolam is among about 35 benzodiazepines currently used medically, and was synthesized in 1975 by Walser and Fryer at Hoffmann-LaRoche, Inc in the United States. Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs. The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus. As of 2010, it is the most commonly used benzodiazepine in anaesthetic medicine. In acute medicine, midazolam has become more popular than other benzodiazepines, such as lorazepam and diazepam, because it is shorter lasting, is more potent, and causes less pain at the injection site. Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility. In 2018 it was revealed the CIA considered using Midazolam as a “truth serum” on terrorist suspects in project “Medication”.

Medical Uses

Seizures

Midazolam is sometimes used for the acute management of seizures. Long-term use for the management of epilepsy is not recommended due to the significant risk of tolerance (which renders midazolam and other benzodiazepines ineffective) and the significant side effect of sedation. A benefit of midazolam is that in children it can be given in the cheek or in the nose for acute seizures, including status epilepticus. Midazolam is effective for status epilepticus that has not improved following other treatments or when intravenous access cannot be obtained, and has advantages of being water-soluble, having a rapid onset of action and not causing metabolic acidosis from the propylene glycol vehicle (which is not required due to its solubility in water), which occurs with other benzodiazepines.

Drawbacks include a high degree of breakthrough seizures – due to the short half-life of midazolam – in over 50% of people treated, as well as treatment failure in 14-18% of people with refractory status epilepticus. Tolerance develops rapidly to the anticonvulsant effect, and the dose may need to be increased by several times to maintain anticonvulsant therapeutic effects. With prolonged use, tolerance and tachyphylaxis can occur and the elimination half-life may increase, up to days. There is evidence buccal and intranasal midazolam is easier to administer and more effective than rectally administered diazepam in the emergency control of seizures.

Procedural Sedation

Intravenous midazolam is indicated for procedural sedation (often in combination with an opioid, such as fentanyl), for preoperative sedation, for the induction of general anaesthesia, and for sedation of people who are ventilated in critical care units. Midazolam is superior to diazepam in impairing memory of endoscopy procedures, but propofol has a quicker recovery time and a better memory-impairing effect. It is the most popular benzodiazepine in the intensive care unit (ICU) because of its short elimination half-life, combined with its water solubility and its suitability for continuous infusion. However, for long-term sedation, lorazepam is preferred due to its long duration of action, and propofol has advantages over midazolam when used in the ICU for sedation, such as shorter weaning time and earlier tracheal extubation.

Midazolam is sometimes used in neonatal intensive care units. When used, additional caution is required in newborns; midazolam should not be used for longer than 72 hours due to risks of tachyphylaxis, and the possibility of development of a benzodiazepine withdrawal syndrome, as well as neurological complications. Bolus injections should be avoided due to the increased risk of cardiovascular depression, as well as neurological complications. Midazolam is also sometimes used in newborns who are receiving mechanical ventilation, although morphine is preferred, owing to its better safety profile for this indication.

Sedation using midazolam can be used to relieve anxiety and manage behaviour in children undergoing dental treatment.

Agitation

Midazolam, in combination with an antipsychotic drug, is indicated for the acute management of schizophrenia when it is associated with aggressive or out-of-control behaviour.

End of Life Care

In the final stages of end-of-life care, midazolam is routinely used at low doses via subcutaneous injection to help with agitation, myoclonus, restlessness or anxiety in the last hours or days of life. At higher doses during the last weeks of life, midazolam is considered a first line agent in palliative continuous deep sedation therapy when it is necessary to alleviate intolerable suffering not responsive to other treatments, but the need for this is rare.

Administration

Routes of administration of midazolam can be oral, intranasal, buccal, intravenous, and intramuscular.

  • Dosing:
    • Perioperative use: 0.15 to 0.40 mg/kg IV.
    • Premedication: 0.07 to 0.10 mg/kg IM.
    • Intravenous sedation: 0.05 to 0.15 mg/kg IV.

Contraindications

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, in alcohol- or other drug-dependent individuals or those with comorbid psychiatric disorders. Additional caution is required in critically ill patients, as accumulation of midazolam and its active metabolites may occur. Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects. Contraindications include hypersensitivity, acute narrow-angle glaucoma, shock, hypotension, or head injury. Most are relative contraindications.

Side Effects

Refer to Long-Term Effects of Benzodiazepines.

Side effects of midazolam in the elderly are listed above. People experiencing amnesia as a side effect of midazolam are generally unaware their memory is impaired, unless they had previously known it as a side effect.

Long-term use of benzodiazepines has been associated with long-lasting deficits of memory, and show only partial recovery six months after stopping benzodiazepines. It is unclear whether full recovery occurs after longer periods of abstinence. Benzodiazepines can cause or worsen depression. Paradoxical excitement occasionally occurs with benzodiazepines, including a worsening of seizures. Children and elderly individuals or those with a history of excessive alcohol use and individuals with a history of aggressive behaviour or anger are at increased risk of paradoxical effects. Paradoxical reactions are particularly associated with intravenous administration. After night-time administration of midazolam, residual ‘hangover’ effects, such as sleepiness and impaired psychomotor and cognitive functions, may persist into the next day. This may impair the ability of users to drive safely and may increase the risk of falls and hip fractures. Sedation, respiratory depression and hypotension due to a reduction in systematic vascular resistance, and an increase in heart rate can occur. If intravenous midazolam is given too quickly, hypotension may occur. A “midazolam infusion syndrome” may result from high doses, and is characterised by delayed arousal hours to days after discontinuation of midazolam, and may lead to an increase in the length of ventilatory support needed.

In susceptible individuals, midazolam has been known to cause a paradoxical reaction, a well-documented complication with benzodiazepines. When this occurs, the individual may experience anxiety, involuntary movements, aggressive or violent behaviour, uncontrollable crying or verbalization, and other similar effects. This seems to be related to the altered state of consciousness or disinhibition produced by the drug. Paradoxical behaviour is often not recalled by the patient due to the amnesia-producing properties of the drug. In extreme situations, flumazenil can be administered to inhibit or reverse the effects of midazolam. Antipsychotic medications, such as haloperidol, have also been used for this purpose.

Midazolam is known to cause respiratory depression. In healthy humans, 0.15 mg/kg of midazolam may cause respiratory depression, which is postulated to be a central nervous system (CNS) effect. When midazolam is administered in combination with fentanyl, the incidence of hypoxemia or apnoea becomes more likely.

Although the incidence of respiratory depression/arrest is low (0.1-0.5%) when midazolam is administered alone at normal doses, the concomitant use with CNS acting drugs, mainly analgesic opiates, may increase the possibility of hypotension, respiratory depression, respiratory arrest, and death, even at therapeutic doses. Potential drug interactions involving at least one CNS depressant were observed for 84% of midazolam users who were subsequently required to receive the benzodiazepine antagonist flumazenil. Therefore, efforts directed toward monitoring drug interactions and preventing injuries from midazolam administration are expected to have a substantial impact on the safe use of this drug.

Pregnancy and Breastfeeding

Midazolam, when taken during the third trimester of pregnancy, may cause risk to the neonate, including benzodiazepine withdrawal syndrome, with possible symptoms including hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of hypotonia and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Other neonatal withdrawal symptoms include hyperexcitability, tremor, and gastrointestinal upset (diarrhoea or vomiting). Breastfeeding by mothers using midazolam is not recommended.

Elderly

Additional caution is required in the elderly, as they are more sensitive to the pharmacological effects of benzodiazepines, metabolise them more slowly, and are more prone to adverse effects, including drowsiness, amnesia (especially anterograde amnesia), ataxia, hangover effects, confusion, and falls.

Tolerance, Dependence, and Withdrawal

A benzodiazepine dependence occurs in about one-third of individuals who are treated with benzodiazepines for longer than 4 weeks, which typically results in tolerance and benzodiazepine withdrawal syndrome when the dose is reduced too rapidly. Midazolam infusions may induce tolerance and a withdrawal syndrome in a matter of days. The risk factors for dependence include dependent personality, use of a benzodiazepine that is short-acting, high potency and long-term use of benzodiazepines. Withdrawal symptoms from midazolam can range from insomnia and anxiety to seizures and psychosis. Withdrawal symptoms can sometimes resemble a person’s underlying condition. Gradual reduction of midazolam after regular use can minimise withdrawal and rebound effects. Tolerance and the resultant withdrawal syndrome may be due to receptor down-regulation and GABAA receptor alterations in gene expression, which causes long-term changes in the function of the GABAergic neuronal system.

Chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines. Prolonged infusions with midazolam results in the development of tolerance; if midazolam is given for a few days or more a withdrawal syndrome can occur. Therefore, preventing a withdrawal syndrome requires that a prolonged infusion be gradually withdrawn, and sometimes, continued tapering of dose with an oral long-acting benzodiazepine such as clorazepate dipotassium. When signs of tolerance to midazolam occur during intensive care unit sedation the addition of an opioid or propofol is recommended. Withdrawal symptoms can include irritability, abnormal reflexes, tremors, clonus, hypertonicity, delirium and seizures, nausea, vomiting, diarrhoea, tachycardia, hypertension, and tachypnoea. In those with significant dependence, sudden discontinuation may result in withdrawal symptoms such as status epilepticus that may be fatal.

Overdose

Refer to Benzodiazepine Overdose.

A midazolam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. Benzodiazepine overdose in healthy individuals is rarely life-threatening with proper medical support; however, the toxicity of benzodiazepines increases when they are combined with other CNS depressants such as alcohol, opioids, or tricyclic antidepressants. The toxicity of benzodiazepine overdose and risk of death is also increased in the elderly and those with obstructive pulmonary disease or when used intravenously. Treatment is supportive; activated charcoal can be used within an hour of the overdose. The antidote for an overdose of midazolam (or any other benzodiazepine) is flumazenil. While effective in reversing the effects of benzodiazepines it is not used in most cases as it may trigger seizures in mixed overdoses and benzodiazepine dependent individuals.

Symptoms of midazolam overdose can include:

  • Ataxia.
  • Dysarthria.
  • Nystagmus.
  • Slurred speech.
  • Somnolence (difficulty staying awake).
  • Mental confusion.
  • Hypotension.
  • Respiratory arrest.
  • Vasomotor collapse.
  • Impaired motor functions:
    • Impaired reflexes.
    • Impaired coordination.
    • Impaired balance.
    • Dizziness.
  • Coma.
  • Death.

Detection in Body Fluids

Concentrations of midazolam or its major metabolite, 1-hydroxymidazolam glucuronide, may be measured in plasma, serum, or whole blood to monitor for safety in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalised patients, or to assist in a forensic investigation of a case of fatal overdosage. Patients with renal dysfunction may exhibit prolongation of elimination half-life for both the parent drug and its active metabolite, with accumulation of these two substances in the bloodstream and the appearance of adverse depressant effects.

Interactions

Protease inhibitors, nefazodone, sertraline, grapefruit, fluoxetine, erythromycin, diltiazem, clarithromycin inhibit the metabolism of midazolam, leading to a prolonged action. St John’s wort, rifapentine, rifampin, rifabutin, phenytoin enhance the metabolism of midazolam leading to a reduced action. Sedating antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opioids, antipsychotics and alcohol enhance the sedative effects of midazolam. Midazolam is metabolised almost completely by cytochrome P450-3A4. Atorvastatin administration along with midazolam results in a reduced elimination rate of midazolam. St John’s wort decreases the blood levels of midazolam. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations.

Pharmacology

Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of 1.5-2.5 hours. In the elderly, as well as young children and adolescents, the elimination half-life is longer. Midazolam is metabolised into an active metabolite alpha1-hydroxymidazolam. Age-related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite. However, the active metabolite of midazolam is minor and contributes to only 10 percent of biological activity of midazolam. Midazolam is poorly absorbed orally, with only 50% of the drug reaching the bloodstream. Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. The therapeutic as well as adverse effects of midazolam are due to its effects on the GABAA receptors; midazolam does not activate GABAA receptors directly but, as with other benzodiazepines, it enhances the effect of the neurotransmitter GABA on the GABAA receptors (↑ frequency of Cl- channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benzodiazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, induction of sleep, reduction in anxiety, anterograde amnesia, muscle relaxation and anticonvulsant effects.

Pharmacokinetics

  • Volume of Distribution: 1-2.5L/kg in normal healthy individuals.
  • Protein Binding: 96% Plasma protein bound.
  • Onset of Action: 3-15 minutes.
  • Elimination Half-Life: 1.5-3 hours.

Society and Culture

Cost

Midazolam is available as a generic medication.

Availability

Midazolam is available in the United States as a syrup or as an injectable solution.

Dormicum brand midazolam is marketed by Roche as white, oval, 7.5-mg tablets in boxes of two or three blister strips of 10 tablets, and as blue, oval, 15-mg tablets in boxes of two (Dormonid 3x) blister strips of 10 tablets. The tablets are imprinted with “Roche” on one side and the dose of the tablet on the other side. Dormicum is also available as 1-, 3-, and 10-ml ampoules at a concentration of 5 mg/ml. Another manufacturer, Novell Pharmaceutical Laboratories, makes it available as Miloz in 3- and 5-ml ampoules. Midazolam is the only water-soluble benzodiazepine available. Another maker is Roxane Laboratories; the product in an oral solution, Midazolam HCl Syrup, 2 mg/ml clear, in a red to purplish-red syrup, cherry in flavour. It becomes soluble when the injectable solution is buffered to a pH of 2.9-3.7. Midazolam is also available in liquid form. It can be administered intramuscularly, intravenously, intrathecally, intranasally, buccally, or orally.

Legal Status

In the Netherlands, midazolam is a List II drug of the Opium Law. Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances. In the United Kingdom, midazolam is a Schedule 3/Class C controlled drug. In the United States, midazolam (DEA number 2884) is on the Schedule IV list of the Controlled Substances Act as a non-narcotic agent with low potential for abuse.

Marketing Authorisation

In 2011, the European Medicines Agency (EMA) granted a marketing authorisation for a buccal application form of midazolam, sold under the trade name Buccolam. Buccolam was approved for the treatment of prolonged, acute, convulsive seizures in people from three months to less than 18 years of age. This was the first application of a paediatric-use marketing authorisation.

Use in Executions

The drug has been introduced for use in executions by lethal injection in certain jurisdictions in the United States in combination with other drugs. It was introduced to replace pentobarbital after the latter’s manufacturer disallowed that drug’s use for executions. Midazolam acts as a sedative but will fail to render the condemned prisoner unconscious, at which time vecuronium bromide and potassium chloride are administered, stopping the prisoner’s breathing and heart, respectively. Due to the fact that the condemned prisoner is not unconscious but merely sedated, two very different things, those following two drugs can cause extreme pain and panic in the soon to die prisoner.

Midazolam has been used as part of a three-drug cocktail, with vecuronium bromide and potassium chloride in Florida and Oklahoma prisons. Midazolam has also been used along with hydromorphone in a two-drug protocol in Ohio and Arizona.

The usage of midazolam in executions became controversial after condemned inmate Clayton Lockett apparently regained consciousness and started speaking midway through his 2014 execution when the state of Oklahoma attempted to execute him with an untested three-drug lethal injection combination using 100 mg of midazolam. Prison officials reportedly discussed taking him to a hospital before he was pronounced dead of a heart attack 40 minutes after the execution began. An observing doctor stated that Lockett’s vein had ruptured. It is not clear whether his death was caused by one or more of the drugs or to a problem in the administration procedure, nor is it clear what quantities of vecuronium bromide and potassium chloride were released to his system before the execution was cancelled.

Notable Incidents

The state of Florida used midazolam to execute William Frederick Happ in October 2013.

The state of Ohio used midazolam in the execution of Dennis McGuire in January 2014; it took McGuire 24 minutes to die after the procedure started, and he gasped and appeared to be choking during that time, leading to questions about the dosing and timing of the drug administration, as well as the choice of drugs.

The execution of Ronald Bert Smith in the state of Alabama on 08 December 2016, “went awry soon after (midazolam) was administered” again putting the effectiveness of the drug in question.

In October 2016, the state of Ohio announced that it would resume executions in January 2017, using a formulation of midazolam, vecuronium bromide, and potassium chloride, but this was blocked by a Federal judge. On 26 July 2017, Ronald Phillips was executed with a three-drug cocktail including midazolam after the Supreme Court refused to grant a stay. Prior to this, the last execution in Ohio had been that of Dennis McGuire. Murderer Gary Otte’s lawyers unsuccessfully challenged his Ohio execution, arguing that midazolam might not protect him from serious pain when the other drugs are administered. He died without incident in about 14 minutes on 13 September 2017.

On 24 April 2017, the state of Arkansas carried out a double-execution of Jack Harold Jones, 52, and Marcel Williams, 46. The state of Arkansas attempted to execute eight people before its supply of midazolam expired on 30 April 2017. Two of them were granted a stay of execution, and another, Ledell T. Lee, 51, was executed on 20 April 2017.

On 28 October 2021, the state of Oklahoma carried out the execution of inmate John Marion Grant, 60, using midazolam as part of its three-drug cocktail hours after the US Supreme Court ruled to lift a stay of execution for Oklahoma death row inmates. The execution was the state’s first since 2015. Witnesses to the execution said that when the first drug, midazolam, began to flow at 4:09 pm, Grant started convulsing about two dozen times and vomited. Grant continued breathing, and a member of the execution team wiped the vomit off his face. At 4:15 pm., officials said Grant was unconscious, and he was pronounced dead at 4:21 pm.

Legal Challenges

In Glossip v. Gross, attorneys for three Oklahoma inmates argued that midazolam could not achieve the level of unconsciousness required for surgery, meaning severe pain and suffering was likely. They argued that midazolam was cruel and unusual punishment and thus contrary to the Eighth Amendment to the United States Constitution. In June 2015, the US Supreme Court ruled that they had failed to prove that midazolam was cruel and unusual when compared to known, available alternatives.

The state of Nevada is also known to use midazolam in execution procedures. In July 2018, one of the manufacturers accused state officials of obtaining the medication under false pretences. This incident was the first time a drug company successfully, though temporarily, halted an execution. A previous attempt in 2017, to halt an execution in the state of Arizona by another drug manufacturer was not successful.

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What is Amisulpride?

Introduction

Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes.

It is sold under the brand names Barhemsys (as an antiemetic) and Solian, Socian, Deniban and others (as an antipsychotic). It is also used to treat dysthymia.

It is usually classed with the atypical antipsychotics. Chemically it is a benzamide and like other benzamide antipsychotics, such as sulpiride, it is associated with a high risk of elevating blood levels of the lactation hormone, prolactin (thereby potentially causing the absence of the menstrual cycle, breast enlargement, even in males, breast milk secretion not related to breastfeeding, impaired fertility, impotence, breast pain, etc.), and a low risk, relative to the typical antipsychotics, of causing movement disorders.

Amisulpride is indicated for use in the US in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.

Amisulpride is believed to work by blocking, or antagonising, the dopamine D2 receptor, reducing its signalling. The effectiveness of amisulpride in treating dysthymia and the negative symptoms of schizophrenia is believed to stem from its blockade of the presynaptic dopamine D2 receptors. These presynaptic receptors regulate the release of dopamine into the synapse, so by blocking them amisulpride increases dopamine concentrations in the synapse. This increased dopamine concentration is theorised to act on dopamine D1 receptors to relieve depressive symptoms (in dysthymia) and the negative symptoms of schizophrenia.

It was introduced by Sanofi-Aventis in the 1990s. Its patent expired by 2008, and generic formulations became available. It is marketed in all English-speaking countries except for Canada. A New York City based company, LB Pharmaceuticals, has announced the ongoing development of LB-102, also known as N-methyl amisulpride, an antipsychotic specifically targeting the United States. A poster presentation at European Neuropsychopharmacology seems to suggest that this version of amisulpride, known as LB-102 displays the same binding to D2, D3 and 5HT7 that amisulpride does.

Brief History

The US Food and Drug Administration (FDA) approved amisulpride based on evidence from four clinical trials of 2323 subjects undergoing surgery or experiencing nausea and vomiting after the surgery. The trials were conducted at 80 sites in the United States, Canada and Europe.

Two trials (Trials 1 and 2) enrolled subjects scheduled to have surgery. Subjects were randomly assigned to receive either amisulpride or a placebo drug at the beginning of general anaesthesia. In Trial 1, subjects received amisulpride or placebo alone, and in Trial 2, they received amisulpride or placebo in combination with one medication approved for prevention of nausea and vomiting. Neither the subjects nor the health care providers knew which treatment was being given until after the trial was complete.

The trials counted the number of subjects who had no vomiting and did not use additional medications for nausea or vomiting in the first day (24 hours) after the surgery. The results then compared amisulpride to placebo.

The other two trials (Trials 3 and 4) enrolled subjects who were experiencing nausea and vomiting after surgery. In Trial 3, subjects did not receive any medication to prevent nausea and vomiting before surgery and in Trial 4 they received the medication, but the treatment did not work. In both trials, subjects were randomly assigned to receive either amisulpride or placebo. Neither the subjects nor the health care providers knew which treatment was being given until after the trial was complete.

The trials counted the number of subjects who had no vomiting and did not use additional medications for nausea or vomiting in the first day (24 hours) after the treatment. The trial compared amisulpride to placebo.

Medical Uses

Schizophrenia

Although according to other studies it appears to have comparable efficacy to olanzapine in the treatment of schizophrenia. Amisulpride augmentation, similarly to sulpiride augmentation, has been considered a viable treatment option (although this is based on low-quality evidence) in clozapine-resistant cases of schizophrenia. Another recent study concluded that amisulpride is an appropriate first-line treatment for the management of acute psychosis.

Postoperative Nausea and Vomiting

Amisulpride is indicated for use in the United States in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.

Contraindications

Amisulpride’s use is contraindicated in the following disease states:

  • Pheochromocytoma.
  • Concomitant prolactin-dependent tumours e.g. prolactinoma, breast cancer.
  • Movement disorders (e.g. Parkinson’s disease and dementia with Lewy bodies).
  • Lactation.
  • Children before the onset of puberty.

Neither is it recommended to use amisulpride in patients with hypersensitivities to amisulpride or the excipients found in its dosage form.

Adverse Effects

  • Very Common (≥10% incidence):
    • Extrapyramidal side effects (EPS; including dystonia, tremor, akathisia, parkinsonism).
  • Common (≥1%, <10% incidence):
    • Insomnia.
    • Hypersalivation.
    • Nausea.
    • Headache.
    • Hyperactivity.
    • Vomiting.
    • Hyperprolactinaemia (which can lead to galactorrhoea, breast enlargement and tenderness, sexual dysfunction, etc.).
    • Weight gain (produces less weight gain than chlorpromazine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, zotepine and more (although not statistically significantly) weight gain than haloperidol, lurasidone, ziprasidone and approximately as much weight gain as aripiprazole and asenapine).
    • Anticholinergic side effects (although it does not bind to the muscarinic acetylcholine receptors and hence these side effects are usually quite mild) such as
      • Constipation.
      • Dry mouth.
      • Disorder of accommodation.
      • Blurred vision.
  • Rare (<1% incidence):
    • Hyponatraemia.
    • Bradycardia.
    • Hypotension.
    • Palpitations.
    • Urticaria.
    • Seizures.
    • Mania.
    • Oculogyric crisis.
    • Tardive dyskinesia.
    • Blood dyscrasias such as leucopenia, neutropenia and agranulocytosis.
    • QT interval prolongation (in a recent meta-analysis of the safety and efficacy of 15 antipsychotic drugs amisulpride was found to have the 2nd highest effect size for causing QT interval prolongation).
    • Somnolence.

Hyperprolactinaemia results from antagonism of the D2 receptors located on the lactotrophic cells found in the anterior pituitary gland. Amisulpride has a high propensity for elevating plasma prolactin levels as a result of its poor blood-brain barrier penetrability and hence the resulting greater ratio of peripheral D2 occupancy to central D2 occupancy. This means that to achieve the sufficient occupancy (~60–80%) of the central D2 receptors in order to elicit its therapeutic effects a dose must be given that is enough to saturate peripheral D2 receptors including those in the anterior pituitary.

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.

Overdose

Torsades de pointes is common in overdose. Amisulpride is moderately dangerous in overdose (with the TCAs being very dangerous and the SSRIs being modestly dangerous).

Interactions

Amisulpride should not be used in conjunction with drugs that prolong the QT interval (such as citalopram, bupropion, clozapine, tricyclic antidepressants, sertindole, ziprasidone, etc.), reduce heart rate and those that can induce hypokalaemia. Likewise it is imprudent to combine antipsychotics due to the additive risk for tardive dyskinesia and neuroleptic malignant syndrome.

Pharmacology

Pharmacodynamics

Amisulpride functions primarily as a dopamine D2 and D3 receptor antagonist. It has high affinity for these receptors with dissociation constants of 3.0 and 3.5 nM, respectively. Although standard doses used to treat psychosis inhibit dopaminergic neurotransmission, low doses preferentially block inhibitory presynaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason, low-dose amisulpride has also been used to treat dysthymia.

Amisulpride and its relatives sulpiride, levosulpiride, and sultopride have been shown to bind to the high-affinity GHB receptor at concentrations that are therapeutically relevant (IC50 = 50 nM for amisulpride).

Amisulpride, sultopride and sulpiride respectively present decreasing in vitro affinities for the D2 receptor (IC50 = 27, 120 and 181 nM) and the D3 receptor (IC50 = 3.6, 4.8 and 17.5 nM).

Though it was long widely assumed that dopaminergic modulation is solely responsible for the respective antidepressant and antipsychotic properties of amisulpride, it was subsequently found that the drug also acts as a potent antagonist of the serotonin 5-HT7 receptor (Ki = 11.5 nM). Several of the other atypical antipsychotics such as risperidone and ziprasidone are potent antagonists at the 5-HT7 receptor as well, and selective antagonists of the receptor show antidepressant properties themselves. To characterise the role of the 5-HT7 receptor in the antidepressant effects of amisulpride, a study prepared 5-HT7 receptor knockout mice. The study found that in two widely used rodent models of depression, the tail suspension test, and the forced swim test, those mice did not exhibit an antidepressant response upon treatment with amisulpride. These results suggest that 5-HT7 receptor antagonism mediates the antidepressant effects of amisulpride.

Amisulpride also appears to bind with high affinity to the serotonin 5-HT2B receptor (Ki = 13 nM), where it acts as an antagonist. The clinical implications of this, if any, are unclear. In any case, there is no evidence that this action mediates any of the therapeutic effects of amisulpride.

Amisulpride shows stereoselectivity in its actions. Aramisulpride ((R)-amisulpride) has higher affinity for the 5-HT7 receptor (Ki = 47 nM vs. 1,900 nM) while esamisulpride ((S)-amisulpride) has higher affinity for the D2 receptor (4.0 nM vs. 140 nM). An 85:15 ratio of aramisulpride to esamisulpride (SEP-4199) which provides more balanced 5-HT7 and D2 receptor antagonism than racemic amisulpride (50:50 ratio of enantiomers) is under development for the treatment of bipolar depression.

Society and Culture

Brand Names

Brand names include: Amazeo, Amipride (AU), Amival, Solian (AU, IE, RU, UK, ZA), Soltus, Sulpitac (IN), Sulprix (AU), Midora (RO) and Socian (BR).

Availability

Amisulpride was not approved by the Food and Drug Administration for use in the United States until February 2020, but it is used in Europe, Israel, Mexico, India, New Zealand and Australia to treat psychosis and schizophrenia.

An IV formulation of Amisulpride was approved for the treatment of postoperative nausea and vomiting (“PONV”) in the United States in February 2020.

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What is Amineptine?

Introduction

Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family.

It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a lesser extent as a norepinephrine reuptake inhibitor.

Amineptine was developed by the French Society of Medical research in the 1960s. Introduced in France in 1978 by the pharmaceutical company Servier, amineptine soon gained a reputation for abuse due to its short-lived, but pleasant, stimulant effect experienced by some patients.

After its release into the European market, cases of hepatotoxicity emerged, some serious. This, along with the potential for abuse, led to the suspension of the French marketing authorization for Survector in 1999.

Amineptine was never approved by the US Food and Drug Administration (FDA) for marketing in the US, meaning that it is not legal to market or sell amineptine for any medical uses in the US.

Medical Uses

Amineptine was approved in France for severe clinical depression of endogenous origin in 1978.

Contraindications

  • Chorea
  • Hypersensitivity: Known hypersensitivity to amineptine, in particular antecedents of hepatitis after dosage of the product.
  • MAO inhibitors.

Precautions for Use

Warnings and precautions before taking amineptine:

  • Breast feeding.
  • Children less than 15-year of age.
  • General anaesthesia: Discontinue the drug 24 to 48 hours before anaesthesia.
  • Official sports/Olympic Games: Prohibited substance.
  • Pregnancy (first trimester).

Effects on the Foetus

  • Lacking information in humans.
  • Non-teratogenic in rodents.

Side Effects

Dermatological

Severe acne due to amineptine was first reported in 1988 by various authors – Grupper, Thioly-Bensoussan, Vexiau, Fiet, Puissant, Gourmel, Teillac, Levigne, to name a few – simultaneously in the same issue of Annales de dermatologie et de vénéréologie and in the 12 March 1988 issue of The Lancet. A year later, Dr Martin-Ortega and colleagues in Barcelona, Spain reported a case of “acneiform eruption” in a 54-year-old woman whose intake of amineptine was described as “excessive.” One year after that, Vexiau and colleagues reported six women, one of whom never admitted to using amineptine, getting severe acne concentrated in the face, back and thorax, the severity of which varied with the dosage. Most of them were treated unsuccessfully with isotretinoin (Accutane) for about 18 months; two of the three that discontinued amineptine experienced a reduction in cutaneous symptoms, with the least affected patient going into remission.

Psychiatric

Psychomotor excitation can very rarely occur with this drug.

  • Insomnia.
  • Irritability.
  • Nervousness.
  • Suicidal ideation. Seen early in the treatment, by lifting of psychomotor inhibition.

Abuse and Dependence

The risk of addiction is low, but exists nonetheless. Between 1978 and 1988, there were 186 cases of amineptine addiction reported to the French Regional Centres of Pharmacovigilance; an analysis of 155 of those cases found that they were predominantly female, and that two-thirds of cases had known risk factors for addiction. However, a 1981 study of known opiate addicts and schizophrenia patients found no drug addiction in any of the subjects. In a 1990 study of eight amineptine dependence cases, the gradual withdrawal of amineptine could be achieved without problems in six people; in two others, anxiety, psychomotor agitation, and/or bulimia appeared.

Withdrawal

Pharmacodependence is very common with amineptine compared to other antidepressants. A variety of psychological symptoms can occur during withdrawal from amineptine, such as anxiety and agitation.

Cardiovascular

Very rarely:

  • Arterial hypotension.
  • Palpitations.
  • Vasomotor episode.

Hepatic

Amineptine can rarely cause hepatitis, of the cytolytic, cholestatic varieties. Amineptine-induced hepatitis, which is sometimes preceded by a rash, is believed to be due to an immunoallergic reaction. It resolves upon discontinuation of the offending drug. The risk of getting this may or may not be genetically determined.

Additionally, amineptine is known to rarely elevate transaminases, alkaline phosphatase, and bilirubin.

Mixed hepatitis, which is very rare, generally occurs between the 15th and 30th day of treatment. Often preceded by sometimes intense abdominal pains, nausea, vomiting or a rash, the jaundice is variable. Hepatitis is either of mixed type or with cholestatic prevalence. The evolution was, in all the cases, favourable to the discontinuation of the drug. The mechanism is discussed (immunoallergic and/or toxic).

In circa 1994 Spain, there was a case associating acute pancreatitis and mixed hepatitis, after three weeks of treatment.

Lazaros and colleagues at the Western Attica General Hospital in Athens, Greece reported two cases of drug induced hepatitis 18 and 15 days of treatment.

One case of cytolytic hepatitis occurred after ingestion of only one tablet.

Gastrointestinal

Acute pancreatitis (very rare) A case associating acute pancreatitis and mixed hepatitis after three weeks of treatment.

Immunological

In 1989, Sgro and colleagues at the Centre de Pharmacovigilance in Dijon reported a case of anaphylactic shock in a woman who had been taking amineptine.

Pharmacology

Pharmacodynamics

Amineptine inhibits the reuptake of dopamine and, to a much lesser extent, of norepinephrine. In addition, it has been found to induce the release of dopamine. However, amineptine is much less efficacious as a dopamine releasing agent relative to D-amphetamine, and the drug appears to act predominantly as a dopamine reuptake inhibitor. In contrast to the case for dopamine, amineptine does not induce the release of norepinephrine, and hence acts purely as a norepinephrine reuptake inhibitor. Unlike other TCAs, amineptine interacts very weakly or not at all with the serotonin, adrenergic, dopamine, histamine, and muscarinic acetylcholine receptors. The major metabolites of amineptine have similar activity to that of the parent compound, albeit with lower potency.

No human data appear to be available for binding or inhibition of the monoamine transporters by amineptine.

Pharmacokinetics

Peak plasma levels of amineptine following a single 100 mg oral dose have been found to range between 277 and 2,215 ng/mL (818-6,544 nM), with a mean of 772 ng/mL (2,281 nM), whereas maximal plasma concentrations of its major metabolite ranged between 144 and 1,068 ng/mL (465–3,452 nM), with a mean of 471 ng/mL (1,522 nM). After a single 200 mg oral dose of amineptine, mean peak plasma levels of amineptine were around 750 to 940 ng/mL (2,216-2,777 nM), while those of its major metabolite were about 750 to 970 ng/mL (2,216-3,135 nM). The time to peak concentrations is about 1 hour for amineptine and 1.5 hours for its major metabolite. The elimination half-life of amineptine is about 0.80 to 1.0 hours and that of its major metabolite is about 1.5 to 2.5 hours. Due to their very short elimination half-lives, amineptine and its major metabolite do not accumulate significantly with repeated administration.

Society and Culture

Brand Names

Amineptine has been sold under a variety of brand names including Survector, Maneon, Directim, Neolior, Provector, and Viaspera.

Legal Status

It had been proposed that Amineptine become a Schedule I controlled substance in the United States in July 2021.

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What is Citalopram?

Introduction

Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.

It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and social phobia. The antidepressant effects may take one to four weeks to occur. It is taken by mouth.

Common side effects include nausea, trouble sleeping, sexual problems, shakiness, feeling tired, and sweating. Serious side effects include an increased risk of suicide in those under the age of 25, serotonin syndrome, glaucoma, and QT prolongation. It should not be used in persons who take or have recently taken a MAO inhibitor. Antidepressant discontinuation syndrome may occur when stopped. There are concerns that use during pregnancy may harm the foetus.

Citalopram was approved for medical use in the United States in 1998. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2019, it was the 30th most commonly prescribed medication in the United States, with more than 21 million prescriptions.

Brief History

Citalopram was first synthesized in 1972 by chemist Klaus Bøgesø and his research group at the pharmaceutical company Lundbeck and was first marketed in 1989 in Denmark. It was first marketed in the US in 1998. The original patent expired in 2003, allowing other companies to legally produce and market generic versions.

Medical Uses

Depression

In the United States, citalopram is approved to treat major depressive disorder. Citalopram appears to have comparable efficacy and superior tolerability relative to other antidepressants. In the National Institute for Health and Clinical Excellence ranking of ten antidepressants for efficacy and cost-effectiveness, citalopram is fifth in effectiveness (after mirtazapine, escitalopram, venlafaxine, and sertraline) and fourth in cost-effectiveness. The ranking results were based on a 2009 meta-analysis by Andrea Cipriani; an update of the analysis in 2018 produced broadly similar results.

Evidence for effectiveness of citalopram for treating depression in children is uncertain.

Panic Disorder

Citalopram is licensed in the UK and other European countries for panic disorder, with or without agoraphobia.

Other

Citalopram may be used off-label to treat anxiety, and dysthymia, premenstrual dysphoric disorder, body dysmorphic disorder, and obsessive-compulsive disorder (OCD).

It appears to be as effective as fluvoxamine and paroxetine in OCD. Some data suggest the effectiveness of intravenous infusion of citalopram in resistant OCD. Citalopram is well tolerated and as effective as moclobemide in social anxiety disorder. There are studies suggesting that citalopram can be useful in reducing aggressive and impulsive behaviour. It appears to be superior to placebo for behavioural disturbances associated with dementia. It has also been used successfully for hypersexuality in early Alzheimer’s disease.

A meta-analysis, including studies with fluoxetine, paroxetine, sertraline, escitalopram, and citalopram versus placebo, showed SSRIs to be effective in reducing symptoms of premenstrual syndrome, whether taken continuously or just in the luteal phase. For alcoholism, citalopram has produced a modest reduction in alcoholic drink intake and increase in drink-free days in studies of alcoholics, possibly by decreasing desire or reducing the reward.

While on its own citalopram is less effective than amitriptyline in the prevention of migraines, in refractory cases, combination therapy may be more effective.

Citalopram and other SSRIs can be used to treat hot flashes.

A 2009 multisite randomised controlled study found no benefit and some adverse effects in autistic children from citalopram, raising doubts whether SSRIs are effective for treating repetitive behaviour in children with autism.

Some research suggests citalopram interacts with cannabinoid protein-couplings in the rat brain, and this is put forward as a potential cause of some of the drug’s antidepressant effect.

Administration

Citalopram is typically taken in one dose, either in the morning or evening. It can be taken with or without food. Its absorption does not increase when taken with food, but doing so can help prevent nausea. Nausea is often caused when the 5HT3 receptors actively absorb free serotonin, as this receptor is present within the digestive tract. The 5HT3 receptors stimulate vomiting. This side effect, if present, should subside as the body adjusts to the medication.

Citalopram is considered safe and well tolerated in the therapeutic dose range. Distinct from some other agents in its class, it exhibits linear pharmacokinetics and minimal drug interaction potential, making it a better choice for the elderly or comorbid patients.

Adverse Effects

Sexual dysfunction is often a side effect with SSRIs.

Citalopram theoretically causes side effects by increasing the concentration of serotonin in other parts of the body (e.g. the intestines). Other side effects, such as increased apathy and emotional flattening, may be caused by the decrease in dopamine release associated with increased serotonin. Citalopram is also a mild antihistamine, which may be responsible for some of its sedating properties.

Other common side effects of citalopram include drowsiness, insomnia, nausea, weight changes (usually weight gain), increase in appetite, vivid dreaming, frequent urination, dry mouth, increased sweating, trembling, diarrhoea, excessive yawning, severe tinnitus, and fatigue. Less common side effects include bruxism, vomiting, cardiac arrhythmia, blood pressure changes, dilated pupils, anxiety, mood swings, headache, hyperactivity and dizziness. Rare side effects include convulsions, hallucinations, severe allergic reactions and photosensitivity. If sedation occurs, the dose may be taken at bedtime rather than in the morning. Some data suggests citalopram may cause nightmares. Citalopram is associated with a higher risk of arrhythmia than other SSRIs.

Withdrawal symptoms can occur when this medicine is suddenly stopped, such as paraesthesia, sleeping problems (difficulty sleeping and intense dreams), feeling dizzy, agitated or anxious, nausea, vomiting, tremors, confusion, sweating, headache, diarrhoea, palpitations, changes in emotions, irritability, and eye or eyesight problems. Treatment with citalopram should be reduced gradually when treatment is finished.

Citalopram and other SSRIs can induce a mixed state, especially in those with undiagnosed bipolar disorder.  According to an article published in 2020, one of the other rare side effects of Citalopram could be triggering visual snow syndrome; which does not resolve after the discontinuation of the medicine.

Sexual Dysfunction

Some people experience persistent sexual side effects after they stop taking SSRIs. This is known as Post-SSRI Sexual Dysfunction (PSSD). Common symptoms in these cases include genital anaesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication issues, and nipple insensitivity in women. The prevalence of PSSD is unknown, and there is no established treatment.

Abnormal Heart Rhythm

In August 2011, the US Food and Drug Administration (FDA) announced, “Citalopram causes dose-dependent QT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day”. A further clarification issued in March 2012, restricted the maximum dose to 20 mg for subgroups of patients, including those older than 60 years and those taking an inhibitor of cytochrome P450 2C19.7.

Endocrine Effects

As with other SSRIs, citalopram can cause an increase in serum prolactin level. Citalopram has no significant effect on insulin sensitivity in women of reproductive age and no changes in glycaemic control were seen in another trial.

Exposure in Pregnancy

Antidepressant exposure (including citalopram) during pregnancy is associated with shorter duration of gestation (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). Antidepressant exposure is not associated with an increased risk of spontaneous abortion. It is uncertain whether there is an increased prevalence of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy.

Interactions

Citalopram should not be taken with St John’s wort, tryptophan or 5-HTP as the resulting drug interaction could lead to serotonin syndrome. With St John’s wort, this may be caused by compounds in the plant extract reducing the efficacy of the hepatic cytochrome P450 enzymes that process citalopram. It has also been suggested that such compounds, including hypericin, hyperforin and flavonoids, could have SSRI-mimetic effects on the nervous system, although this is still subject to debate. One study found that Hypericum extracts had similar effects in treating moderate depression as citalopram, with fewer side effects.

Tryptophan and 5-HTP are precursors to serotonin. When taken with an SSRI, such as citalopram, this can lead to levels of serotonin that can be lethal. This may also be the case when SSRIs are taken with SRAs (serotonin releasing agents) such as in the case of MDMA. It is possible that SSRIs could reduce the effects associated due to an SRA, since SSRIs stop the reuptake of Serotonin by blocking SERT. This would allow less serotonin in and out of the transporters, thus decreasing the likelihood of neurotoxic effects. However, these concerns are still disputed as the exact pharmacodynamic effects of citalopram and MDMA have yet to be fully identified.[citation needed]

SSRIs, including citalopram, can increase the risk of bleeding, especially when coupled with aspirin, NSAIDs, warfarin, or other anticoagulants. Citalopram is contraindicated in individuals taking MAOIs, owing to a potential for serotonin syndrome.

Taking citalopram with omeprazole may cause higher blood levels of citalopram. This is a potentially dangerous interaction, so dosage adjustments may be needed or alternatives may be prescribed.

SSRI discontinuation syndrome has been reported when treatment is stopped. It includes sensory, gastrointestinal symptoms, dizziness, lethargy, and sleep disturbances, as well as psychological symptoms such as anxiety/agitation, irritability, and poor concentration. Electric shock-like sensations are typical for SSRI discontinuation. Tapering off citalopram therapy, as opposed to abrupt discontinuation, is recommended in order to diminish the occurrence and severity of discontinuation symptoms. Some doctors choose to switch a patient to Prozac (fluoxetine) when discontinuing citalopram as fluoxetine has a much longer half-life (i.e. stays in the body longer compared to citalopram). This may avoid many of the severe withdrawal symptoms associated with citalopram discontinuation. This can be done either by administering a single 20 mg dose of fluoxetine or by beginning on a low dosage of fluoxetine and slowly tapering down. Either of these prescriptions may be written in liquid form to allow a very slow and gradual tapering down in dosage. Alternatively, a patient wishing to stop taking citalopram may visit a compounding pharmacy where their prescription may be re-arranged into progressively smaller dosages.

Overdose

Overdosage may result in vomiting, sedation, disturbances in heart rhythm, dizziness, sweating, nausea, tremor, and rarely amnesia, confusion, coma, or convulsions.  Overdose deaths have occurred, sometimes involving other drugs, but also with citalopram as the sole agent. Citalopram and N-desmethylcitalopram may be quantified in blood or plasma to confirm a diagnosis of poisoning in hospitalised patients or to assist in a medicolegal death investigation. Blood or plasma citalopram concentrations are usually in a range of 50-400 μg/l in persons receiving the drug therapeutically, 1000-3000 μg/l in patients who survive acute overdosage and 3-30 mg/l in those who do not survive. It is the most dangerous of SSRIs in overdose.

Suicidality

In the United States, citalopram carries a boxed warning stating it may increase suicidal thinking and behaviour in those under age 24.

Stereochemistry

Citalopram has one stereocentre, to which a 4-fluoro phenyl group and an N, N-dimethyl-3-aminopropyl group bind. As a result of this chirality, the molecule exists in (two) enantiomeric forms (mirror images). They are termed S-(+)-citalopram and R-(–)-citalopram.

Citalopram is sold as a racemic mixture, consisting of 50% (R)-(−)-citalopram and 50% (S)-(+)-citalopram. Only the (S)-(+) enantiomer has the desired antidepressant effect. Lundbeck now markets the (S)-(+) enantiomer, the generic name of which is escitalopram. Whereas citalopram is supplied as the hydrobromide, escitalopram is sold as the oxalate salt (hydrooxalate). In both cases, the salt forms of the amine make these otherwise lipophilic compounds water-soluble.

Metabolism

Citalopram is metabolised in the liver mostly by CYP2C19, but also by CYP3A4 and CYP2D6. Metabolites desmethylcitalopram and didesmethylcitalopram are significantly less energetic and their contribution to the overall action of citalopram is negligible. The half-life of citalopram is about 35 hours. Approximately 80% is cleared by the liver and 20% by the kidneys. The elimination process is slower in the elderly and in patients with liver or kidney failure. With once-daily dosing, steady plasma concentrations are achieved in about a week. Potent inhibitors of CYP2C19 and 3A4 might decrease citalopram clearance. Tobacco smoke exposure was found to inhibit the biotransformation of citalopram in animals, suggesting that the elimination rate of citalopram is decreased after tobacco smoke exposure. After intragastric administration, the half-life of the racemic mixture of citalopram was increased by about 287%.

Society and Culture

Brand Names

Citalopram is sold under these brand names:

  • Akarin (Denmark, Nycomed).
  • C Pram S (India).
  • Celapram (Australia and New Zealand).
  • Celexa (US and Canada, Forest Laboratories, Inc.).
  • Celica (Australia).
  • Ciazil (Australia and New Zealand).
  • Cilate (South Africa).
  • Cilift (South Africa).
  • Cimal (South America, by Roemmers and Recalcine).
  • Cipralex (South Africa).
  • Cipram (Denmark and Turkey, H. Lundbeck A/S).
  • Cipramil (Australia, Brazil, Belgium, Chile, Finland, Germany, Netherlands, Iceland, Ireland, Israel, New Zealand, Norway, Russia, South Africa, Sweden, and the United Kingdom).
  • Cipraned, Cinapen (Greece).
  • Ciprapine (Ireland).
  • Ciprotan (Ireland).
  • Citabax, Citaxin (Poland).
  • Cital (Poland).
  • Citalec (Czech Republic and Slovakia).
  • Citalex (Iran and Serbia).
  • Citalo (Australia, Egypt, and Pakistan).
  • Citalopram (Canada, Denmark, Finland, Germany, Ireland, New Zealand, Spain, Sweden, Switzerland, United Kingdom, the US).
  • Citol (Russia).
  • Citox (Mexico).
  • Citrol (Europe and Australia).
  • Citta (Brazil).
  • Dalsan (Eastern Europe).
  • Denyl (Brazil).
  • Elopram (Italy).
  • Estar (Pakistan).
  • Humorup (Argentina).
  • Humorap (Peru, Bolivia).
  • Lopraxer (Greece).
  • Oropram (Iceland, Actavis).
  • Opra (Russia).
  • Pram (Russia).
  • Pramcit (Pakistan).
  • Procimax (Brazil).
  • Recital (Israel, Thrima Inc. for Unipharm Ltd.).
  • Sepram (Finland).
  • Seropram (various European countries, including Czech Republic).
  • Szetalo (India).
  • Talam (Europe and Australia).
  • Temperax (Argentina, Chile, and Peru).
  • Vodelax (Turkey).
  • Zentius (South America, by Roemmers and Recalcine).
  • Zetalo (India).
  • Cipratal (Kuwait, GCC).
  • Zylotex (Portugal).

European Commission Fine

On 19 June 2013, the European Commission imposed a fine of €93.8 million on the Danish pharmaceutical company Lundbeck, plus a total of €52.2 million on several generic pharmaceutical-producing companies. This was in response to Lundbeck entering an agreement with the companies to delay their sales of generic citalopram after Lundbeck’s patent on the drug had expired, thus reducing competition in breach of European antitrust law.

What is Benzatropine?

Introduction

Benzatropine (an international non-proprietary name, INN), known as benztropine in the United States and Japan, is a medication used to treat a type of movement disorder due to antipsychotics known as dystonia and parkinsonism.

It is not useful for tardive dyskinesia. It is taken by mouth or by injection into a vein or muscle. Benefits are seen within two hours and last for up to ten hours.

Common side effects include dry mouth, blurry vision, nausea, and constipation. Serious side effect may include urinary retention, hallucinations, hyperthermia, and poor coordination. It is unclear if use during pregnancy or breastfeeding is safe. Benzatropine is an anticholinergic which works by blocking the activity of the muscarinic acetylcholine receptor.

Benzatropine was approved for medical use in the United States in 1954. It is available as a generic medication. In 2017, it was the 226th most commonly prescribed medication in the United States, with more than two million prescriptions. It is sold under the brand name Cogentin among others.

Medical Uses

Benzatropine is used to reduce extrapyramidal side effects of antipsychotic treatment. Benzatropine is also a second-line drug for the treatment of Parkinson’s disease. It improves tremor, and may alleviate rigidity and bradykinesia. Benzatropine is also sometimes used for the treatment of dystonia, a rare disorder that causes abnormal muscle contraction, resulting in twisting postures of limbs, trunk, or face.

Adverse Effects

These are principally anticholinergic:

  • Dry mouth.
  • Blurred vision.
  • Cognitive changes.
  • Drowsiness.
  • Constipation.
  • Urinary retention.
  • Tachycardia.
  • Anorexia.
  • Severe delirium and hallucinations (in overdose).

While some studies suggest that use of anticholinergics increases the risk of tardive dyskinesia (a long-term side effect of antipsychotics), other studies have found no association between anticholinergic exposure and risk of developing tardive dyskinesia, although symptoms may be worsened.

Drugs that decrease cholinergic transmission may impair storage of new information into long-term memory. Anticholinergic agents can also impair time perception.

Pharmacology

Benzatropine is a centrally acting anticholinergic/antihistamine agent. It is a selective M1 muscarinic acetylcholine receptor antagonist. Benzatropine partially blocks cholinergic activity in the basal ganglia and has also been shown to increase the availability of dopamine by blocking its reuptake and storage in central sites, and as a result, increasing dopaminergic activity. Animal studies have indicated that anticholinergic activity of benzatropine is approximately one-half that of atropine, while its antihistamine activity approaches that of mepyramine. Its anticholinergic effects have been established as therapeutically significant in the management of Parkinsonism. Benzatropine antagonises the effect of acetylcholine, decreasing the imbalance between the neurotransmitters acetylcholine and dopamine, which may improve the symptoms of early Parkinson’s disease.

Benzatropine analogues are atypical dopamine reuptake inhibitors, which might make them useful for people with akathisia secondary to antipsychotic therapy.

Benzatropine also acts as a functional inhibitor of acid sphingomyelinase (FIASMA).

Benzatropine has been also identified, by a high throughput screening approach, as a potent differentiating agent for oligodendrocytes, possibly working through M1 and M3 muscarinic receptors. In preclinical models for multiple sclerosis, benzatropine decreased clinical symptoms and enhanced re-myelination.

Other Animals

In veterinary medicine, benzatropine is used to treat priapism in stallions.

Naming

Since 1959, benzatropine is the official INN name of the medication under the INN scheme, the medication naming system coordinated by the World Health Organisation (WHO); it is also the British Approved Name (BAN) given in the British Pharmacopoeia, and has been the official non-proprietary name in Australia since 2015. Regional variations of the “a” spelling are also used in French, Italian, Portuguese, and Spanish, as well as Latin (all medications are assigned a Latin name by WHO).

“Benztropine” is the official United States Adopted Name (USAN), the medication naming system coordinated by the USAN Council, co-sponsored by the American Medical Association (AMA), the United States Pharmacopeial Convention (USP), and the American Pharmacists Association (APhA). It is also the Japanese Accepted Name (JAN) and was used in Australia until 2015, when it was harmonised with the INN.

Both names may be modified to account for the methanesulfonate salt as which the medication is formulated: the modified INN (INNm) and BAN (BANM) is benzatropine mesilate, while the modified USAN is benztropine mesylate. The modified JAN is a hybrid form, benztropine mesilate.

The misspelling benzotropine is also occasionally seen in the literature.

What is Nordazepam?

Introduction

Nordazepam (INN; marketed under brand names Nordaz, Stilny, Madar, Vegesan, and Calmday; also known as nordiazepam, desoxydemoxepam, and desmethyldiazepam) is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has amnesic, anticonvulsant, anxiolytic, muscle relaxant, and sedative properties. However, it is used primarily in the treatment of anxiety disorders. It is an active metabolite of diazepam, chlordiazepoxide, clorazepate, prazepam, pinazepam, and medazepam.

Nordazepam is among the longest lasting (longest half-life) benzodiazepines, and its occurrence as a metabolite is responsible for most cumulative side-effects of its myriad of pro-drugs when they are used repeatedly at moderate-high doses; the nordazepam metabolite oxazepam is also active (and is a more potent, full benzodiazepine-site agonist), which contributes to nordazepam cumulative side-effects but occur too minutely to contribute to the cumulative side-effects of nordazepam pro-drugs (except when they are abused chronically in extremely supra-therapeutic doses).

Side effects

Common side effects of nordazepam include somnolence, which is more common in elderly patients and/or people on high-dose regimens. Hypotonia, which is much less common, is also associated with high doses and/or old age.

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. As with many other drugs, changes in liver function associated with aging or diseases such as cirrhosis, may lead to impaired clearance of nordazepam.

Pharmacology

Nordazepam is a partial agonist at the GABAA receptor, which makes it less potent than other benzodiazepines, particularly in its amnesic and muscle-relaxing effects. Its elimination half life is between 36 and 200 hours, with wide variation among individuals; factors such as age and gender are known to impact it. The variation of reported half-lives are attributed to differences in nordazepam metabolism and that of its metabolites as nordazepam is hydroxylated to active metabolites such as oxazepam, before finally being glucuronidated and excreted in the urine. This can be attributed to extremely variable hepatic and renal metabolic functions among individuals depending upon a number of factors (including age, ethnicity, disease, and current or previous use/abuse of other drugs/medicines).

Pregnancy and Nursing Mothers

Nordazepam, like other benzodiazepines, easily crosses the placental barrier, so the drug should not be administered during the first trimester of pregnancy. In case of serious medical reasons, nordazepam can be given in late pregnancy, but the foetus, due to the pharmacological action of the drug, may experience side effects such as hypothermia, hypotonia, and sometimes mild respiratory depression. Since nordazepam and other benzodiazepines are excreted in breast milk, the substance should not be administered to mothers who are breastfeeding. Discontinuing of breast-feeding is indicated for regular intake by the mother.

Recreational Use

Refer to Benzodiazepine Use Disorder.

Nordazepam and other sedative-hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Many drivers have blood levels far exceeding the therapeutic dose range, suggesting benzodiazepines are commonly used in doses higher than the recommended doses.

What is Fosazepam?

Introduction

Fosazepam is a drug which is a benzodiazepine derivative; it is a water soluble derivative of diazepam. It has sedative and anxiolytic effects, and is a derivative of diazepam which has been substituted with a dimethylphosphoryl group to improve solubility in water.

Background

Fosazepam has similar effects on sleep as other benzodiazepines. In a clinical trial it was reported that fosazepam to lead to increased sleep duration with less broken sleep but sleep quality was worsened with suppressed deep sleep and increased light sleep. Adverse effects included feelings of impaired morning vitality and upon discontinuing the drug benzodiazepine withdrawal symptoms of anxiety, impaired concentration and impaired morning vitality were experienced. Another clinical trial also found worsening of sleep while on benzodiazepines as well as during withdrawal with suppression of deep sleep stages including REM (rapid eye movement) sleep, with increased light sleep upon withdrawal. The main metabolites of fosazepam are 3-hydroxyfosazepam and the active metabolite desmethyldiazepam which has a very long elimination half-life of about 3 days. Tolerance to the hypnotic effects of fosazepam starts to develop after about 7 days of use. Due to the very long elimination half-life of the active metabolite of fosazepam it is not recommended for use as a hypnotic. The main pharmacological effects of fosazepam may be due to its metabolite nordiazepam (desmethyldiazepam), rather than the parent drug. The long-acting active metabolite nordazepam (refer to nordiazepam) can cause extended sedative effects at high doses or with prolonged use, and may produce residual sedation upon awakening.

Fosazepam is of relatively low potency compared to other benzodiazepine derivatives, with a 100 mg dose of fosazepam equivalent to 10 mg of nitrazepam. 60 mg of fosazepam has also been estimated to be equivalent to about 5-10 mg of diazepam. Fosazepam has similar effects to nitrazepam, but with a shorter duration of action and less tendency to cause over sedation, motor-impairment, amnesia, rebound insomnia, and morning grogginess.

What is Intensive Short-Term Dynamic Psychotherapy?

Introduction

Intensive short-term dynamic psychotherapy (ISTDP) is a form of short-term psychotherapy developed through empirical, video-recorded research by Habib Davanloo.

The therapy’s primary goal is to help the patient overcome internal resistance to experiencing true feelings about the present and past which have been warded off because they are either too frightening or too painful. The technique is intensive in that it aims to help the patient experience these warded-off feelings to the maximum degree possible; it is short-term in that it tries to achieve this experience as quickly as possible; it is dynamic because it involves working with unconscious forces and transference feelings.

Patients come to therapy because of either symptoms or interpersonal difficulties. Symptoms include traditional psychological problems like anxiety and depression, but they also include physical symptoms without medically identifiable cause, such as headache, shortness of breath, diarrhoea, or sudden weakness. The ISTDP model attributes these to the occurrence of distressing situations where painful or forbidden emotions are triggered outside of awareness. Within psychiatry, these phenomena are classified as “Somatoform Disorders” in DSM-IV-TR.

The therapy itself was developed during the 1960s to 1990s by Habib Davanloo, a psychiatrist and psychoanalyst from Montreal. He video recorded patient sessions and watched the recordings in minute detail to determine as precisely as possible what sorts of interventions were most effective in overcoming resistance, which he believed was acting to keep painful or frightening feelings out of awareness and prevent interpersonal closeness.

ISTDP is taught by Habib Davanloo at McGill University, as well as in other University and post-graduate settings around the world. The ISTDP Institute offers on-line ISTDP training materials, including introductory videos and skill-building exercises.

Origins and Theoretical Foundation

In 1895, Josef Breuer and Sigmund Freud published their Studies on Hysteria, which looked at a series of case studies where patients presented with dramatic neurological symptoms, such as “Anna O” who suffered headaches, partial paralysis, loss of sensation, and visual disturbances. These symptoms did not conform to known patterns of neurological disease, and neurologists were thus unable to account for symptoms in purely anatomical or physiological terms. Breuer’s breakthrough was the discovery that symptomatic relief could be brought about by encouraging patients to speak freely about emotionally difficult aspects of their lives. Experiencing these emotions which had been previously outside of awareness seemed to be the curative factor. This cure became known as catharsis, and the experiencing of the previously forbidden or painful emotion was abreaction.

Freud tried various techniques to deal with the fact that patients generally seemed resistant to experiencing painful feelings. He moved from hypnosis to free association, interpretation of resistance, and dream interpretation. With each step, therapy became longer. Freud himself was quite open about the possibility that there were many patients for whom analysis could bring little or no relief, and he discusses the factors in his 1937 paper “Analysis Terminable and Interminable.”

From the 1930s through the 1950s, a number of analysts were researching methods of shortening the course of therapy without sacrificing therapeutic effectiveness. These included Sándor Ferenczi, Franz Alexander, Peter Sifneos, David Malan, and Habib Davanloo. One of the first discoveries was that the patients who appeared to benefit most from therapy were those who could rapidly engage, could describe a specific therapeutic focus, and could quickly move to experience their previously warded-off feelings. These also happened to represent those patients who were the healthiest to begin with and therefore had the least need for the therapy being offered. Clinical research revealed that these “rapid responders” were able to recover quickly with therapy because they were the least traumatised and therefore had the smallest burden of repressed emotion, and so were least resistant to experiencing the emotions related to trauma. However, these patients represented only a small minority of those arriving at psychiatric clinics; the vast majority remained unreachable with the newly developing techniques.

A number of psychiatrists began directing their psychotherapeutic research into methods of overcoming resistance. Dr. David Malan popularised a model of resistance, known as the Triangle of Conflict, which had first been proposed by Henry Ezriel. At the bottom of the triangle are the patient’s true, impulse-laden feelings, outside of conscious awareness. When those emotions rise to a certain degree and threaten to break into conscious awareness, they trigger anxiety. The patient manages this anxiety by deploying defences, which lessen anxiety by pushing emotions back into the unconscious.

The emotions at the bottom of Malan’s Triangle of Conflict originate in the patient’s past, and Malan’s second triangle, the Triangle of Persons, originally proposed by Menninger, explains that old emotions generated from the past are triggered in current relationships and also get triggered in the relationship with the therapist. The question of how maladaptive patterns of interpersonal behaviour could arise from early childhood experiences in the family of origin was postulated within psychoanalytic theory. Independent empirical support came from Bowlby’s newly arising field of Attachment Theory.

Bowlby and Attachment Trauma

John Bowlby, a British psychiatrist and psychoanalyst, was very interested in the impact on a child of adverse experiences in relation to its primary attachment figures (usually the mother, but often the father and others) in early life. He concluded, in opposition to received psychoanalytic dogma of the day, that childhood experience was far more important than unconscious fantasy. He also elucidated the nature of attachment, a system of behaviours exhibited by human and other mammalian infants which are innate and have the goal of physical proximity to the mother. For instance, a child taken out of its mother’s arms cries loudly in protest, and it is only quieted by being restored to its mother’s arms. Bowlby observed that the innate attachment system would be activated by loss of proximity to the mother, and that long-lasting trauma to the child could result from attachment interruption. Long term consequences included increased propensity to psychiatric disorders, poor relationship function, and decreased life satisfaction.

Bowlby conducted numerous studies and noted strong correlations between adverse early-life circumstances – primarily the lack of a consistent and nurturing relationship with the mother – as the source of numerous difficulties, including persistent depression, anxiety, or delinquency in adulthood. Childhood traumatisation to the attachment bond, usually through separation from or loss of the primary mother or mother-substitute, led to adult difficulties. Since Bowlby, the effects of trauma over development have consistently been shown to have a significant detrimental impact on adult psychological functioning.

Davanloo’s Discovery of the Unconscious Consequences of Attachment Trauma

In the 1960s, while Bowlby was observing children directly, Davanloo was beginning his work with symptomatic and character-disturbed adults. As he began his video-recording work and became progressively successful against higher levels of resistance, he noted that particular themes reappeared with striking consistency in patient after patient.

First, the therapist’s efforts to get to know the patient’s true feelings often aroused a simultaneous mixed feeling in the patient, composed of deep appreciation for the therapist’s relentless efforts to get to know the patient deeply, combined with equally deep irritation at the therapist for challenging the patient to abandon long-held resistances which could thwart the therapeutic effort.

Davanloo noted, in concert with Malan’s Triangle of Conflict, that patients would unconsciously resist the therapist’s efforts to get to the root of their difficulties. He also observed, from his videotaped sessions, that patients would simultaneously send off signals of their unconscious anxiety. Davanloo carefully monitored these signals of anxiety and saw that they represented the rise of complex mixed feelings with the therapist. The mix represented that part of the patient seeking relief from painful symptoms but also an active desire to avoid painful, repressed feelings.

As Davanloo became more skilled at unlocking the patient’s true unconscious feelings, he noted an often very predictable sequence of feelings. The sequence was by no means invariable, but it occurred frequently enough to allow the therapist to hypothesise its existence in a majority of cases.

First, after a high rise of mixed feeling with the therapist, manifested as signals of intense anxiety (tension in skeletal muscle, often manifested as wringing of the hands, accompanied with deep, sighing respirations), there would often be a breakthrough of rage, accompanied by an immediate drop in anxiety. This rage, Davanloo discovered, is intensely felt. It often has a violent impulse associated with it, sometimes even a murderous impulse. Once patients feel this rage, they are able to describe vividly detailed fantasies of what the rage would do if it were to take on a life of its own.

The rage is a product of thwarted efforts to attach from the past. Those thwarted efforts to love and be loved yield pain, in the form of what Bowlby described as protest. The pain yields a reactive rage at the loved person who thwarted attachment efforts.

Complete experiencing of the rageful impulse is typically accompanied by a tremendous relief at finally getting something out which has yearned for release. However, the relief is typically short lived.

Next, Davanloo almost invariably noted that patients then experience a tremendous wave of guilt about the rage. The guilt is a product of the fact that the old rageful feelings were with a person who was also loved. It is this guilt, Davanloo discovered, which is the key ingredient in symptom formation and character difficulties. Symptoms and interpersonal difficulties (usually unconscious efforts to ward off intimacy and closeness) are the product of guilt, which turns the rage back on the self. For instance, the rage of a two-year-old toward a mother who dies may be experienced in the present as suicidal feelings (self-directed murderous rage).

Beneath the guilty feelings from the past, Davanloo almost invariably noted painful feelings about thwarted efforts at emotional closeness to parents and others in childhood. Finally, at the deepest layer of feelings are the still powerful yearnings for closeness, attachment, and love.

The goal of the ISTDP therapist is, as rapidly as possible, to help the patient overcome resistance, and then experience all the waves of mixed, genuine feeling, previously unconscious, triggered by the intense therapeutic process. Those feelings are traced back to their origins in the past, and then both therapist and patient come to understand how the patient came to be the “consciously confused, unconsciously driven” person in the present. Old pockets of emotion are drained, the patient has a clearer self-narrative, and self-destructive symptoms and defences are renounced. The understanding gained is not just cognitive, but goes to the fundamental, emotional core. The influence of Freud’s early trauma theory is evident.

Specific Therapeutic Interventions

Davanloo discovered the layers of the dynamic unconscious through a process of developing specific interventions which allow the therapist to reach those layers. Those interventions, applied in a specific fashion at specific times in the therapeutic process, are all calculated to overcome the patient’s resistance as quickly and completely as possible, to allow the earliest and fullest experience of true feelings about the present and past as quickly as possible. Those interventions are known as pressure, challenge, and head-on collision.

I. Pressure: Therapeutic Encouragement and Reaching through to the Patient

Pressure is the principal ingredient of ISTDP, and it takes many forms. Initially, pressure takes the form of encouraging the patient to describe symptoms and interpersonal difficulties as specifically as possible, so both patient and therapist get the clearest picture possible of the precise difficulties. It starts from the moment the patient walks into the room, in the form of the question, “Are there some difficulties you are experiencing which you would like us to have a look at?”

The primary form of pressure is pressure toward feeling. Again, this is exerted mainly in the form of questions, such as, “How did you feel toward your boss for humiliating you in front of your staff? We see that you got anxious and depressed, but how did you feel?”

Pressure can be toward the patient’s will: “Can we look to your feelings? Do you want us to look to your feelings?”

Pressure is also exerted toward the therapeutic task: “Our goal here, if you want, is to get to the root, the engine, driving your difficulties. So, can we look at a specific time when you experienced anxiety? This will give us a clear picture of the problem which we can use to get to the engine.”

In its essence, pressure is encouragement from the therapist to the patient. It is encouragement to renounce defences, tolerate anxiety, and walk, with the therapist, into those places which have previously been off-limits. It is a way of saying, “There’s nothing in there we cannot face together, and we do so in your service, to relieve you of painful difficulties.”

Patients with low resistance are often quite responsive to pressure alone. However, as explained above, those are the patients who are healthiest to begin with. For patients with higher levels of resistance, usually the product of a more traumatised early phase of life, pressure quickly leads to the patient erecting barriers with the therapist. Those barriers are the patient’s habitual defences against avoided feelings. The combination of intentional (conscious) and unintentional (unconscious) defences is called the resistance. The therapist is constantly monitoring for both the rise in anxiety and the appearance of resistance. When resistance does make its appearance, new interventions, in addition to pressure, are called for.

II. Challenge: Pointing Out and Interrupting Defences in Concert with the Patient

Challenge is a two-stage process. The first stage is clarification, which is the therapist’s effort to confirm that resistance is operating, and also to acquaint the patient with the specific defence being deployed. Patients are often quite unaware of their own defences. Clarification takes the form of a question, meant to clarify the defence to both patient and therapist: “Do you notice that when you speak of being angry with your boss that you smile and giggle? Is a smile something you sometimes do to cover up a deeper feeling?”

When a defence is properly clarified, both patient and therapist can work together against it, because it represents an obstacle to the therapeutic task of getting to the patient’s true feelings. A defence which has not been clarified is still invisible to the patient. It is also important to note that in childhood, defences can be a useful tool in emotionally overwhelming or traumatic situations. According to Los Angeles-based psychiatrist Katherine Watkins, M.D.:

“defenses such as dissociation and repression can shield us from intense feelings that we are developmentally unprepared to experience and process. However as we grow up, this shielding cuts us off from our full range of feelings, even when we are now emotionally able to handle the feelings.”

Challenge to the defences represents an exhortation to the patient to abandon the defence: “Again you smile when I ask you about feelings in relation to being humiliated by your husband. If you don’t smile, how were you truly feeling?” This particular intervention is a very powerful one in the therapist’s arsenal. As with all powerful interventions, if it is misapplied, the consequences can be severe: rapid misalliance with the therapist, worsening of symptoms, and treatment dropout. This is because the patient perceives a premature challenge, applied when a defence has not been clarified, as a criticism or a personal attack.

A common misunderstanding of ISTDP is that the therapist’s role is to badger the patient through the use of Challenge. However, the proper use of challenge is as an aid or enhancement to the therapeutic alliance by removing an obstacle to the rise in complex feelings with the therapist. If challenge originates as a product of frustration in the therapist or as a misunderstanding of the unconscious, then stalemate is virtually assured.

The main purpose of challenge is to remove any obstacles in the way of the mutually agreed upon task of getting to the engine of the patient’s present difficulties: warded-off, complex feelings in relation to traumatising experiences with important attachment figures in the past.

The majority of patients are able to experience their true mixed feelings with a combination of Pressure and properly clarified Challenge. However, a sizable minority of patients erect a massive wall of resistance with the therapist. This wall is erected automatically and is an over-learned, habitual response, used to avoid emotional intimacy, both with the therapist and with other important figures in the patient’s personal orbit. When the therapist observes that the patient’s resistance has fully crystallised, it is time to deploy the ultimate intervention.

III. Head-On Collision: Pointing Out the Reality of the Defences and Encouragement to Overcome Them

The Head-on Collision is an intervention aimed not at any single defence but rather aimed at the entire defensive structure being deployed by the patient. It is an urgent appeal to the patient to exert maximal effort to overcome the resistance, and it takes the form of a summary statement to the patient which explains the consequences of continuing to resist:

Let’s take a look at what’s happening here. You have come on your own free will, because you are experiencing a problem which causes you pain. We have set out to get to the root of your difficulties, but every time we attempt to move toward it, you put up this massive wall. The wall keeps me out, and it keeps you from knowing your own true feelings. If you keep me out, you keep me useless. Is that what you want? Because, as you see, you are certainly capable of keeping me useless to you. My first question is, why would you want me to be useless? You see, the consequences of this would be that I would be unable to help you. I’d like to, but the nature of this work is that I can’t help everyone. Sometimes I fail. However, can you afford to fail? How much longer do you want to carry this burden?

This complex intervention is simultaneously aimed at the patient’s will, is a reminder of the task, and is a wake-up call to the therapeutic alliance to exert maximal effort against the resistance. It is a reminder, in stark terms, that the therapeutic task is in jeopardy and may well fail. Finally, it is a reminder to the patient of the consequences of failure, as well as an implied reminder that success is also possible.

The interventions of Pressure, Challenge, and Head-on Collision, all aimed at helping the patient experience true feelings in relation to the present and past, allowed Davanloo to expand the scope of patients who can be helped by short-term psychodynamic psychotherapy. A model which initially worked only with highly motivated patients able to describe a clearly problematic area can now be applied to patients whose difficulties are diffuse and whose motivation is also initially quite diffuse. The results are deep, lasting changes in areas of both symptomatic and interpersonal disturbances.

It is also worth stressing that ISTDP, unlike traditional psychodynamic therapies, assiduously avoids interpretation until such time as the unconscious is open. The use of trial interpretations is explicitly avoided. The phase of interpretation only commences once it is clear to both therapist and patient that there has been a passage of previously unconscious emotion. Quite often, it is then the patient who takes the lead in interpreting:

“The incredible rage I felt toward you when you refused to let me off the hook regarding my feelings is exactly the same rage that I felt toward my father when I was five years old and found out he had been killed in the war and wasn’t coming home. I buried the rage that day because I felt so guilty about it. That’s the day I became depressed.”

Evidence Base

Davanloo’s initial research was published in the form of a qualitative case series of approximately 200 patients. He maintains a large video library of treated cases which he uses for teaching conferences, though this has not yet been made available for other psychotherapy researchers to independently verify and quantify Davanloo’s claims. Recent studies however, support the efficacy of the ISTDP technique, as described below. He claims efficacy with psychological symptoms, medically unexplained symptoms (so-called functional or somatoform disorders), and characterological disturbances (referred to as Personality Disorders in DSM).

Empirical research into the efficacy of ISTDP, and other brief psychodynamic psychotherapies is active. There are now over 60 published outcome studies in ISTDP including 40 randomised controlled trials for depression, anxiety, personality, somatic symptom and substance use disorders. There are also over 20 studies showing the cost effectiveness of the method through reducing doctor visits, medication costs, hospital costs and disability costs. Summary of cost effectiveness studies to 2018

ISTDP has been investigated for:

  • Personality Disorders.
  • Depression and Treatment Resistant Depression.
  • Anxiety Disorders.
  • Functional Neurological Disorders.
  • Somatic Symptom Disorders: at least 20 studies as of October 2019.
  • Summary of ISTDP Somatic Condition Studies:
    • Cost effectiveness studies: at least 22 studies as of October 2019.
    • As an Adjunct to Care in Severe Mental Disorders.
    • Substance Use Disorders.

A Cochrane systematic review examined the efficacy of short-term psychodynamic psychotherapies for common mental disorders such as depression, anxiety and personality disorders. Without distinguishing between different forms of STDP from Davanloo’s ISTDP, modest to large short-term gains were reported for a broad range of people experiencing common mental disorders. Further research is required to determine the effectiveness and long term benefits of psychodynamic psychotherapies for common mental disorders. Neuroscientist and Nobel Prize winner, Eric Kandel refers to Davanloo’s technique and its effectiveness in providing relief from emotional disturbances.

Relationship to Cognitive Therapy

Cognitive therapy (CT), developed by Aaron T. Beck, focuses on illogical thoughts as the main driver of emotional difficulties. These beliefs, such as, “Everything I attempt inevitably fails,” are postulated to cause emotional states like depression or hopelessness. The therapist collaborates with the patient to determine which faulty cognitions are currently accepted by the patient as true. Together, the patient and therapist discover these cognitions and collaboratively explore the evidence for and against them. Relief of symptoms comes from replacing unfounded cognitions with more reality-based thoughts. CBT has been shown effective in numerous trials[citation needed], particularly for depression and anxiety disorders.

While ISTDP accepts the presence of faulty cognitions, the causality is thought to be reversed. The ISTDP therapist would posit that unconscious emotions lead to unconscious anxiety, which is managed by unconscious defences. These defences can certainly include hopeless, helpless, or self-deprecating cognitions. Rather than examining evidence for and against a thought like, “I am unable to know my own true feelings,” an ISTDP therapist might say, “If you adopt that position, which is essentially a position of helplessness, we will not get to the engine driving your difficulties. If you renounce this helpless position, how are you truly feeling right now?”

Both the CT and ISTDP therapist call the thought into question, with the goal of ultimately liberating the patient. The difference is that the ISTDP therapist sees the faulty cognition as preventing access to the true, buried feelings, while the CT therapist sees the faulty cognition as the cause of the painful emotions leading to the painful psychological state. It may well be the case that causality flows in both directions, dependent on the individual, the emotions, and the cognitions involved. As of this writing, though both CT and ISTDP show good evidence of clinical efficacy, the theoretical question of whether feelings drive thoughts or thoughts drive feelings remains unresolved; it could well be the case that thought and feeling are inextricably bound, and that we have not yet developed adequate psychological or neuroscientific concepts and tools to frame these sorts of questions properly.