What is a Therapeutic Index?

Introduction

The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug.

It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. The related terms therapeutic window or safety window refer to a range of doses which optimize between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.

Classically, in an established clinical indication setting of an approved drug, TI refers to the ratio of the dose of drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose in 50% of subjects, TD50) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED50). In contrast, in a drug development setting TI is calculated based on plasma exposure levels.

In the early days of pharmaceutical toxicology, TI was frequently determined in animals as lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the population (ED50). Today, more sophisticated toxicity endpoints are used.

For Humans (TD50 / ED50).

For many drugs, there are severe toxicities that occur at sublethal doses in humans, and these toxicities often limit the maximum dose of a drug. A higher therapeutic index is preferable to a lower one: a patient would have to take a much higher dose of such a drug to reach the toxic threshold than the dose taken to elicit the therapeutic effect.

Generally, a drug or other therapeutic agent with a narrow therapeutic range (i.e. having little difference between toxic and therapeutic doses) may have its dosage adjusted according to measurements of the actual blood levels achieved in the person taking it. This may be achieved through therapeutic drug monitoring (TDM) protocols. TDM is recommended for use in the treatment of psychiatric disorders with lithium due to its narrow therapeutic range.

Terms

  • ED = Effective dose.
  • TD = Toxic dose.
  • LD = Lethal dose.
  • TI = Therapeutic index.
  • TR = Therapeutic ratio.

Therapeutic Index in Drug Development

A high therapeutic index (TI) is preferable for a drug to have a favourable safety and efficacy profile. At early discovery/development stage, the clinical TI of a drug candidate is not known. However, understanding the preliminary TI of a drug candidate is of utmost importance as early as possible since TI is an important indicator of the probability of the successful development of a drug. Recognising drug candidates with potentially suboptimal TI at earliest possible stage helps to initiate mitigation or potentially re-deploy resources.

In a drug development setting, TI is the quantitative relationship between efficacy (pharmacology) and safety (toxicology), without considering the nature of pharmacological or toxicological endpoints themselves. However, to convert a calculated TI to something that is more than just a number, the nature and limitations of pharmacological and/or toxicological endpoints must be considered. Depending on the intended clinical indication, the associated unmet medical need and/or the competitive situation, more or less weight can be given to either the safety or efficacy of a drug candidate with the aim to create a well balanced indication-specific safety vs efficacy profile.

In general, it is the exposure of a given tissue to drug (i.e. drug concentration over time), rather than dose, that drives the pharmacological and toxicological effects. For example, at the same dose there may be marked inter-individual variability in exposure due to polymorphisms in metabolism, DDIs or differences in body weight or environmental factors. These considerations emphasize the importance of using exposure rather than dose for calculating TI. To account for delays between exposure and toxicity, the TI for toxicities that occur after multiple dose administrations should be calculated using the exposure to drug at steady state rather than after administration of a single dose.

A review published by Muller and Milton in Nature Reviews Drug Discovery critically discusses the various aspects of TI determination and interpretation in a translational drug development setting for both small molecules and biotherapeutics.

Range of Therapeutic Indices

The therapeutic index varies widely among substances, even within a related group.

For instance, the opioid painkiller remifentanil is very forgiving, offering a therapeutic index of 33,000:1, while Diazepam, a benzodiazepine sedative-hypnotic and skeletal muscle relaxant, has a less forgiving therapeutic index of 100:1. Morphine is even less so with a therapeutic index of 70.

Less safe are cocaine (a stimulant and local anaesthetic) and ethanol (colloquially, the “alcohol” in alcoholic beverages, a widely available sedative consumed worldwide): the therapeutic indices for these substances are 15:1 and 10:1, respectively.

Even less safe are drugs such as digoxin, a cardiac glycoside; its therapeutic index is approximately 2:1.

Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimise toxicity, include: paracetamol (acetaminophen), dimercaprol, theophylline, warfarin and lithium carbonate.

Some antibiotics and antifungals require monitoring to balance efficacy with minimising adverse effects, including: gentamicin, vancomycin, amphotericin B (nicknamed ‘amphoterrible’ for this very reason), and polymyxin B.

Cancer Radiotherapy

Radiotherapy aims to minimize the size of tumours and kill cancer cells with high energy. The source of high energy arises from x-rays, gamma rays, charged particles and heavy particles. The therapeutic ratio in radiotherapy for cancer treatment is related to the maximum radiation dose by which death of cancer cells is locally controlled and the minimum radiation dose by which cells in normal tissues have low acute and late morbidity. Both of parameters have sigmoidal dose-response curves. Thus, a favourable outcome in dose-response curve is the response of tumour tissue is greater than that of normal tissue to the same dose, meaning that the treatment is effective to tumours and does not cause serious morbidity to normal tissue. Reversely, overlapping response of two tissues is highly likely to cause serious morbidity to normal tissue and ineffective treatment to tumours. The mechanism of radiation therapy is categorised into direct and indirect radiation. Both direct and indirect radiations induce DNA to have a mutation or chromosomal rearrangement during its repair process. Direct radiation creates a free DNA radical from radiation energy deposition that damages DNA. Indirect radiation occurs from radiolysis of water, creating a free hydroxyl radical, hydronium and electron. Then, hydroxyl radical transfers its radical to DNA. Or together with hydronium and electron, a free hydroxyl radical can damage base region of DNA.

Cancer cells have imbalance of signals in cell cycle. G1 and G2/M arrest are found to be major checkpoints by irradiation in human cells. G1 arrest delays repair mechanism before synthesis of DNA in S phase and mitosis in M phase, suggesting key checkpoint to lead survival of cells. G2/M arrest occurs when cells need to repair after S phase before the mitotic entry. It was also known that S phase is the most resistant to radiation and M phase was the most sensitive to radiation. p53, a tumour suppressor protein that plays a role in G1 and G2/M arrest, enabled the understanding of the cell cycle by radiation. For example, irradiation to myeloid leukaemia cell leads to an increase in p53 and a decrease in the level of DNA synthesis. Patients with Ataxia telangiectasia delays have hypersensitivity to radiation due to the delay of accumulation of p53.[9] In this case, cells are able to replicate without repair of their DNA, prone to incidence of cancer. Most cells are in G1 and S phase and irradiation at G2 phase showed increased radiosensitivity and thus G1 arrest has been on focus for therapeutic treatment. Irradiation to a tissue creates response to both irradiated and non-irridiated cells. It was found that even cells up to 50-75 cell diameter distant from irradiated cells have phenotype of enhanced genetic instability such as micronucleation. This suggests the effect of cell-to-cell communication such as paracrine and juxtacrine signalling. Normal cells do not lose DNA repair mechanism whereas cancer cells often lose during radiotherapy. However, the nature of high energy radiation can override the ability of damaged normal cell to repair, leading to cause another risk for carcinogenesis. This suggests a significant risk associated with radiation therapy. Thus, it is desirable to improve the therapeutic ratio during radiotherapy. Employing IG-IMRT, protons and heavy ions are likely to minimise dose to normal tissues by altered fractionation. Molecular targeting to DNA repair pathway can lead to radiosensitisation or radioprotection. Examples are direct and indirect inhibitors on DNA double-strand breaks. Direct inhibitors target proteins (PARP family) and kinases (ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target proteins tumour cell signalling proteins such as EGFR and insulin growth factor.

The effective therapeutic index can be affected by targeting, in which the therapeutic agent is concentrated in its area of effect. For example, in radiation therapy for cancerous tumours, shaping the radiation beam precisely to the profile of a tumour in the “beam’s eye view” can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index. Similarly, chemotherapy or radiotherapy with infused or injected agents can be made more efficacious by attaching the agent to an oncophilic substance, as is done in peptide receptor radionuclide therapy for neuroendocrine tumours and in chemoembolisation or radioactive microspheres therapy for liver tumours and metastases. This concentrates the agent in the targeted tissues and lowers its concentration in others, increasing efficacy and lowering toxicity.

Safety Ratio

Sometimes the term safety ratio is used instead, particularly when referring to psychoactive drugs used for non-therapeutic purposes, e.g. recreational use. In such cases, the effective dose is the amount and frequency that produces the desired effect, which can vary, and can be greater or less than the therapeutically effective dose.

The Certain Safety Factor, also referred to as the Margin of Safety (MOS), is the ratio of the lethal dose to 1% of population to the effective dose to 99% of the population (LD1/ED99). This is a better safety index than the LD50 for materials that have both desirable and undesirable effects, because it factors in the ends of the spectrum where doses may be necessary to produce a response in one person but can, at the same dose, be lethal in another.

Synergistic Effect

A therapeutic index does not consider drug interactions or synergistic effects. For example, the risk associated with benzodiazepines increases significantly when taken with alcohol, opiates, or stimulants when compared with being taken alone. Therapeutic index also does not take into account the ease or difficulty of reaching a toxic or lethal dose. This is more of a consideration for recreational drug users, as the purity can be highly variable.

Protective Index

The protective index is a similar concept, except that it uses TD50 (median toxic dose) in place of LD50. For many substances, toxic effects can occur at levels far below those needed to cause death, and thus the protective index (if toxicity is properly specified) is often more informative about a substance’s relative safety. Nevertheless, the therapeutic index is still useful as it can be considered an upper bound for the protective index, and the former also has the advantages of objectivity and easier comprehension.

Therapeutic Window

The therapeutic window (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects. Medication with a small therapeutic window must be administered with care and control, frequently measuring blood concentration of the drug, to avoid harm. Medications with narrow therapeutic windows include theophylline, digoxin, lithium, and warfarin.

Optimal Biological Dose

Optimal biological dose (OBD) is the quantity of a drug that will most effectively produce the desired effect while remaining in the range of acceptable toxicity.

Maximum Tolerated Dose

The maximum tolerated dose (MTD) refers to the highest dose of a radiological or pharmacological treatment that will produce the desired effect without unacceptable toxicity. The purpose of administering MTD is to determine whether long-term exposure to a chemical might lead to unacceptable adverse health effects in a population, when the level of exposure is not sufficient to cause premature mortality due to short-term toxic effects. The maximum dose is used, rather than a lower dose, to reduce the number of test subjects (and, among other things, the cost of testing), to detect an effect that might occur only rarely. This type of analysis is also used in establishing chemical residue tolerances in foods. Maximum tolerated dose studies are also done in clinical trials.

MTD is an essential aspect of a drug’s profile. All modern healthcare systems dictate a maximum safe dose for each drug, and generally have numerous safeguards (e.g. insurance quantity limits and government-enforced maximum quantity/time-frame limits) to prevent the prescription and dispensing of quantities exceeding the highest dosage which has been demonstrated to be safe for members of the general patient population.

Patients are often unable to tolerate the theoretical MTD of a drug due to the occurrence of side-effects which are not innately a manifestation of toxicity (not considered to severely threaten a patients health) but cause the patient sufficient distress and/or discomfort to result in non-compliance with treatment. Such examples include emotional “blunting” with antidepressants, pruritus with opiates, and blurred vision with anticholinergics.

What is Temazepam?

Introduction

Temazepam, sold under the brand names Restoril among others, is a medication used to treat insomnia.

Such use should generally be for less than ten days. It is taken by mouth. Effects generally begin within an hour and last for up to eight hours.

Common side effects include sleepiness, anxiety, confusion, and dizziness. Serious side effects may include hallucinations, abuse, anaphylaxis, and suicide. Use is generally not recommended together with opioids. If the dose is rapidly decreased withdrawal may occur. Use during pregnancy or breastfeeding is not recommended. Temazepam is an intermediate acting benzodiazepine and hypnotic. It works by affecting GABA within the brain.

Temazepam was patented in 1962 and came into medical use in 1969. It is available as a generic medication. In 2017, it was the 142nd most commonly prescribed medication in the United States, with more than four million prescriptions.

Brief History

Temazepam was synthesized in 1964, but it came into use in 1981 when its ability to counter insomnia was realised. By the late 1980s, temazepam was one of the most popular and widely prescribed hypnotics on the market and it became one of the most widely prescribed drugs.

Medical Uses

In sleep laboratory studies, temazepam significantly decreased the number of nightly awakenings, but has the drawback of distorting the normal sleep pattern. It is officially indicated for severe insomnia and other severe or disabling sleep disorders. The prescribing guidelines in the UK limit the prescribing of hypnotics to two to four weeks due to concerns of tolerance and dependence.

The United States Air Force uses temazepam as one of the hypnotics approved as a “no-go pill” to help aviators and special-duty personnel sleep in support of mission readiness. “Ground tests” are necessary prior to required authorisation being issued to use the medication in an operational situation, and a 12-hour restriction is imposed on subsequent flight operation. The other hypnotics used as “no-go pills” are zaleplon and zolpidem, which have shorter mandatory recovery periods.

Contraindications

Use of temazepam should be avoided, when possible, in individuals with these conditions:

  • Ataxia (gross lack of coordination of muscle movements).
  • Severe hypoventilation.
  • Acute narrow-angle glaucoma.
  • Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of two).
  • Severe renal deficiencies (e.g. patients on dialysis).
  • Sleep apnoea.
  • Severe depression, particularly when accompanied by suicidal tendencies.
  • Acute intoxication with alcohol, narcotics, or other psychoactive substances.
  • Myasthenia gravis (autoimmune disorder causing muscle weakness).
  • Hypersensitivity or allergy to any drug in the benzodiazepine class.

Special Caution Needed

Temazepam should not be used in pregnancy, as it may cause harm to the foetus. The safety and effectiveness of temazepam has not been established in children; therefore, temazepam should generally not be given to individuals under 18 years of age, and should not be used at all in children under six months old. Benzodiazepines also require special caution if used in the elderly, alcohol- or drug-dependent individuals, and individuals with comorbid psychiatric disorders.

Temazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial but incomplete tolerance develops to these impairments. The smallest possible effective dose should be used in elderly or very ill patients, as a risk of apnoea and/or cardiac arrest exists. This risk is increased when temazepam is given concomitantly with other drugs that depress the central nervous system (CNS).

Misuse and Dependence

Because benzodiazepines can be abused and lead to dependence, their use should be avoided in people in certain particularly high-risk groups. These groups include people with a history of alcohol or drug dependence, people significantly struggling with their mood or people with longstanding mental health difficulties. If temazepam must be prescribed to people in these groups, they should generally be monitored very closely for signs of misuse and development of dependence.

Adverse Effects

Refer to Benzodiazepine Withdrawal Syndrome.

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

Common

Side effects typical of hypnotic benzodiazepines are related to CNS depression, and include somnolence, sedation, dizziness, fatigue, ataxia, headache, lethargy, impairment of memory and learning, longer reaction time and impairment of motor functions (including coordination problems), slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, blurred vision (in higher doses), and inattention. Euphoria was rarely reported with its use. According to the FDA, temazepam had an incidence of euphoria of 1.5%, much more rarely reported than headaches and diarrhoea. Anterograde amnesia may also develop, as may respiratory depression in higher doses.

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

Less Common

Hyperhydrosis, hypotension, burning eyes, increased appetite, changes in libido, hallucinations, faintness, nystagmus, vomiting, pruritus, gastrointestinal disturbances, nightmares, palpitation and paradoxical reactions including restlessness, aggression, violence, overstimulation and agitation have been reported, but are rare (less than 0.5%).

Before taking temazepam, one should ensure that at least 8 hours are available to dedicate to sleep. Failing to do so can increase the side effects of the drug.

Like all benzodiazepines, the use of this drug in combination with alcohol potentiates the side effects, and can lead to toxicity and death.

Though rare, residual “hangover” effects after night-time administration of temazepam occasionally occur. These include sleepiness, impaired psychomotor and cognitive functions which may persist into the next day, impaired driving ability, and possible increased risks of falls and hip fractures, especially in the elderly.

Tolerance

Chronic or excessive use of temazepam may cause drug tolerance, which can develop rapidly, so this drug is not recommended for long-term use. In 1979, the US Institute of Medicine and the National Institute on Drug Abuse stated that most hypnotics lose their sleep-inducing properties after about three to 14 days. In use longer than one to two weeks, tolerance will rapidly develop towards the ability of temazepam to maintain sleep, resulting in a loss of effectiveness. Some studies have observed tolerance to temazepam after as little as one week’s use. Another study examined the short-term effects of the accumulation of temazepam over seven days in elderly inpatients, and found little tolerance developed during the accumulation of the drug. Other studies examined the use of temazepam over six days and saw no evidence of tolerance. A study in 11 young male subjects showed significant tolerance occurs to temazepam’s thermoregulatory effects and sleep inducing properties after one week of use of 30-mg temazepam. Body temperature is well correlated with the sleep-inducing or insomnia-promoting properties of drugs.

In one study, the drug sensitivity of people who had used temazepam for one to 20 years was no different from that of controls. An additional study, in which at least one of the authors is employed by multiple drug companies, examined the efficacy of temazepam treatment on chronic insomnia over three months, and saw no drug tolerance, with the authors even suggesting the drug might become more effective over time.

Establishing continued efficacy beyond a few weeks can be complicated by the difficulty in distinguishing between the return of the original insomnia complaint and withdrawal or rebound related insomnia. Sleep EEG studies on hypnotic benzodiazepines show tolerance tends to occur completely after one to four weeks with sleep EEG returning to pre-treatment levels. The paper concluded that due to concerns about long-term use involving toxicity, tolerance and dependence, as well as to controversy over long-term efficacy, wise prescribers should restrict benzodiazepines to a few weeks and avoid continuing prescriptions for months or years. A review of the literature found the nonpharmacological treatment options were a more effective treatment option for insomnia due to their sustained improvements in sleep quality.

Physical Dependence

Temazepam, like other benzodiazepine drugs, can cause physical dependence and addiction. Withdrawal from temazepam or other benzodiazepines after regular use often leads to benzodiazepine withdrawal syndrome, which resembles symptoms during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can also occur from standard dosages and after short-term use. Abrupt withdrawal from therapeutic doses of temazepam after long-term use may result in a severe benzodiazepine withdrawal syndrome. Gradual and careful reduction of the dosage, preferably with a long-acting benzodiazepine with long half-life active metabolites, such as chlordiazepoxide or diazepam, are recommended to prevent severe withdrawal syndromes from developing. Other hypnotic benzodiazepines are not recommended. A study in rats found temazepam is cross tolerant with barbiturates and is able to effectively substitute for barbiturates and suppress barbiturate withdrawal signs. Rare cases are reported in the medical literature of psychotic states developing after abrupt withdrawal from benzodiazepines, even from therapeutic doses. Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions. Patients who were treated in the hospital with temazepam or nitrazepam have continued taking these after leaving the hospital. Hypnotic uses in the hospital were recommended to be limited to five nights’ use only, to avoid the development of withdrawal symptoms such as insomnia.

Interactions

As with other benzodiazepines, temazepam produces additive CNS-depressant effects when co-administered with other medications which themselves produce CNS depression, such as barbiturates, alcohol, opiates, tricyclic antidepressants, nonselective MAO inhibitors, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines, and anaesthetics. Administration of theophylline or aminophylline has been shown to reduce the sedative effects of temazepam and other benzodiazepines.

Unlike many benzodiazepines, pharmacokinetic interactions involving the P450 system have not been observed with temazepam. Temazepam shows no significant interaction with CYP3A4 inhibitors (e.g. itraconazole, erythromycin). Oral contraceptives may decrease the effectiveness of temazepam and speed up its elimination half-life.

Overdose

Refer to Benzodiazepine Overdose.

Overdose (or an excess dose(s)) of temazepam results in increasing CNS effects, including:

  • Somnolence (difficulty staying awake).
  • Mental confusion.
  • Respiratory depression.
  • Hypotension.
  • Impaired motor functions.
  • Impaired or absent reflexes.
  • Impaired coordination.
  • Impaired balance.
  • Dizziness, sedation.
  • Coma.
  • Death.

Temazepam had the highest rate of drug intoxication, including overdose, among common benzodiazepines in cases with and without combination with alcohol in a 1985 study. Temazepam and nitrazepam were the two benzodiazepines most commonly detected in overdose-related deaths in an Australian study of drug deaths. A 1993 British study found temazepam to have the highest number of deaths per million prescriptions among medications commonly prescribed in the 1980s (11.9, versus 5.9 for benzodiazepines overall, taken with or without alcohol).

A 1995 Australian study of patients admitted to hospital after benzodiazepine overdose corroborated these results, and found temazepam overdose much more likely to lead to coma than other benzodiazepines (odds ratio 1.86). The authors noted several factors, such as differences in potency, receptor affinity, and rate of absorption between benzodiazepines, could explain this higher toxicity. Although benzodiazepines have a high therapeutic index, temazepam is one of the more dangerous of this class of drugs. The combination of alcohol and temazepam makes death by alcohol poisoning more likely.

Pharmacology

Temazepam is a white, crystalline substance, very slightly soluble in water, and sparingly soluble in alcohol. Its main pharmacological action is to increase the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor. This causes sedation, motor impairment, ataxia, anxiolysis, an anticonvulsant effect, muscle relaxation, and a reinforcing effect. As a medication before surgery, temazepam decreased cortisol in elderly patients. In rats, it triggered the release of vasopressin into paraventricular nucleus of the hypothalamus and decreased the release of ACTH under stress.

Pharmacokinetics

Oral administration of 15 to 45 mg of temazepam in humans resulted in rapid absorption with significant blood levels achieved in fewer than 30 minutes and peak levels at two to three hours. In a single- and multiple-dose absorption, distribution, metabolism, and excretion (ADME) study, using tritium-labelled drug, temazepam was well absorbed and found to have minimal (8%) first-pass drug metabolism. No active metabolites were formed and the only significant metabolite present in blood was the O-conjugate. The unchanged drug was 96% bound to plasma proteins. The blood-level decline of the parent drug was biphasic, with the short half-life ranging from 0.4-0.6 hours and the terminal half-life from 3.5-18.4 hours (mean 8.8 hours), depending on the study population and method of determination.

Temazepam has very good bioavailability, with almost 100% being absorbed following being taken by mouth. The drug is metabolized through conjugation and demethylation prior to excretion. Most of the drug is excreted in the urine, with about 20% appearing in the faeces. The major metabolite was the O-conjugate of temazepam (90%); the O-conjugate of N-desmethyl temazepam was a minor metabolite (7%).

Society and Culture

Recreational Use

Refer to Benzodiazepine Use Disorder.

Temazepam is a drug with a moderate potential for misuse.

Benzodiazepines have been abused orally and intravenously. Different benzodiazepines have different abuse potential; the more rapid the increase in the plasma level following ingestion, the greater the intoxicating effect and the more open to abuse the drug becomes. The speed of onset of action of a particular benzodiazepine correlates well with the ‘popularity’ of that drug for abuse. The two most common reasons for preference were that a benzodiazepine was ‘strong’ and that it gave a good ‘high’.

A 1995 study found that temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than most other benzodiazepines.

A 1985 study found that temazepam and triazolam maintained significantly higher rates of self-injection than a variety of other benzodiazepines. The study tested and compared the abuse liability of temazepam, triazolam, diazepam, lorazepam, oxazepam, flurazepam, alprazolam, chlordiazepoxide, clonazepam, nitrazepam, flunitrazepam, bromazepam, and clorazepate. The study tested self-injection rates on human, baboon, and rat subjects. All test subjects consistently showed a strong preference for temazepam and triazolam over all the rest of the benzodiazepines included in the study.

North America

In North America, temazepam misuse is not widespread. Other benzodiazepines are more commonly prescribed for insomnia. In the United States, temazepam is the fifth-most prescribed benzodiazepine, however there is a major drop off from the top four most prescribed (alprazolam, lorazepam, diazepam, and clonazepam in that order). Individuals abusing benzodiazepines obtain the drug by getting prescriptions from several doctors, forging prescriptions, or buying diverted pharmaceutical products on the illicit market. North America has never had a serious problem with temazepam misuse, but is becoming increasingly vulnerable to the illicit trade of temazepam.

Australia

Temazepam is a Schedule 4 drug and requires a prescription. The drug accounts for most benzodiazepine sought by forgery of prescriptions and through pharmacy burglary in Victoria. Due to rife intravenous abuse, the Australian government decided to put it under a more restrictive schedule than it had been, and since March 2004 temazepam capsules have been withdrawn from the Australian market, leaving only 10 mg tablets available. Benzodiazepines are commonly detected by Customs at different ports and airports, arriving by mail, also found occasionally in the baggage of air passengers, mostly small or medium quantities (up to 200-300 tablets) for personal use. From 2003 to 2006, customs detected about 500 illegal importations of benzodiazepines per year, most frequently diazepam. Quantities varied from single tablets to 2,000 tablets.

United Kingdom

In 1987, temazepam was the most widely abused legal prescription drug in the United Kingdom. The use of benzodiazepines by street-drug abusers was part of a polydrug abuse pattern, but many of those entering treatment facilities were declaring temazepam as their main drug of abuse. Temazepam was the most commonly used benzodiazepine in a study, published 1994, of injecting drug users in seven cities, and had been injected from preparations of capsules, tablets, and syrup. The increase in use of heroin, often mixed with other drugs, which most often included temazepam, diazepam, and alcohol, was a major factor in the increase in drug-related deaths in Glasgow and Edinburgh in 1990-1992. Temazepam use was particularly associated with violent or disorderly behaviours and contact with the police in a 1997 study of young single homeless people in Scotland. The BBC series Panorama featured an episode titled “Temazepam Wars”, dealing with the epidemic of temazepam abuse and directly related crime in Paisley, Scotland. The trend was mocked in the 1995 Black Grape song “Temazi Party” (also called “Tramazi Party”).

Medical Research Issues

The Journal of Clinical Sleep Medicine published a paper expressing concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs used as hypnotics in humans. The paper cites a systematic review of the medical literature concerning insomnia medications and states almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry, while this is not the case in general medicine or psychiatry. It cites another study that “found that the odds ratio for finding results favourable to industry in industry-sponsored trials was 3.6 times as high as in non–industry-sponsored studies”. Issues discussed regarding industry-sponsored studies include: comparison of a drug to a placebo, but not to an alternative treatment; unpublished studies with unfavourable outcomes; and trials organized around a placebo baseline followed by drug treatment, but not counterbalanced with parallel-placebo-controlled studies. Quoting a 1979 report that too little research into hypnotics was independent of the drug manufacturers, the authors conclude, “the public desperately needs an equipoised assessment of hypnotic benefits and risks” and the NIH and VA should provide leadership to that end.

Street Terms

Street terms for temazepam include king kong pills (formerly referred to barbiturates, now more commonly refers to temazepam), jellies, jelly, Edinburgh eccies, tams, terms, mazzies, temazies, tammies, temmies, beans, eggs, green eggs, wobbly eggs, knockouts, hardball, norries, oranges (common term in Australia and New Zealand), rugby balls, ruggers, terminators, red and blue, no-gos, num nums, blackout, green devils, drunk pills, brainwash, mind erasers, neurotrashers, tem-tem’s (combined with buprenorphine), mommy’s big helper, vitamin T, big T, TZ, The Mazepam, Resties (North America) and others.

Availability

Temazepam is available in English-speaking countries under the following brand names:

  • Euhypnos.
  • Normison.
  • Norkotral.
  • Nortem.
  • Remestan.
  • Restoril.
  • Temaze.
  • Temtabs.
  • Tenox.

In Spain, the drug is sold as ‘temzpem’. In Hungary the drug is sold as Signopam.

Legal Status

  • In Austria, temazepam is listed in UN71 Schedule III under the Psychotropic Substances Decree of 1997.
    • The drug is considered to have a high potential for abuse and addiction, but has accepted medical use for the treatment of severe insomnia.
  • In Australia, temazepam is a Schedule 4 – Prescription Only medicine.
    • It is primarily used for the treatment of insomnia, and is also seen as pre-anaesthetic medication.
  • In Canada, temazepam is a Schedule IV controlled substance requiring a registered doctor’s prescription.
  • In Denmark, temazepam is listed as a Class D substance under the Executive Order 698 of 1993 on Euphoric Substances which means it has a high potential for abuse, but is used for medical and scientific purposes.
  • In Finland, temazepam is more tightly controlled than other benzodiazepines.
    • The temazepam product Normison was pulled out of shelves and banned because the liquid inside gelatin capsules had caused a large increase in intravenous temazepam use.
    • The other temazepam product, Tenox, was not affected and remains as prescription medicine.
    • Temazepam intravenous use has not decreased to the level before Normison came to the market.
  • In France, temazepam is listed as a psychotropic substance as are other similar drugs.
    • It is prescribed with a non-renewable prescription (a new doctor visit every time), available only in 7 or 14-pill packaging for one or two weeks.
    • One brand was withdrawn from the market in 2013.
  • In Hong Kong, temazepam is regulated under Schedule 1 of Hong Kong’s Chapter 134 Dangerous Drugs Ordinance.
    • Temazepam can only be used legally by health professionals and for university research purposes.
    • The substance can be given by pharmacists under a prescription.
    • Anyone who supplies the substance without prescription can be fined HKD$10,000.
    • The penalty for trafficking or manufacturing the substance is a $5,000,000-fine and life imprisonment.
    • Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000-fine and/or seven years of jail time.
  • In Ireland, temazepam is a Schedule 3 controlled substance with strict restrictions.
  • In the Netherlands, temazepam is available for prescription as 10- or 20-mg tablets and capsules.
    • Formulations of temazepam containing less than 20 mg are included in List 2 of the Opium Law, while formulations containing 20 mg or more of the drug (along with the gel-capsules) are a List 1 substance of the Opium Law, thus subject to more stringent regulation.
    • Besides being used for insomnia, it is also occasionally used as a preanesthetic medication.
  • In Norway, temazepam is not available as a prescription drug.
    • It is regulated as a Class A substance under Norway’s Narcotics Act.
  • In Portugal, temazepam is a Schedule IV controlled drug under Decree-Law 15/93.
  • In Singapore, temazepam is a Class A controlled drug (Schedule I), making it illegal to possess and requiring a private prescription from a licensed physician to be dispensed.
  • In Slovenia, it is regulated as a Group II (Schedule 2) controlled substance under the Production and Trade in Illicit Drugs Act.
  • In South Africa, temazepam is a Schedule 5 drug, requiring a special prescription, and is restricted to 10- to 30-mg doses.
  • In Sweden, temazepam is classed as a “narcotic” drug listed as both a List II (Schedule II) which denotes it is a drug with limited medicinal use and a high risk of addiction, and is also listed as a List V (Schedule V) substance which denotes the drug is prohibited in Sweden under the Narcotics Drugs Act (1968).
    • Temazepam is banned in Sweden and possession and distribution of even small amounts is punishable by a prison sentence and a fine.
  • In Switzerland, temazepam is a Class B controlled substance, like all other benzodiazepines.
    • This means it is a prescription-only drug.
  • In Thailand, temazepam is a Schedule II controlled drug under the Psychotropic Substances Act.
    • Possession and distribution of the drug is illegal.
  • In the United Kingdom, temazepam is a Class C controlled drug under the Misuse of Drugs Act 1971 (Schedule 3 under the Misuse of Drugs Regulations 2001).
    • If prescribed privately (not on the NHS), temazepam is available only by a special controlled drug prescription form (FP10PCD) and pharmacies are obligated to follow special procedures for storage and dispensing.
    • Additionally, all manufacturers in the UK have replaced the gel-capsules with solid tablets.
    • Temazepam requires safe custody and up until June 2015 was exempt from CD prescription requirements.
  • In the United States, Temazepam is currently a Schedule IV drug under the international Convention on Psychotropic Substances of 1971 and is only available by prescription.
    • Specially coded prescriptions may be required in certain states.

What is Tranylcypromine?

Introduction

Tranylcypromine (sold under the trade name Parnate among others) is a monoamine oxidase inhibitor (MAOI); more specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO).

It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.

Tranylcypromine is a propylamine formed from the cyclisation of amphetamine’s side chain; therefore, it is classified as a substituted amphetamine.

Brief History

Tranylcypromine was originally developed as an analogue of amphetamine. Although it was first synthesized in 1948, its MAOI action was not discovered until 1959. Precisely because tranylcypromine was not, like isoniazid and iproniazid, a hydrazine derivative, its clinical interest increased enormously, as it was thought it might have a more acceptable therapeutic index than previous MAOIs.

The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961. It was withdrawn from the market in February 1964 due to a number of patient deaths involving hypertensive crises with intracranial bleeding. However, it was reintroduced later that year with more limited indications and specific warnings of the risks.

Medical Uses

Tranylcypromine is used to treat major depressive disorder, including atypical depression, especially when there is an anxiety component, typically as a second-line treatment. It is also used in depression that is not responsive to reuptake inhibitor antidepressants, such as the SSRIs, TCAs, or bupropion.

Contraindications

Contraindications include:

  • Porphyria.
  • Cardiovascular or cerebrovascular disease.
  • Pheochromocytoma.
  • Tyramine, found in several foods, is metabolized by MAO. Ingestion and absorption of tyramine causes extensive release of norepinephrine, which can rapidly increase blood pressure to the point of causing hypertensive crisis.
  • Concomitant use of serotonin-enhancing drugs, including SSRIs, serotonergic TCAs, dextromethorphan, and meperidine may cause serotonin syndrome.
  • Concomitant use of MRAs, including fenfluramine, amphetamine, and pseudoephedrine may cause toxicity via serotonin syndrome or hypertensive crisis.
  • L-DOPA given without carbidopa may cause hypertensive crisis.

Dietary Restrictions

Tyramine is a common component in many foods, and is normally rapidly metabolised by MAO-A. Individuals not taking MAOIs may consume at least 2 grams of tyramine in a meal and not experience an increase in blood pressure, whereas those taking MAOIs such as tranylcypromine may experience a sharp increase in blood pressure following consumption of as little as 10 mg of tyramine, which can lead to hypertensive crisis.

Foods containing tyramine include aged cheeses, cured meats, tofu and certain red wines. Some, such as yeast extracts, contain enough tyramine to be potentially fatal in a single serving. Spoiled food is also likely to contain dangerous levels of tyramine.

Adverse Effects

Incidence of Adverse Effects

  • Very common (>10% incidence) adverse effects include:
    • Dizziness secondary to orthostatic hypotension (17%).
  • Common (1-10% incidence) adverse effects include:
    • Tachycardia (5-10%).
    • Hypomania (7%).
    • Paresthesia (5%).
    • Weight loss (2%).
    • Confusion (2%).
    • Dry mouth (2%).
    • Sexual function disorders (2%).
    • Hypertension (1-2 hours after ingestion) (2%).
    • Rash (2%).
    • Urinary retention (2%).
  • Other (unknown incidence) adverse effects include:
    • Increased/decreased appetite.
    • Blood dyscrasias.
    • Chest pain.
    • Diarrhoea.
    • Oedema.
    • Hallucinations.
    • Hyperreflexia.
    • Insomnia.
    • Jaundice.
    • Leg cramps.
    • Myalgia.
    • Palpitations.
    • Sensation of cold.
    • Suicidal ideation.
    • Tremor.

Of note, there has not been found to be a correlation between sex and age below 65 regarding incidence of adverse effects.

Tranylcypromine is not associated with weight gain and has a low risk for hepatotoxicity compared to the hydrazine MAOIs.

It is generally recommended that MAOIs be discontinued prior to anaesthesia; however, this creates a risk of recurrent depression. In a retrospective observational cohort study, patients on tranylcypromine undergoing general anaesthesia had a lower incidence of intraoperative hypotension, while there was no difference between patients not taking an MAOI regarding intraoperative incidence of bradycardia, tachycardia, or hypertension. The use of indirect sympathomimetic drugs or drugs affecting serotonin reuptake, such as meperidine or dextromethorphan poses a risk for hypertension and serotonin syndrome respectively; alternative agents are recommended. Other studies have come to similar conclusions. Pharmacokinetic interactions with anaesthetics are unlikely, given that tranylcypromine is a high-affinity substrate for CYP2A6 and does not inhibit CYP enzymes at therapeutic concentrations.

Tranylcypromine abuse has been reported at doses ranging from 120-600 mg per day. It is thought that higher doses have more amphetamine-like effects and abuse is promoted by the fast onset and short half-life of tranylcypromine.

Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation.

Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.

Interactions

In addition to contraindicated concomitant medications, tranylcypromine inhibits CYP2A6, which may reduce the metabolism and increase the toxicity of substrates of this enzyme, such as:

  • Dexmedetomidine.
  • Nicotine.
  • TSNAs (found in cured tobacco products, including cigarettes).
  • Valproate.

Norepinephrine reuptake inhibitors prevent neuronal uptake of tyramine and may reduce its pressor effects.

Pharmacology

Pharmacodynamics

Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase. Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAOA. This leads to an increase in the availability of monoamines, such as serotonin, norepinephrine, and dopamine, as well as a marked increase in the availability of trace amines, such as tryptamine, octopamine, and phenethylamine. The clinical relevance of increased trace amine availability is unclear.

It may also act as a norepinephrine reuptake inhibitor at higher therapeutic doses. Compared to amphetamine, tranylcypromine shows low potency as a dopamine releasing agent, with even weaker potency for norepinephrine and serotonin release.

Tranylcypromine has also been shown to inhibit the histone demethylase, BHC110/LSD1. Tranylcypromine inhibits this enzyme with an IC50 < 2 μM, thus acting as a small molecule inhibitor of histone demethylation with an effect to de-repress the transcriptional activity of BHC110/LSD1 target genes. The clinical relevance of this effect is unknown.

Tranylcypromine has been found to inhibit CYP46A1 at nanomolar concentrations. The clinical relevance of this effect is unknown.

Pharmacokinetics

Tranylcypromine reaches its maximum concentration (tmax) within 1-2 hours. After a 20 mg dose, plasma concentrations reach at most 50-200 ng/mL. While its half-life is only about 2 hours, its pharmacodynamic effects last several days to weeks due to irreversible inhibition of MAO.

Metabolites of tranylcypromine include 4-hydroxytranylcypromine, N-acetyltranylcypromine, and N-acetyl-4-hydroxytranylcypromine, which are less potent MAO inhibitors than tranylcypromine itself. Amphetamine was once thought to be a metabolite of tranylcypromine, but has not been shown to be.

Tranylcypromine inhibits CYP2A6 at therapeutic concentrations.

Research

Tranylcypromine is known to inhibit LSD1, an enzyme that selectively demethylates two lysines found on histone H3. Genes promoted downstream of LSD1 are involved in cancer cell growth and metastasis, and several tumour cells express high levels of LSD1. Tranylcypromine analogues with more potent and selective LSD1 inhibitory activity are being researched in the potential treatment of cancers.

Tranylcypromine may have neuroprotective properties applicable to the treatment of Parkinson’s disease, similar to the MAO-B inhibitors selegiline and rasagiline. As of 2017, only one clinical trial in Parkinsonian patients has been conducted, which found some improvement initially and only slight worsening of symptoms after a 1.5 year follow-up.

On This Day … 27 July

People (Births)

  • 1906 – Herbert Jasper, Canadian psychologist and neurologist (d. 1999).

People (Deaths)

  • 1931 – Auguste Forel, Swiss neuroanatomist and psychiatrist (b. 1848).

Herbert Jasper

Herbert Henri Jasper OC GOQ FRSC (27 July 1906 to 11 March 1999) was a Canadian psychologist, physiologist, neurologist, and epileptologist.

Born in La Grande, Oregon, he attended Reed College in Portland, Oregon and received his PhD in psychology from the University of Iowa in 1931 and earned a Doctor of Science degree from the University of Paris for research in neurobiology.

From 1946 to 1964 he was Professor of Experimental Neurology at the Montreal Neurological Institute, McGill University and then from 1965 to 1976 he was Professor of Neurophysiology, Université de Montréal. He did his most important research with Wilder Penfield at McGill University. He was a member of the American Academy of Neurology and the American Association for the Advancement of Science. He was also a member of the Canadian Neurological Society and the Royal Society of Medicine. He wrote more than 350 scientific publications.

Auguste Forel

Auguste-Henri Forel (01 September 1848 to 27 July 1931) was a Swiss myrmecologist, neuroanatomist, psychiatrist and eugenicist, notable for his investigations into the structure of the human brain and that of ants. For example, he is considered a co-founder of the neuron theory. Forel is also known for his early contributions to sexology and psychology. From 1978 until 2000 Forel’s image appeared on the 1000 Swiss franc banknote.

Scientific Work

Forel’s prize essay on the ants of Switzerland was published in three parts in a Swiss scientific journal, beginning in 1874. The work was reissued as a single volume in 1900, at which time it was also translated into English. His myrmecological five-volume magnum opus, Le Monde Social des Fourmis, was published in 1923. In 1898, Forel was credited with discovering Trophallaxis among ants.

Forel’s predilection for finding in ants the analogues of human social and political behaviours was always controversial. In the foreword to his 1927 edition of British Ants: their life history and classification, Donisthorpe opined, “I should wish … to protest against the ants being employed as a supposed weapon in political controversy. In my opinion an entomological work is not the appropriate means for the introduction of political theories of any kind, still less for their glaring advertisement. But in 1937, the work was excerpted in Sir J.A. Hammerton’s Outline of Great Books with praise for its relevance to the study of human psychology and as “the most important contribution to insect psychology ever made by a single student.”

Forel realized from experiments that neurons were the basic elements of the nervous system. He found that the neuromuscular junction communicated by mere contact and did not require the anastomosis of fibres. This came to be called the Contact Theory of Forel. The word “neuron” was coined by Wilhelm von Waldeyer who published a review of the work of Forel and others in 1891. Waldeyer synthesized ideas without actually conducting any research himself and published it in Deutsche medizinische Wochenschrift a widely read journal which made him popular. Forel was very bitter about Waldeyer’s achievement of fame that it is thought to have contributed to the decline in his interest in neuroanatomy and neurology. Less controversially, Forel first described in 1877 the zona incerta area in the brain. He gave it this name as it a “region of which nothing certain can be said”.

Forel International School is named after him.

What is Trimipramine?

Introduction

Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression.

It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or “second-generation” TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.

Brief History

Trimipramine was developed by Rhône-Poulenc. It was patented in 1959 and first appeared in the literature in 1961. The drug was first introduced for medical use in 1966, in Europe. It was not introduced in the United States until later in 1979 or 1980.

Medical Uses

Trimipramine’s primary use in medicine is in the treatment of major depressive disorder, especially where sedation is helpful due to its prominent sedative effects. The drug is also an effective anxiolytic, and can be used in the treatment of anxiety. In addition to depression and anxiety, trimipramine is effective in the treatment of insomnia, and unlike most other hypnotics, does not alter the normal sleep architecture. In particular, it does not suppress REM sleep, and dreams are said to “brighten” during treatment. Trimipramine also has some weak antipsychotic effects with a profile of activity described as similar to that of clozapine, and may be useful in the treatment of psychotic symptoms such as in delusional depression or schizophrenia.

Contraindications

Contraindications include:

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

Side Effects

The side effects of trimipramine have been said to be similar to those of other tertiary amine TCAs, with a preponderance of anticholinergic and sedative effects. However, trimipramine has also been said to be associated with a different side effect profile compared to other TCAs and in general with fewer side effects, chiefly due to its lack of norepinephrine reuptake inhibition and relatively lower anticholinergic effects (although it is still a potent anticholinergic). Somnolence is the most common side effect of the drug. Dry mouth is the most common anticholinergic side effect, but others like constipation, urinary retention, and blurred vision are also present.

It is described as being associated with minimal or no orthostatic hypotension, at least in comparison to clomipramine, in spite of its potent and comparable activity as an alpha-1 blocker. However, it has also been said to have a rate of orthostatic hypotension similar to that of other TCAs. Trimipramine is said to be less epileptogenic than other TCAs, although seizures have still been reported in association with it. It is also less cardiotoxic than other TCAs and cardiotoxicity is said to be minimal, with a “very favourable profile”.

List of Side Effects

Common adverse effects include:

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

Adverse effects with an unknown incidence includes:

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

Rare adverse effects include:

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

Overdose

Refer to Tricyclic Antidepressant Overdose.

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

Interactions

Trimipramine should not be given with sympathomimetic agents such as epinephrine (adrenaline), ephedrine, isoprenaline, norepinephrine (noradrenaline), phenylephrine and phenylpropanolamine.

Barbiturates may increase the rate of metabolism. Trimipramine should be administered with care in patients receiving therapy for hyperthyrodism.

Genotoxicity

Heavy exposure to any tricyclic antidepressants was associated with an elevated rate ratio for breast cancer 11–15 years later. However, on tests done on Drosophila melanogaster, nongenotoxic TCAs (amitriptyline, maprotiline, nortriptyline, and protriptyline), and genotoxic TCAs (amoxapine, clomipramine, desipramine, doxepin, imipramine, and trimipramine) were identified.

Pharmacology

Pharmacodynamics

The mechanism of action of trimipramine in terms of its antidepressant effects differs from that of other TCAs and is not fully clear. The mechanism of action of its anxiolytic effects is similarly unclear. Trimipramine is a very weak reuptake inhibitor of serotonin, norepinephrine, and dopamine (see below), and unlike most other TCAs, has been claimed to be devoid of clinically significant monoamine reuptake inhibition. The effects of the drug are thought to be mainly due to receptor antagonism as follows:

  • Very strong: H1.
  • Strong: 5-HT2A, α1-adrenergic.
  • Moderate: D2, mACh.
  • Weak: 5-HT2C, D1, α2-adrenergic.

In spite of its atypical nature and different profile of activity, trimipramine has been shown in head-to-head clinical studies to possess equivalent effectiveness to other antidepressants, including but not limited to other TCAs (e.g. amitriptyline, imipramine, doxepin, amineptine), tetracyclic antidepressants (TeCAs) (e.g. maprotiline), monoamine oxidase inhibitors (MAOIs) (e.g. phenelzine, isocarboxazid), and selective serotonin reuptake inhibitors (e.g. fluoxetine). In addition, trimipramine has been found to possess greater anxiolytic effects than other TCAs such as amitriptyline and doxepin in head-to-head comparisons. Indeed, its prominent anxiolytic effects have been said to distinguish it from most other TCAs. The atypicality of trimipramine in relation to its lack of monoamine reuptake inhibition is described as challenging the monoamine hypothesis of depression.

The major metabolite of trimipramine, desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants.

Monoamine Reuptake Inhibition

Studies have generally found only very weak inhibition of serotonin and norepinephrine reuptake with trimipramine, and the drug has been described by various authors as devoid of monoamine reuptake inhibition. Richelson & Pfenning (1984) found a relatively high Ki for the NET of 510 nM in rat brain synaptosomes and Tatsumi et al. (1997) found a relatively high KD of 149 nM for the SERT in human HEK293 cells, but other authors and a more recent study with an improved design have not had the same findings. In the most recent study, by Haenisch et al. (2011), the researchers suggested that the discrepant findings from the Tatsumi et al. study were due to methodological differences, in particular the use of radioligand binding in isolated membranes (KD) to study interactions as opposed to actual functional reuptake inhibition (IC50).

Trimipramine is extensively metabolized, so its metabolites may contribute to its pharmacology, including potentially to monoamine reuptake inhibition. In what was the only study to date to have assessed the activity profiles of the metabolites of trimipramine, Haenisch et al. (2011) assayed desmethyltrimipramine, 2-hydroxytrimipramine, and trimipramine-N-oxide in addition to trimipramine and found that these metabolites showed IC50 values for the SERT, NET, and DAT similar to those of trimipramine (see table to the right). Like other secondary amine TCAs, desmethyltrimipramine was slightly more potent than trimipramine in its norepinephrine reuptake inhibition but less potent in its inhibition of serotonin reuptake. However, desmethyltrimipramine still showed only very weak inhibition of the NET.

Therapeutic concentrations of trimipramine are between 0.5 and 1.2 μM (150-350 ng/mL) and hence significant monoamine reuptake inhibition would not be expected with it or its metabolites. However, these concentrations are nearly 2-fold higher if the active metabolites of trimipramine are also considered, and studies of other TCAs have found that they cross the blood-brain barrier and accumulate in the brain to levels of up to 10-fold those in the periphery. As such, trimipramine and its metabolites might at least partially inhibit reuptake of serotonin and/or norepinephrine, though not of dopamine, at therapeutic concentrations, and this could be hypothesized to contribute at least in part to its antidepressant effects. This is relevant as Haenisch et al. has stated that these are the only actions known at present which could explain or at least contribute to the antidepressant effects of trimipramine. That said, blockade of the 5-HT2A, 5-HT2C, and α2-adrenergic receptors, as with mirtazapine, has also been implicated in antidepressant effects.

In any case, there is also clinical and animal evidence that trimipramine does not inhibit the reuptake of monoamines. Unlike other TCAs, it does not downregulate β3-adrenergic receptors, which is likely the reason that it does not cause orthostatic hypotension. It can be safely combined with MAOIs apparently without risk of serotonin syndrome or hypertensive crisis. Indeed, in rabbits, whereas hyperpyrexia (a symptom of serotonin syndrome) occurs with imipramine and an MAOI and to a lesser extent with amitriptyline and an MAOI, it does not occur at all with trimipramine and an MAOI, likely due to trimipramine’s lack of serotonin reuptake inhibition.

Antihistamine Activity

Trimipramine is a very potent antihistamine; it has the third highest affinity for the H1 receptor (Ki = 0.27 nM) after mirtazapine (Ki = 0.14 nM) and doxepin (Ki = 0.24 nM) among the TCAs and tetracyclic antidepressants (TeCAs). The TeCA mianserin (Ki = 0.40) and the TCA amitriptyline (Ki = 1.0) are also very potent H1 receptor antagonists, whereas other TCAs and TeCAs are less potent. These TCAs and TeCAs, including trimipramine, are far more potent than the standard antihistamine diphenhydramine (approximately 800 times for doxepin and 250 times for trimipramine), and are among the most potent antihistamines available.

Trimipramine is also an antagonist of the H2 receptor with lower potency and has been found to be effective in the treatment of duodenal ulcers.

As a Hypnotic

Blockade of the H1 receptor is responsible for the sedative effects of trimipramine and other TCAs and their effectiveness in the treatment of insomnia.

Most antidepressants suppress REM sleep, in parallel with their alleviation of depressive symptoms (although suppression of REM sleep is not required for antidepressant effects). This includes TCAs (e.g. amitriptyline, nortriptyline), TeCAs (e.g. mianserin, maprotiline), MAOIs (e.g. clorgiline, pargyline), and SSRIs (e.g. fluoxetine, zimelidine, indalpine). Trimipramine is unique in that it is an exception and produces antidepressant effects without compromising or otherwise affecting REM sleep. Even long-term treatment with trimipramine for up to 2 years has not been found to suppress REM sleep. In addition, trimipramine has been found to decrease nocturnal cortisol levels to normal and to normalize cortisol response in depressed patients; hence, it normalizes the hypothalamic-pituitary-adrenal axis, whereas imipramine and other antidepressants tend to increase nocturnal cortisol secretion.

In clinical studies, trimipramine has been found in doses of 50 to 200 mg/day to significantly increase sleep efficiency and total sleep time and to decrease waking time for up to 3 weeks in patients with insomnia. It also improved subjectively perceived sleep quality and well-being during daytime. Monitoring of patients upon discontinuation of trimipramine found that it did not cause rebound insomnia or worsening of sleep quality in subjective evaluations of sleep, although objective measurements found total sleep time below baseline in a subset of patients during trimipramine withdrawal.

Antidopaminergic Activity

Trimipramine is a weak but significant antagonist of the dopamine D1 and D2 receptors, and also binds to the D4 receptor (Ki = 275 nM). Its affinities for various monoamine receptors including the D2 and 5-HT2A receptors closely resemble those of the atypical antipsychotic clozapine. In accordance, high doses of trimipramine have been found to have antipsychotic effects in schizophrenic patients, notably without causing extrapyramidal symptoms, and trimipramine has recently been found to be effective in reducing psychotic symptoms in patients with delusional depression. The lack of extrapyramidal symptoms with trimipramine may be related to its affinity for the D4 receptor, these both being properties it shares with clozapine. Unlike other TCAs, but reminiscent of antipsychotics, trimipramine has been found to markedly increase plasma prolactin levels (a marker of D2 receptor antagonism) at a dose of 75 mg/day and to increase nocturnal prolactin secretion at doses of 75 and 200 mg/day. These findings are suggestive of important antidopaminergic actions of trimipramine.

Unlike various other TCAs, trimipramine shows marked antagonism of presynaptic dopamine autoreceptors, potentially resulting in increased dopaminergic neurotransmission. This effect has also been observed with low-potency tricyclic antipsychotics like thioridazine and chlorprothixene. Notably, these two antipsychotics have been claimed many times to also possess antidepressant effects. As such, blockade of inhibitory dopamine autoreceptors and hence facilitation of dopaminergic signalling could be involved in the antidepressant effects of trimipramine. However, other authors have attributed the claimed antidepressant effects of antipsychotics like the two previously mentioned to α2-adrenergic receptor antagonism, although trimipramine specifically has only weak affinity for this receptor. Aside from antidepressant effects, low doses of antipsychotics have been found to increase REM sleep, and so dopamine autoreceptor antagonism could be involved in the unique effects of trimipramine in terms of REM sleep and sleep architecture.

Pharmacokinetics

The time to peak concentrations following a dose is 2 to 4 hours. The typical antidepressant therapeutic range of trimipramine concentrations is 150 to 300 ng/mL. The terminal half-life of trimipramine has been variously reported to be as little as 8 hours (in plasma) and as long as 24 hours. In any case, the terminal half-life of trimipramine is described as shorter than that of other TCAs, which makes it ideal for use in the treatment of insomnia.

Trimipramine is a racemic compound with two enantiomers. CYP2C19 is responsible for the demethylation of (D)- and (L)-trimipramine to (D)- (L)-desmethyltrimipramine, respectively, and CYP2D6 is responsible for the 2-hydroxylation of (D)- and (L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively. CYP2D6 also metabolises (L)-trimipramine into (L)-2-hydroxytrimipramine.

Chemistry

Trimipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include imipramine, desipramine, and clomipramine. Trimipramine is a derivative of imipramine with a methyl group added to its side chain and is also known as 2′-methylimipramine or β-methylimipramine. The tri- prefix in its name may allude to the fact that its side chain features three methyl groups. Trimipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desmethyltrimipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), and doxepin. The chemical name of trimipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine and its free base form has a chemical formula of C20H26N2 with a molecular weight of 294.434 g/mol. The drug is used commercially as the maleate salt. The CAS Registry Number of the free base is 739-71-9 and of the maleate is 521-78-8.

Society and Culture

Generic Names

Trimipramine is the generic name of the drug and its INN, USAN, BAN, and DCF, while trimipramine maleate is its USAN, USP, BANM, and JAN. Its generic name in Latin is trimipraminum, in German is trimipramin, and in Spanish is trimipramina.

Brand Names

Trimipramine is marketed throughout the world mainly under the brand name Surmontil. Other notable brand names of trimipramine have included Herphonal, Rhotrimine, Sapilent, Stangyl, and Tydamine.

Availability

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

What are the Adverse Effects of Venlafaxine?

Introduction

The following list shows the rates of adverse symptoms seen in people taking venlafaxine.

Very Common (>>10% Incidence)

  • Headache:
    • An often transient side effect that is common to most serotonin reuptake inhibitors and that most often occurs at the beginning of therapy or after a dose escalation.
  • Nausea:
    • An adverse effect that is more common with venlafaxine than with the SSRIs.
    • Usually transient and less severe in those receiving the extended release formulations.
  • Insomnia.
  • Asthenia (weakness).
  • Dizziness.
  • Ejaculation disorder:
    • Sexual side effects can be seen with virtually any antidepressant, especially those that inhibit the reuptake of serotonin (including venlafaxine).
  • Somnolence.
  • Dry mouth.
  • Sweating.
  • Withdrawal.

Common (1-10% incidence)

  • Constipation.
  • Nervousness.
  • Abnormal vision.
  • Anorgasmia.
  • Hypertension.
  • Impotence.
  • Paraesthesia.
  • Tremor.
  • Vasodilation.
  • Vomiting.
  • Weight loss.
  • Chills.
  • Palpitations.
  • Confusion.
  • Depersonalisation.
  • Night sweats.
  • Menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g. menorrhagia, metrorrhagia).
  • Urinary frequency increased.
  • Abnormal dreams.
  • Decreased libido.
  • Increased muscle tonus.
  • Yawning.
  • Sweating.
  • Abnormality of accommodation.
  • Abnormal ejaculation/orgasm (males).
  • Urinary hesitancy.
  • Serum cholesterol increased (especially when treatment is prolonged and it may be dose-dependent).

Uncommon (0.1-1% incidence)

  • Face oedema.
  • Intentional injury (self-injury).
  • Malaise.
  • Moniliasis.
  • Neck rigidity.
  • Pelvic pain.
  • Photosensitivity reaction.
  • Suicide attempt.
  • Withdrawal syndrome (Antidepressant Discontinuation Syndrome).
  • Hypotension.
  • Postural hypotension.
  • Syncope.
  • Tachycardia.
  • Bruxism.
  • Ecchymosis.
  • Mucous membrane bleeding.
  • Gastrointestinal bleeding.
  • Abnormal liver function tests.
  • Hyponatraemia.
  • Weight gain.
  • Apathy.
  • Hallucinations.
  • Myoclonus.
  • Rash.
  • Abnormal orgasm (females).
  • Urinary retention (the inability to pass urine).
  • Angioedema.
  • Agitation.
  • Impaired coordination & balance.
  • Alopecia (hair loss).
  • Tinnitus (hearing bells).
  • Proteinuria (protein in urine).

Rare (0.01-0.1% incidence)

  • Syndrome of inappropriate antidiuretic hormone secretion (SIADH).
  • Thrombocytopenia.
  • Prolonged bleeding time.
  • Seizures.
  • Mania.
  • Neuroleptic malignant syndrome (NMS).
  • Serotonin syndrome.
  • Akathisia/psychomotor restlessness.
  • Urinary incontinence.

Very Rare (<0.01% incidence)

  • Anaphylaxis.
  • QT prolongation.
  • Ventricular fibrillation.
  • Ventricular tachycardia (including torsades de pointes).
  • Pancreatitis.
  • Blood dyscrasias (including agranulocytosis, aplastic anaemia, neutropenia and pancytopenia).
  • Elevated serum prolactin.
  • Delirium.
  • Extrapyramidal reactions (including dystonia and dyskinesia).
  • Tardive dyskinesia.
  • Pulmonary eosinophilia.
  • Erythema multiforme.
  • Stevens-Johnson syndrome.
  • Pruritus.
  • Urticaria.
  • Toxic epidermal necrolysis.
  • Angle closure glaucoma.

What is Valproate?

Introduction

Valproate and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalised seizures. They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.

Common side effects of valproate include nausea, vomiting, sleepiness, and dry mouth. Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended. Other serious risks include pancreatitis and an increased suicide risk. Valproate is known to cause serious abnormalities in babies if taken during pregnancy, and as such it is not typically recommended for women of childbearing age who have migraines.

Valproate’s precise mechanism of action is unclear. Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases. Valproic acid is a branched short-chain fatty acid (SCFA) made from valeric acid.

Valproate was first made in 1881 and came into medical use in 1962. It is on the World Health Organisation’s (WHO’s) List of Essential Medicines and is available as a generic medication. It is marketed under the brand names Depakote, among others. In 2018, it was the 131st most commonly prescribed medication in the United States, with more than 5 million prescriptions.

Brief History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian. Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a “metabolically inert” solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for anti-seizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine prophylaxis and bipolar disorder.

Terminology

Valproic acid (VPA) is an organic weak acid. The conjugate base is valproate. The sodium salt of the acid is sodium valproate and a coordination complex of the two is known as valproate semisodium.

Medical Uses

It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.

Epilepsy

Valproate has a broad spectrum of anticonvulsant activity, although it is primarily used as a first-line treatment for tonic-clonic seizures, absence seizures and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms. It has also been successfully given intravenously to treat status epilepticus.

Mental Illness

Bipolar Disorder

Valproate products are also used to treat manic or mixed episodes of bipolar disorder.

Schizophrenia

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia.

There is limited evidence that adding valproate to antipsychotics may be effective for overall response and also for specific symptoms, especially in terms of excitement and aggression. Valproate was associated with a number of adverse events among which sedation and dizziness appeared more frequently than in the control groups.

Dopamine Dysregulation Syndrome

Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the dopamine dysregulation syndrome that arise from the treatment of Parkinson’s disease with levodopa.

Migraines

Valproate is also used to prevent migraine headaches. Because this medication can be potentially harmful to the fetus, valproate should be considered for those able to become pregnant only after the risks have been discussed.

Other

The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects.

Adverse Effects

Most common adverse effects include:

  • Nausea (22%).
  • Drowsiness (19%).
  • Dizziness (12%).
  • Vomiting (12%).
  • Weakness (10%).

Serious adverse effects include:

  • Bleeding.
  • Low blood platelets.
  • Encephalopathy.
  • Suicidal behaviour and thoughts.
  • Low body temperature.

Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and foetal abnormalities.

There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height. Valproic acid can also cause mydriasis, a dilation of the pupils. There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome (PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder. Weight gain is also possible.

Pregnancy

Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug. More rarely, with several other defects, including a “valproate syndrome”. Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth. While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.

Children of mothers taking valproate during pregnancy are at risk for lower IQs. Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%. A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%. The normal incidence for autism in the general population is estimated at less than one percent. A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.

Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or foetal exposure. This condition resolved after discontinuing valproate therapy.

Women who intend to become pregnant should switch to a different medication if possible, or decrease their dose of valproate. Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have worse outcomes for the foetus than exposure to valproate). Studies have shown that taking folic acid supplements can reduce the risk of congenital neural tube defects. The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the European Union, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.

Elderly

Valproate in elderly people with dementia caused increased sleepiness. More people stopped the medication for this reason. Additional side effects of weight loss and decreased food intake was also associated in one half of people who become sleepy.

Contraindications

Contraindications include:

  • Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.
  • Known hypersensitivity to valproate or any of the ingredients used in the preparation.
  • Urea cycle disorders.
  • Hepatic porphyria.
  • Hepatotoxicity.
  • Mitochondrial disease.
  • Pancreatitis.
  • Porphyria.

Interactions

Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves. It may also potentiate the CNS depressant effects of alcohol. It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including carbamazepine, lamotrigine, phenytoin and phenobarbitone) and itself. It may also interact with:

  • Aspirin: may increase valproate concentrations. May also interfere with valproate’s metabolism.
  • Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions.
  • Carbapenem antibiotics: reduces valproate levels, potentially leading to seizures.
  • Cimetidine: inhibits valproate’s metabolism in the liver, leading to increased valproate concentrations.
  • Erythromycin: inhibits valproate’s metabolism in the liver, leading to increased valproate concentrations.
  • Ethosuximide: may increase ethosuximide concentrations and lead to toxicity.
  • Felbamate: may increase plasma concentrations of valproate.
  • Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine.
  • Oral contraceptives: may reduce plasma concentrations of valproate.
  • Primidone: may accelerate metabolism of valproate, leading to a decline of serum levels and potential breakthrough seizure.
  • Rifampin: increases the clearance of valproate, leading to decreased valproate concentrations
  • Warfarin: may increase warfarin concentration and prolong bleeding time.
  • Zidovudine: may increase zidovudine serum concentration and lead to toxicity.

Overdose and Toxicity

Excessive amounts of valproic acid can result in sleepiness, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. In general, serum or plasma valproic acid concentrations are in a range of 20-100 mg/l during controlled therapy, but may reach 150-1500 mg/l following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography. In contrast to other antiepileptic drugs, at present there is little favourable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, partly due to valproate’s weak acid property (pKa of 4.9).

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body. Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored. Supplemental L-carnitine is indicated in patients having an acute overdose and also prophylactically in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly than L-carnitine.

Pharmacology

Pharmacodynamics

Although the mechanism of action of valproate is not fully understood, traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA). The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate. In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.

Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism. Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.

It also has histone-deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.

Endocrine Actions

Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a nonsteroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels. In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses oestrogen concentrations. These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.

Valproic acid has been found to directly stimulate androgen biosynthesis in the gonads via inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased 4-androstenedione levels in men. High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.

Metabolism

The vast majority of valproate metabolism occurs in the liver. In adult patients taking valproate alone, 30-50% of an administered dose is excreted in urine as a glucuronide conjugate. The other major pathway in the metabolism of valproate is mitochondrial beta-oxidation, which typically accounts for over 40% of an administered dose. Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose of valproate is excreted unchanged (i.e. as valproate) in urine.

Valproate is known to be metabolized by the Cytochrome P450 enzymes: CYP2A6, CYP2B6, CYP2C9, and CYP3A5. It is also known to be metabolised by the UDP-glucuronosyltransferase enzymes: UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.[70] Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include: 2-ene-valproic acid, 3Z-ene-valproic acid, 3E-ene-valproic acid, 4-ene-valproic acid, valproic acid β-O-glucuronide, 3-oxovalproic acid, 3-hydroxyvalproic acid, 4-hydroxyvalproic acid, 5-hydroxyvalproic acid, and valproyl-CoA, among others.

Chemistry

Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid.

Society and Culture

Valproate is available as a generic medication.

Off-Label Uses

In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.

Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.

Formulations

Valproate exists in two main molecular variants: sodium valproate and valproic acid without sodium (often implied by simply valproate). A mixture between these two is termed semisodium valproate. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more mass of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself.

Brand Names of Valproic Acid

Branded products include:

  • Absenor (Orion Corporation Finland).
  • Convulex (G.L. Pharma GmbH Austria).
  • Depakene (Abbott Laboratories in US and Canada).
  • Depakine (Sanofi Aventis France).
  • Depakine (Sanofi Synthelabo Romania).
  • Depalept (Sanofi Aventis Israel).
  • Deprakine (Sanofi Aventis Finland).
  • Encorate (Sun Pharmaceuticals India).
  • Epival (Abbott Laboratories US and Canada).
  • Epilim (Sanofi Synthelabo Australia and South Africa).
  • Stavzor (Noven Pharmaceuticals Inc.).
  • Valcote (Abbott Laboratories Argentina).
  • Valpakine (Sanofi Aventis Brazil).
  • Orfiril (Desitin Arzneimittel GmbH Norway).

Brand names of sodium valproate

  • Portugal:
    • Tablets – Diplexil-R by Bial.
  • United States:
    • Intravenous injection – Depacon by Abbott Laboratories.
    • Syrup – Depakene by Abbott Laboratories. (Note Depakene capsules are valproic acid).
    • Depakote tablets are a mixture of sodium valproate and valproic acid.
    • Tablets – Eliaxim by Bial.
  • Australia:
    • Epilim Crushable Tablets Sanofi.
    • Epilim Sugar Free Liquid Sanofi.
    • Epilim Syrup Sanofi.
    • Epilim Tablets Sanofi.
    • Sodium Valproate Sandoz Tablets Sanofi.
    • Valpro Tablets Alphapharm.
    • Valproate Winthrop Tablets Sanofi.
    • Valprease tablets Sigma.
  • New Zealand:
    • Epilim by Sanofi-Aventis.
  • UK:
    • Depakote Tablets (as in USA).
    • Tablets – Orlept by Wockhardt and Epilim by Sanofi.
    • Oral solution – Orlept Sugar Free by Wockhardt and Epilim by Sanofi.
    • Syrup – Epilim by Sanofi-Aventis.
    • Intravenous injection – Epilim Intravenous by Sanofi.
    • Extended release tablets – Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio.
    • Enteric-coated tablets – Epilim EC200 by Sanofi is a 200-mg sodium valproate enteric-coated tablet.
  • UK Only:
    • Capsules – Episenta prolonged release by Beacon.
    • Sachets – Episenta prolonged release by Beacon.
    • Intravenous solution for injection – Episenta solution for injection by Beacon.
  • Germany, Switzerland, Norway, Finland, Sweden:
    • Tablets – Orfiril by Desitin Pharmaceuticals.
    • Intravenous injection – Orfiril IV by Desitin Pharmaceuticals.
  • South Africa:
    • Syrup – Convulex by Byk Madaus.
    • Tablets – Epilim by Sanofi-synthelabo.
  • Malaysia:
    • Tablets – Epilim by Sanofi-Aventis..
  • Romania:
    • Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH.
    • Types are Syrup, Extended release mini tablets, Gastric resistant coated tablets, Gastric resistant soft capsules, Extended release capsules, Extended release tablets and Extended release coated tablets.
  • Canada:
    • Intravenous injection – Epival or Epiject by Abbott Laboratories.
    • Syrup – Depakene by Abbott Laboratories its generic formulations include Apo-Valproic and ratio-Valproic.
  • Japan:
    • Tablets – Depakene by Kyowa Hakko Kirin.
    • Extended release tablets – Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa.
    • Syrup – Depakene by Kyowa Hakko Kogyo.
  • Europe:
    • In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.
  • Taiwan:
    • Tablets (white round tablet) – Depakine (Chinese: 帝拔癲; pinyin: di-ba-dian) by Sanofi Winthrop Industrie (France)>
  • Iran:
    • Tablets – Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo.
    • Slow release tablets – Depakine Chrono by Sanofi Winthrop Industrie (France).
  • Israel:
    • Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by Sanofi-Aventis.
  • India, Russia and CIS countries:
    • Valparin Chrono by Torrent Pharmaceuticals India.
    • Valprol CR by Intas Pharmaceutical (India).
    • Encorate Chrono by Sun Pharmaceutical (India).
    • Serven Chrono by Leeven APL Biotech (India).

Brand Names of Valproate Semisodium

  • Brazil – Depakote by Abbott Laboratories and Torval CR by Torrent do Brasil.
  • Canada – Epival by Abbott Laboratories.
  • Mexico – Epival and Epival ER (extended release) by Abbott Laboratories.
  • United Kingdom – Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventis and generics.
  • United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics.
  • India – Valance and Valance OD by Abbott Healthcare Pvt Ltd, Divalid ER by Linux laboratories Pvt Ltd, Valex ER by Sigmund Promedica, Dicorate by Sun Pharma.
  • Germany – Ergenyl Chrono by Sanofi-Aventis and generics.
  • Chile – Valcote and Valcote ER by Abbott Laboratories.
  • France and other European countries — Depakote.
  • Peru – Divalprax by AC Farma Laboratories.
  • China – Diprate OD.

On This Day … 26 July

People (Births)

Carl Jung

Carl Gustav Jung, born Karl Gustav Jung (26 July 1875 to 06 June 1961), was a Swiss psychiatrist and psychoanalyst who founded analytical psychology. Jung’s work has been influential in the fields of psychiatry, anthropology, archaeology, literature, philosophy, psychology and religious studies. Jung worked as a research scientist at the famous Burghölzli hospital, under Eugen Bleuler. During this time, he came to the attention of Sigmund Freud, the founder of psychoanalysis. The two men conducted a lengthy correspondence and collaborated, for a while, on a joint vision of human psychology.

Freud saw the younger Jung as the heir he had been seeking to take forward his “new science” of psychoanalysis and to this end secured his appointment as President of his newly founded International Psychoanalytical Association. Jung’s research and personal vision, however, made it impossible for him to follow his older colleague’s doctrine and a schism became inevitable. This division was personally painful for Jung and resulted in the establishment of Jung’s analytical psychology as a comprehensive system separate from psychoanalysis.

Among the central concepts of analytical psychology is individuation – the lifelong psychological process of differentiation of the self out of each individual’s conscious and unconscious elements. Jung considered it to be the main task of human development. He created some of the best known psychological concepts, including synchronicity, archetypal phenomena, the collective unconscious, the psychological complex and extraversion and introversion.

Jung was also an artist, craftsman, builder and a prolific writer. Many of his works were not published until after his death and some are still awaiting publication.

Glynis Breakwell

Dame Glynis Marie Breakwell DBE DL FRSA FAcSS (born West Bromwich, 26 July 1952) is the former Vice-Chancellor of the University of Bath in Bath. She is a social psychologist and an active public policy adviser and researcher specialising in leadership, identity process and risk management. In January 2014 she was listed in the Science Council’s list of ‘100 leading UK practising scientists’.

Breakwell has been a Fellow of the British Psychological Society since 1987 and an Honorary Fellow since 2006. She is a chartered health psychologist and in 2002 was elected an Academician of the Academy of Social Sciences.

Breakwell was appointed Dame Commander of the Order of the British Empire in the 2012 New Year Honours for services to higher education. She is also a Deputy Lieutenant of the County of Somerset.

On This Day … 24 July

People (Deaths)

  • 2007 – Albert Ellis, American psychologist and author (b. 1913).
  • 2013 – Virginia E. Johnson, American psychologist and sexologist (b. 1925).

Albert Ellis

Albert Ellis (27 September 1913 to 24 July 2007) was an American psychologist and psychotherapist who founded Rational Emotive Behaviour Therapy (REBT). He held MA and PhD degrees in clinical psychology from Columbia University, and was certified by the American Board of Professional Psychology (ABPP). He also founded, and was the President of, the New York City-based Albert Ellis Institute. He is generally considered to be one of the originators of the cognitive revolutionary paradigm shift in psychotherapy and an early proponent and developer of cognitive-behavioural therapies.

Based on a 1982 professional survey of US and Canadian psychologists, he was considered the second most influential psychotherapist in history (Carl Rogers ranked first in the survey; Sigmund Freud was ranked third). Psychology Today noted that, “No individual—not even Freud himself—has had a greater impact on modern psychotherapy.”

Virginia E. Johnson

Virginia E. Johnson, born Mary Virginia Eshelman (11 February 1925 to 24 July 2013), was an American sexologist, best known as a member of the Masters and Johnson sexuality research team. Along with her partner, William H. Masters, she pioneered research into the nature of human sexual response and the diagnosis and treatment of sexual dysfunctions and disorders from 1957 until the 1990s.

On This Day … 23 July

People (Births)

  • 1933 – Benedict Groeschel, American priest, psychologist, and talk show host (d. 2014).

Benedict Groeschel

Benedict Joseph Groeschel, C.F.R. (23 July 1933 to 03 October 2014) was an American Franciscan friar, Catholic priest, retreat master, author, psychologist, activist, and television host. He hosted the television talk programme Sunday Night Prime (originally Sunday Night Live) broadcast on the Eternal Word Television Network, as well as several serial religious specials.

He founded the Office for Spiritual Development for the Roman Catholic Archdiocese of New York. He was Associate Director of the Trinity Retreat House for clergy and executive director of St. Francis House. He was professor of pastoral psychology at St. Joseph’s Seminary in New York and an adjunct professor at the Institute for Psychological Sciences in Arlington, Virginia. He was one of the founders of the Franciscan Friars of the Renewal and among his close friends were Mother Teresa, Mother Angelica and Alice von Hildebrand.