Author: Andrew Marshall

Founder & Editor of the BootCampMilitaryFitnessInstitute.com, MilitaryGogglebox.com, and Mental-Health-Matters.org.

What is a Paradoxical Reaction?

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Introduction

A paradoxical reaction or paradoxical effect is an effect of a chemical substance, typically a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.

Paradoxical reactions are more commonly observed in people with attention deficit hyperactivity disorder (ADHD).

Substances

Amphetamines

Amphetamines are a class of psychoactive drugs that are stimulants. Paradoxical drowsiness can sometimes occur in adults.

Antibiotics

The paradoxical effect or Eagle effect (named after H. Eagle who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an antimicrobial agent. Initially when an antibiotic agent is added to a culture media, the number of bacteria that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases.

Antidepressants

In rare cases antidepressants can make users obsessively violent or have suicidal compulsions, which is in marked contrast to their intended effect. This can be regarded as a paradoxical reaction but, especially in the case of suicide, may in at least some cases be merely due to differing rates of effect with respect to different symptoms of depression: If generalised overinhibition of a patient’s actions enters remission before that patient’s dysphoria does and if the patient was already suicidal but too depressed to act on their inclinations, the patient may find themselves in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so. Children and adolescents are more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking antidepressants but cases are still very rare.

Antipsychotics

Chlorpromazine, an antipsychotic and antiemetic drug, which is classed as a “major” tranquilizer may cause paradoxical effects such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states.

Barbiturates

Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days. Prerequisity for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital.

Benzodiazepines

Benzodiazepines, a class of psychoactive drugs called the “minor” tranquilisers, have varying hypnotic, sedative, anxiolytic, anticonvulsant, and muscle relaxing properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase in anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behaviour, and even convulsions. Paradoxical adverse effects may even lead to criminal behaviour. Severe behavioural changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania.

Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generates automatic behaviours, anterograde amnesia and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting serotonergic mechanism.

Paradoxical effects of benzodiazepines appear to be dose related, that is, likelier to occur with higher doses.

In a letter to the British Medical Journal, it was reported that a high proportion of parents referred for actual or threatened child abuse were taking medication at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilisers may precipitate a child abuse event.

Self aggression has been reported and also demonstrated in laboratory conditions in a clinical study. Diazepam was found to increase people’s willingness to harm themselves.

Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders.

Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients’ behaviour to baseline levels.

Causes

The mechanism of a paradoxical reaction has as yet (2019) not been fully clarified, in no small part due to the fact that signal transfer of single neurons in subcortical areas of the human brain is usually not accessible.

There are, however, multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates, inhalational anaesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA receptors. The combination of the five subunits of the receptor (see image) can be altered in such a way that for example the receptor’s response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.

There are estimates that about 2-3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.

What are the Adverse Effects of Olanzpine?

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Introduction

Below is a list of the adverse effects of the antipsychotic olanzapine, sorted by frequency of occurrence.

Very Common

Very common adverse effects of olanzapine, occurring more than 10%, include:

  • Weight gain (dose-dependent).
    • Weight gain of over 7% of a person’s initial body weight prior to treatment is in this category of very common too with some estimates of its incidence putting it at around 40.6%.
    • This adverse effect is most likely the result of its potent 5-HT2C receptor and H1 receptor blockade (or more specifically inverse agonism).
  • Somnolence (dose-dependent).
    • Tends to produce a moderate amount of sedation, less than clozapine and chlorpromazine but more than aripiprazole, amisulpride, paliperidone and sertindole and approximately that of quetiapine and risperidone.
  • Hyperprolactinemia elevated blood levels of the hormone, prolactin.
    • Prolactin is one of the hormones that plays a key role in lactation. Long-term uncontrolled hyperprolactinaemia can lead to bone demineralisation (osteoporosis) and an increased risk of fractures (breaks).
    • It tends to produce hyperlacticaemia less often than risperidone, paliperidone and the typical antipsychotics but more often than quetiapine and clozapine.
  • Hypertriglyceridaemia (elevated blood triglycerides).
  • Hypercholesterolaemia (elevated blood cholesterol levels).
  • Hyperglycaemia (elevated blood glucose levels).
    • This may be the result of olanzapine’s inhibitory effects on the M3 receptor which regulates the release of insulin from the pancreas.
  • Brain shrinkage (dose dependent).

Common

Common adverse effects of olanzapine, occurring from 1-10%, include:

  • Gynecomastia.
  • Extrapyramidal symptoms (EPS) (dose-dependent).
    • Tends to produce less extrapyramidal side effects than typical antipsychotics but more extrapyramidal side effects than sertindole, clozapine and quetiapine.
  • Mild and transient constipation and xerostomia (dry mouth).
  • Dizziness.
  • Weight gain of over 15% of one’s initial body weight.
    • Is reported to occur in approximately 7.1% of patients.
  • Glucosuria (glucose in the urine).
    • This is a consequence of hyperglycaemia.
  • Accidental injury.
  • Insomnia.
  • Orthostatic hypotension (a drop in blood pressure that occurs upon standing up).
  • Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment.
    • ALT & AST are liver enzymes which are often tested for as a measure of liver function.
  • Dyspepsia (indigestion).
  • Erectile dysfunction.
    • This is most likely the result of hyperprolactinaemia.
  • Decreased libido.
    • This is most likely the result of hyperprolactinaemia.
  • Rash.
  • Asthenia (weakness).
  • Fatigue.
  • Oedema the accumulation of fluid in the tissues of the body leading to swelling.
  • Akathisia an inner sense of restlessness that presents itself with the inability to stay still.
  • Parkinsonism tremor, muscle rigidity, reduced ability to move and being unstable on one’s feet.
  • Dyskinesia abnormal, involuntary, repetitive, and pointless movements.
  • Vomiting.
  • Coma.
  • Cardiac arrest.

Uncommon

Uncommon adverse effects of olanzapine, occurring from 0.1-1%, include:

  • Leukopenia a comparatively low white blood cell (the cells that defend the body from foreign invaders) count.
  • Neutropaenia a reduced neutrophil (the white blood cells that kill bacteria) count.
  • Bradycardia (low heart rate).
  • QTc interval prolongation (an abnormality in the electrical cycle of the heart).
  • Photosensitivity reaction.
  • Alopecia (hair loss).
  • Urinary incontinence.
  • Urinary retention, the inability to urinate.
  • Amenorrhea the cessation of menses (a woman’s menstrual cycles).
    • This is a complication of hyperprolactinaemia.
  • Breast enlargement (in either sex).
    • This is a complication of hyperprolactinaemia.
  • Galactorrhoea (expulsion of milk from the breasts that’s unrelated to pregnancy or lactation).
    • Most likely the result of hyperprolactinaemia.
  • High creatine phosphokinase (an abnormal laboratory finding).
  • Increased total bilirubin (a by product of the breakdown of haem – a part of blood cells that is used to carry oxygen).
    • In most people this is an indication of impaired liver function.
  • Abdominal pain.

Rare

Rare adverse effects of olanzapine, occurring from 0.01-0.1%, include:

  • Hepatitis.
  • Rash.
  • Seizures.
  • Glaucoma.
  • Blindness.

Very Rare (But Not Necessarily Causally Related)

Very rare adverse effects of olanzapine, occurring less than 0.01%, include:

  • Agranulocytosis, a potentially fatal drop in white blood cell count, basically an exaggerated form of leukopenia.
  • Thrombocytopaenia.
    • A drop in blood platelet counts which are involved in blood clotting.
  • Thromboembolism (blood clots; including pulmonary embolism and deep vein thrombosis).
  • Rhabdomyolysis (breakdown of muscle tissue leading to the release of myoglobin into the bloodstream which in turn damages the kidneys).
  • Alkaline phosphatase increased (an abnormal laboratory parameter).
  • Priapism (a painful and enduring erection).
  • Urinary hesitation.
  • Pancreatitis, swelling of the pancreas which supplies the body with insulin.
  • Neuroleptic malignant syndrome a potentially fatal complication of antipsychotic drug treatment.
    • Presents with hyperthermia, tremor, tachycardia (high heart rate), mental status change (e.g. confusion), etc.
  • Jaundice, which is basically when the body’s ability to clear a by product (called bilirubin) of the breakdown of an essential component of the blood called haem, is impaired leading to yellow discolouration of the skin, eyes and mucous membranes.
  • Diabetic coma.
  • Diabetic ketoacidosis.
    • Type II diabetes mellitus is basically where the body cannot effectively utilise sugars to produce energy due to the fact that its cells have become unresponsive to the hormone, insulin, which allows cells to utilise sugars for energy.
    • This in turn forces the body to burn fats for energy and fats require conversion to ketone bodies in order to be utilised by the cells of the body as an energy source.
    • The ketone bodies are acidic hence when the body is entirely reliant on these ketone bodies for energy the levels in the blood reaches a point where it overwhelms the body’s natural mechanisms to keep blood pH (a measure of acidity) within a safe range, leading to the blood becoming acidic which is potentially damaging to the tissues of the body due to the ability of acidic environments to denature the proteins of the body.
  • Anaphylactic reaction a potentially life-threatening allergic reaction.
  • Sudden cardiac death.

What is Olanzapine?

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Introduction

Olanzapine, sold under the trade name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder.

For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is taken by mouth or by injection into a muscle.

Common side effects include weight gain, movement disorders, dizziness, feeling tired, constipation, and dry mouth. Other side effects include low blood pressure with standing, allergic reactions, neuroleptic malignant syndrome, high blood sugar, seizures, gynecomastia, erectile dysfunction, and tardive dyskinesia. In older people with dementia, its use increases the risk of death. Use in the later part of pregnancy may result in a movement disorder in the baby for some time after birth. Although how it works is not entirely clear, it blocks dopamine and serotonin receptors.

Brief History

Olanzapine was patented in 1971 and approved for medical use in the United States in 1996. It is available as a generic medication. In 2017, it was the 239th-most commonly prescribed medication in the United States, with more than two million prescriptions. Lilly also markets olanzapine in a fixed-dose combination with fluoxetine as olanzapine/fluoxetine (Symbyax).

Chemical Synthesis

The preparation of olanzapine was first disclosed in a series of patents from Eli Lilly & Co. in the 1990s. In the final two steps, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile was reduced with stannous chloride in ethanol to give the substituted thienobenzodiazepine ring system, and this was treated with methylpiperazine in a mixture of dimethyl sulfoxide and toluene as solvent to produce the drug.

Medical Uses

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication, with olanzapine being one such medication. Olanzapine appears to be effective in reducing symptoms of schizophrenia, treating acute exacerbations, and treating early-onset schizophrenia. The usefulness of maintenance therapy, however, is difficult to determine, as more than half of people in trials quit before the 6-week completion date. Treatment with olanzapine (like clozapine) may result in increased weight gain and increased glucose and cholesterol levels when compared to most other second-generation antipsychotic drugs used to treat schizophrenia.

Comparison

The UK National Institute for Health and Care Excellence (NICE), the British Association for Psychopharmacology, and the World Federation of Societies for Biological Psychiatry suggest that little difference in effectiveness is seen between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on a person’s preference and the drug’s side-effect profile. The US Agency for Healthcare Research and Quality concludes that olanzapine is not different from haloperidol in the treatment of positive symptoms and general psychopathology, or in overall assessment, but that it is superior for the treatment of negative and depressive symptoms. It has a lower risk of causing movement disorders than typical antipsychotics.

In a 2013 comparison of fifteen antipsychotic drugs in schizophrenia, olanzapine was ranked third in efficacy. It was 5% more effective than risperidone (fourth), 24-27% more effective than haloperidol, quetiapine, and aripiprazole, and 33% less effective than clozapine (first). A 2013 review of first-episode schizophrenia concluded that olanzapine is superior to haloperidol in providing a lower discontinuation rate, and in short-term symptom reduction, response rate, negative symptoms, depression, cognitive function, discontinuation due to poor efficacy, and long-term relapse, but not in positive symptoms or on the clinical global impressions (CGI) score. In contrast, pooled second-generation antipsychotics showed superiority to first-generation antipsychotics only against the discontinuation, negative symptoms (with a much larger effect seen among industry- compared to government-sponsored studies), and cognition scores. Olanzapine caused less extrapyramidal side effects and less akathisia, but caused significantly more weight gain, serum cholesterol increase, and triglyceride increase than haloperidol.

A 2012 review concluded that among ten atypical antipsychotics, only clozapine, olanzapine, and risperidone were better than first-generation antipsychotics. A 2011 review concluded that neither first- nor second-generation antipsychotics produce clinically meaningful changes in CGI scores, but found that olanzapine and amisulpride produce larger effects on the PANSS and BPRS batteries than five other second-generation antipsychotics or pooled first-generation antipsychotics. A 2010 Cochrane systematic review found that olanzapine may have a slight advantage in effectiveness when compared to aripiprazole, quetiapine, risperidone, and ziprasidone. No differences in effectiveness were detected when comparing olanzapine to amisulpride and clozapine. A 2014 meta-analysis of nine published trials having minimum duration six months and median duration 52 weeks concluded that olanzapine, quetiapine, and risperidone had better effects on cognitive function than amisulpride and haloperidol.

Bipolar Disorder

Olanzapine is recommended by NICE as a first-line therapy for the treatment of acute mania in bipolar disorder. Other recommended first-line treatments are haloperidol, quetiapine, and risperidone. It is recommended in combination with fluoxetine as a first-line therapy for acute bipolar depression, and as a second-line treatment by itself for the maintenance treatment of bipolar disorder.

The Network for Mood and Anxiety Treatments recommends olanzapine as a first-line maintenance treatment in bipolar disorder and the combination of olanzapine with fluoxetine as second-line treatment for bipolar depression.

A review on the efficacy of olanzapine as maintenance therapy in patients with bipolar disorder was published by Dando & Tohen in 2006. A 2014 meta-analysis concluded that olanzapine with fluoxetine was the most effective among nine treatments for bipolar depression included in the analysis.

Other Uses

Olanzapine may be useful in promoting weight gain in underweight adult outpatients with anorexia nervosa. However, no improvement of psychological symptoms was noted.

Olanzapine has been shown to be helpful in addressing a range of anxiety and depressive symptoms in individuals with schizophrenia and schizoaffective disorders, and has since been used in the treatment of a range of mood and anxiety disorders. Olanzapine is no less effective than lithium or valproate and more effective than placebo in treating bipolar disorder. It has also been used for Tourette syndrome and stuttering.

Olanzapine has been studied for the treatment of hyperactivity, aggressive behaviour, and repetitive behaviours in autism.

Olanzapine is frequently prescribed off-label for the treatment of insomnia, including difficulty falling asleep and staying asleep. The daytime sedation experienced with olanzapine is generally comparable to quetiapine and lurasidone, which is a frequent complaint in clinical trials. In some cases, the sedation due to olanzapine impaired the ability of people to wake up at a consistent time every day. Some evidence of efficacy for treating insomnia is seen, but long-term studies (especially for safety) are still needed.

Olanzapine has been recommended to be used in antiemetic regimens in people receiving chemotherapy that has a high risk for vomiting.

Specific Populations

Pregnancy and Lactation

Olanzapine is associated with the highest placental exposure of any atypical antipsychotic. Despite this, the available evidence suggests it is safe during pregnancy, although the evidence is insufficiently strong to say anything with a high degree of confidence. Olanzapine is associated with weight gain, which according to recent studies, may put olanzapine-treated patients’ offspring at a heightened risk for neural tube defects (e.g. spina bifida). Breastfeeding in women taking olanzapine is advised against because olanzapine is secreted in breast milk, with one study finding that the exposure to the infant is about 1.8% that of the mother.

Elderly

Citing an increased risk of stroke, in 2004, the Committee on the Safety of Medicines in the UK issued a warning that olanzapine and risperidone, both atypical antipsychotic medications, should not be given to elderly patients with dementia. In the US, olanzapine comes with a black box warning for increased risk of death in elderly patients. It is not approved for use in patients with dementia-related psychosis. A BBC investigation in June 2008 found that this advice was being widely ignored by British doctors. Evidence suggested that the elderly are more likely to experience weight gain on olanzapine compared to aripiprazole and risperidone.

Adverse Effects

Refer to Adverse Effects of Olanzapine.

The principal side effect of olanzapine is weight gain, which may be profound in some cases and/or associated with derangement in blood-lipid and blood-sugar profiles (see section metabolic effects). A 2013 meta-analysis of the efficacy and tolerance of 15 antipsychotic drugs (APDs) found that it had the highest propensity for causing weight gain out of the 15 APDs compared with an SMD of 0.74. Extrapyramidal side effects, although potentially serious, are infrequent to rare from olanzapine, but may include tremors and muscle rigidity.

It is not recommended to be used by IM injection in acute myocardial infarction, bradycardia, recent heart surgery, severe hypotension, sick sinus syndrome, and unstable angina.

Several patient groups are at a heightened risk of side effects from olanzapine and antipsychotics in general. Olanzapine may produce nontrivial high blood sugar in people with diabetes mellitus. Likewise, the elderly are at a greater risk of falls and accidental injury. Young males appear to be at heightened risk of dystonic reactions, although these are relatively rare with olanzapine. Most antipsychotics, including olanzapine, may disrupt the body’s natural thermoregulatory systems, thus permitting excursions to dangerous levels when situations (exposure to heat, strenuous exercise) occur.

Other side effects include galactorrhoea, amenorrhea, gynecomastia, and erectile dysfunction (impotence).

Paradoxical Effects

Olanzapine is used therapeutically to treat serious mental illness. Occasionally, it can have the opposite effect and provoke serious paradoxical reactions in a small subgroup of people, causing unusual changes in personality, thoughts, or behaviour; hallucinations and excessive thoughts about suicide have also been linked to olanzapine use.

Drug-Induced OCD

Many different types of medication can create or induce pure obsessive-compulsive disorder (OCD) in patients who have never had symptoms before. A new chapter about OCD in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (2013) now specifically includes drug-induced OCD.

Atypical antipsychotics (second-generation antipsychotics), such as olanzapine (Zyprexa), have been proven to induce de novo OCD in patients.

Metabolic Effects

The US Food and Drug Administration (FDA) requires all atypical antipsychotics to include a warning about the risk of developing hyperglycaemia and diabetes, both of which are factors in the metabolic syndrome. These effects may be related to the drugs’ ability to induce weight gain, although some reports have been made of metabolic changes in the absence of weight gain. Studies have indicated that olanzapine carries a greater risk of causing and exacerbating diabetes than another commonly prescribed atypical antipsychotic, risperidone. Of all the atypical antipsychotics, olanzapine is one of the most likely to induce weight gain based on various measures. The effect is dose dependent in humans and animal models of olanzapine-induced metabolic side effects. There are some case reports of olanzapine-induced diabetic ketoacidosis. Olanzapine may decrease insulin sensitivity, though one 3-week study seems to refute this. It may also increase triglyceride levels.

Despite weight gain, a large multicentre, randomised National Institute of Mental Health study found that olanzapine was better at controlling symptoms because patients were more likely to remain on olanzapine than the other drugs. One small, open-label, nonrandomised study suggests that taking olanzapine by orally dissolving tablets may induce less weight gain, but this has not been substantiated in a blinded experimental setting.

Post-Injection Delirium/Sedation Syndrome

Postinjection delirium/sedation syndrome (PDSS) is a rare syndrome that is specific to the long-acting injectable formulation of olanzapine, olanzapine pamoate. The incidence of PDSS with olanzapine pamoate is estimated to be 0.07% of administrations, and is unique among other second-generation, long-acting antipsychotics (e.g. paliperidone palmitate), which do not appear to carry the same risk.[70] PDSS is characterised by symptoms of delirium (e.g. confusion, difficulty speaking, and uncoordinated movements) and sedation. Most people with PDSS exhibit both delirium and sedation (83%). Although less specific to PDSS, a majority of cases (67%) involved a feeling of general discomfort. PDSS may occur due to accidental injection and absorption of olanzapine pamoate into the bloodstream, where it can act more rapidly, as opposed to slowly distributing out from muscle tissue. Using the proper, intramuscular-injection technique for olanzapine pamoate helps to decrease the risk of PDSS, though it does not eliminate it entirely. This is why the FDA advises that people who are injected with olanzapine pamoate be watched for 3 hours after administration, in the event that PDSS occurs.

Animal Toxicology

Olanzapine has demonstrated carcinogenic effects in multiple studies when exposed chronically to female mice and rats, but not male mice and rats. The tumours found were in either the liver or mammary glands of the animals.

Discontinuation

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

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

Overdose

Symptoms of an overdose include tachycardia, agitation, dysarthria, decreased consciousness, and coma. Death has been reported after an acute overdose of 450 mg, but also survival after an acute overdose of 2000 mg. Fatalities generally have occurred with olanzapine plasma concentrations greater than 1000 ng/mL post mortem, with concentrations up to 5200 ng/mL recorded (though this might represent confounding by dead tissue, which may release olanzapine into the blood upon death). No specific antidote for olanzapine overdose is known, and even physicians are recommended to call a certified poison control centre for information on the treatment of such a case. Olanzapine is considered moderately toxic in overdose, more toxic than quetiapine, aripiprazole, and the SSRIs, and less toxic than the monoamine oxidase inhibitors and tricyclic antidepressants.

Interactions

Drugs or agents that increase the activity of the enzyme CYP1A2, notably tobacco smoke, may significantly increase hepatic first-pass clearance of olanzapine; conversely, drugs that inhibit CYP1A2 activity (examples: ciprofloxacin, fluvoxamine) may reduce olanzapine clearance. Carbamazepine, a known enzyme inducer, has decreased the concentration/dose ration of olanzapine by 33% compared to olanzapine alone. Another enzyme inducer, ritonavir, has also been shown to decrease the body’s exposure to olanzapine, due to its induction of the enzymes CYP1A2 and uridine 5′-diphospho-glucuronosyltransferase (UGT). Probenecid increases the total exposure (area under the curve) and maximum plasma concentration of olanzapine. Although olanzapine’s metabolism includes the minor metabolic pathway of CYP2D6, the presence of the CYP2D6 inhibitor fluoxetine does not have a clinically significant effect on olanzapine’s clearance.

Pharmacology

Pharmacodynamics

Olanzapine has a higher affinity for 5-HT2A serotonin receptors than D2 dopamine receptors, which is a common property of most atypical antipsychotics, aside from the benzamide antipsychotics such as amisulpride along with the nonbenzamides aripiprazole, brexpiprazole, blonanserin, cariprazine, melperone, and perospirone.

Olanzapine had the highest affinity of any second-generation antipsychotic towards the P-glycoprotein in one in vitro study. P-glycoprotein transports a myriad of drugs across a number of different biological membranes (found in numerous body systems) including the blood-brain barrier (a semipermeable membrane that filters the contents of blood prior to it reaching the brain); P-GP inhibition could mean that less brain exposure to olanzapine results from this interaction with the P-glycoprotein. A relatively large quantity of commonly encountered foods and medications inhibit P-GP, and pharmaceuticals fairly commonly are either substrates of P-GP, or inhibit its action; both substrates and inhibitors of P-GP effectively increase the permeability of the blood-brain barrier to P-GP substrates and subsequently increase the central activity of the substrate, while reducing the local effects on the GI tract. The mediation of olanzapine in the central nervous system by P-GP means that any other substance or drug that interacts with P-GP increases the risk for toxic accumulations of both olanzapine and the other drug.

Olanzapine is a potent antagonist of the muscarinic M3 receptor, which may underlie its diabetogenic side effects. Additionally, it also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites.

The mode of action of olanzapine’s antipsychotic activity is unknown. It may involve antagonism of dopamine and serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia (TD), and with therapeutic effects. Antagonism of muscarinic acetylcholine receptors is associated with anticholinergic side effects such as dry mouth and constipation; in addition, it may suppress or reduce the emergence of extrapyramidal effects for the duration of treatment, but it offers no protection against the development of TD. In common with other second-generation (atypical) antipsychotics, olanzapine poses a relatively low risk of extrapyramidal side effects including TD, due to its higher affinity for the 5HT2A receptor over the D2 receptor.

Antagonizing H1 histamine receptors causes sedation and may cause weight gain, although antagonistic actions at serotonin 5-HT2C and dopamine D2 receptors have also been associated with weight gain and appetite stimulation.

Pharmacokinetics

Metabolism

Olanzapine is metabolized by the cytochrome P450 (CYP) system; principally by isozyme 1A2 (CYP1A2) and to a lesser extent by CYP2D6. By these mechanisms, more than 40% of the oral dose, on average, is removed by the hepatic first-pass effect. Clearance of olanzapine appears to vary by sex; women have roughly 25% lower clearance than men. Clearance of olanzapine also varies by race; in self-identified African Americans or Blacks, olanzapine’s clearance was 26% higher. A difference in the clearance does not apparent between individuals identifying as Caucasian, Chinese, or Japanese. Routine, pharmacokinetic monitoring of olanzapine plasma levels is generally unwarranted, though unusual circumstances (e.g. the presence of drug-drug interactions) or a desire to determine if patients are taking their medicine may prompt its use.

Chemistry

Olanzapine is unusual in having four well-characterised crystalline polymorphs and many hydrated forms.

Society and Culture

Regulatory Status

Olanzapine is approved by the US FDA for:

  • Treatment – in combination with fluoxetine – of depressive episodes associated with bipolar disorder (December 2003).
  • Long-term treatment of bipolar I disorder (January 2004).
  • Long-term treatment – in combination with fluoxetine – of resistant depression (March 2009).
  • Oral formulation: acute and maintenance treatment of schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder (monotherapy and in combination with lithium or sodium valproate).
  • Intramuscular formulation: acute agitation associated with schizophrenia and bipolar I mania in adults.
  • Oral formulation combined with fluoxetine: treatment of acute depressive episodes associated with bipolar I disorder in adults, or treatment of acute, resistant depression in adults.
  • Treatment of the manifestations of psychotic disorders (September 1996 to March 2000).
  • Short-term treatment of acute manic episodes associated with bipolar I disorder (March 2000).
  • Short-term treatment of schizophrenia instead of the management of the manifestations of psychotic disorders (March 2000).
  • Maintaining treatment response in schizophrenic patients who had been stable for about eight weeks and were then followed for a period of up to eight months (November 2000).

The drug became generic in 2011.

Sales of Zyprexa in 2008 were $2.2 billion in the US and $4.7 billion worldwide.

Controversy and Litigation

Eli Lilly has faced many lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa, as well as by various governmental entities, insurance companies, and others. Lilly produced a large number of documents as part of the discovery phase of this litigation, which started in 2004; the documents were ruled to be confidential by a judge and placed under seal, and later themselves became the subject of litigation.

In 2006, Lilly paid $700 million to settle around 8,000 of these lawsuits, and in early 2007, Lilly settled around 18,000 suits for $500 million, which brought the total Lilly had paid to settle suits related to the drug to $1.2 billion.

A December 2006 New York Times article based on leaked company documents concluded that the company had engaged in a deliberate effort to downplay olanzapine’s side effects. The company denied these allegations and stated that the article had been based on cherry-picked documents. The documents were provided to the Times by Jim Gottstein, a lawyer who represented mentally ill patients, who obtained them from a doctor, David Egilman, who was serving as an expert consultant on the case. After the documents were leaked to online peer-to-peer, file-sharing networks by Will Hall and others in the psychiatric survivors movement, who obtained copies, in 2007 Lilly filed a protection order to stop the dissemination of some of the documents, which Judge Jack B. Weinstein of the Brooklyn Federal District Court granted. Judge Weinstein also criticized the New York Times reporter, Gottstein, and Egilman in the ruling. The Times of London also received the documents and reported that as early as 1998, Lilly considered the risk of drug-induced obesity to be a “top threat” to Zyprexa sales. On 09 October 2000, senior Lilly research physician Robert Baker noted that an academic advisory board to which he belonged was “quite impressed by the magnitude of weight gain on olanzapine and implications for glucose.”

Lilly had threatened Egilman with criminal contempt charges regarding the documents he took and provided to reporters; in September 2007, he agreed to pay Lilly $100,000 in return for the company’s agreement to drop the threat of charges.

In September 2008, Judge Weinstein issued an order to make public Lilly’s internal documents about the drug in a different suit brought by insurance companies, pension funds, and other payors.

In March 2008, Lilly settled a suit with the state of Alaska, and in October 2008, Lilly agreed to pay $62 million to 32 states and the District of Columbia to settle suits brought under state consumer protection laws.

In 2009, Eli Lilly pleaded guilty to a US federal criminal misdemeanour charge of illegally marketing Zyprexa for off-label use and agreed to pay $1.4 billion. The settlement announcement stated “Eli Lilly admits that between September 1999 and 31 March 2001, the company promoted Zyprexa in elderly populations as treatment for dementia, including Alzheimer’s dementia. Eli Lilly has agreed to pay a $515 million criminal fine and to forfeit an additional $100 million in assets.”

Trade Names

Olanzapine is generic and available under many trade names worldwide.

Dosage Forms

Olanzapine is marketed in a number of countries, with tablets ranging from 2.5 to 20 mg. Zyprexa (and generic olanzapine) is available as an orally disintegrating “wafer”, which rapidly dissolves in saliva. It is also available in 10-mg vials for intramuscular injection.

Research

Olanzapine has been studied as an antiemetic, particularly for the control of chemotherapy-induced nausea and vomiting (CINV).

In general, olanzapine appears to be about as effective as aprepitant for the prevention of CINV, though some concerns remain for its use in this population. For example, concomitant use of metoclopramide or haloperidol increases the risk for extrapyramidal symptoms. Otherwise, olanzapine appears to be fairly well tolerated for this indication, with somnolence being the most common side effect.

Olanzapine has been considered as part of an early psychosis approach for schizophrenia. The Prevention through Risk Identification, Management, and Education study, funded by the National Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk for schizophrenia. The study examined 60 patients with prodromal schizophrenia, who were at an estimated risk of 36-54% of developing schizophrenia within a year, and treated half with olanzapine and half with placebo. In this study, patients receiving olanzapine did not have a significantly lower risk of progressing to psychosis. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.

What is a Neuropsychological Test?

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Introduction

Neuropsychological tests are specifically designed tasks that are used to measure a psychological function known to be linked to a particular brain structure or pathway.

Refer to Neuropsychological Assessment.

Tests are used for research into brain function and in a clinical setting for the diagnosis of deficits. They usually involve the systematic administration of clearly defined procedures in a formal environment. Neuropsychological tests are typically administered to a single person working with an examiner in a quiet office environment, free from distractions. As such, it can be argued that neuropsychological tests at times offer an estimate of a person’s peak level of cognitive performance. Neuropsychological tests are a core component of the process of conducting neuropsychological assessment, along with personal, interpersonal and contextual factors.

Most neuropsychological tests in current use are based on traditional psychometric theory. In this model, a person’s raw score on a test is compared to a large general population normative sample, that should ideally be drawn from a comparable population to the person being examined. Normative studies frequently provide data stratified by age, level of education, and/or ethnicity, where such factors have been shown by research to affect performance on a particular test. This allows for a person’s performance to be compared to a suitable control group, and thus provide a fair assessment of their current cognitive function.

According to Larry J. Seidman, the analysis of the wide range of neuropsychological tests can be broken down into four categories. First is an analysis of overall performance, or how well people do from test to test along with how they perform in comparison to the average score. Second is left-right comparisons: how well a person performs on specific tasks that deal with the left and right side of the body. Third is pathognomic signs, or specific test results that directly relate to a distinct disorder. Finally, the last category is differential patterns, which are typically used to diagnose specific diseases or types of damage.

Categories

Most forms of cognition actually involve multiple cognitive functions working in unison, however tests can be organised into broad categories based on the cognitive function which they predominantly assess. Some tests appear under multiple headings as different versions and aspects of tests can be used to assess different functions.

Intelligence

Intelligence testing in a research context is relatively more straightforward than in a clinical context. In research, intelligence is tested and results are generally as obtained, however in a clinical setting intelligence may be impaired so estimates are required for comparison with obtained results. Premorbid estimates can be determined through a number of methods, the most common include: comparison of test results to expected achievement levels based on prior education and occupation and the use of hold tests which are based on cognitive faculties which are generally good indicators of intelligence and thought to be more resistant to cognitive damage, e.g. language.

  • National Adult Reading Test (NART).
  • Wechsler Adult Intelligence Scale (WAIS).
  • Wechsler Intelligence Scale for Children (WISC).
  • Wechsler Preschool and Primary Scale of Intelligence (WPPSI).
  • Wechsler Test of Adult Reading (WTAR).

Memory

Memory is a very broad function which includes several distinct abilities, all of which can be selectively impaired and require individual testing. There is disagreement as to the number of memory systems, depending on the psychological perspective taken. From a clinical perspective, a view of five distinct types of memory, is in most cases sufficient. Semantic memory and episodic memory (collectively called declarative memory or explicit memory); procedural memory and priming or perceptual learning (collectively called non-declarative memory or implicit memory) all four of which are long term memory systems; and working memory or short term memory. Semantic memory is memory for facts, episodic memory is autobiographical memory, procedural memory is memory for the performance of skills, priming is memory facilitated by prior exposure to a stimulus and working memory is a form of short term memory for information manipulation.

  • Benton Visual Retention Test.
  • California Verbal Learning Test.
  • Cambridge Prospective Memory Test (CAMPROMPT).
  • Gollin figure test.
  • Memory Assessment Scales (MAS).
  • Rey Auditory Verbal Learning Test.
  • Rivermead Behavioural Memory Test.
  • Test of Memory and Learning (TOMAL).
  • Mental Attributes Profiling System.
  • Wechsler Memory Scale (WMS).

Language

Language functions include speech, reading and writing, all of which can be selectively impaired.

  • Boston Diagnostic Aphasia Examination.
  • Boston Naming Test.
  • Comprehensive Aphasia Test (CAT).
  • Multilingual Aphasia Examination.

Executive Function

Executive functions is an umbrella term for a various cognitive processes and sub-processes. The executive functions include: problem solving, planning, organisational skills, selective attention, inhibitory control and some aspects of short term memory.

  • Behavioural Assessment of Dysexecutive Syndrome (BADS).
  • CNS Vital Signs (Brief Core Battery).
  • Continuous performance task (CPT).
  • Controlled Oral Word Association Test (COWAT).
  • d2 Test of Attention.
  • Delis-Kaplan Executive Function System (D-KEFS).
  • Digit Vigilance Test.
  • Figural Fluency Test.
  • Halstead Category Test.
  • Hayling and Brixton tests.
  • Kaplan Baycrest Neurocognitive Assessment (KBNA).
  • Kaufman Short Neuropsychological Assessment.
  • Paced Auditory Serial Addition Test (PASAT).
  • Rey-Osterrieth Complex Figure.
  • Ruff Figural Fluency Test.
  • Stroop task.
  • Test of Variables of Attention (T.O.V.A.).
  • Tower of London Test.
  • Trail-Making Test (TMT) or Trails A & B.
  • Wisconsin Card Sorting Test (WCST).
  • Symbol Digit Modalities Test.
  • Test of Everyday Attention (TEA).

Visuospatial

Neuropsychological tests of visuospatial function should cover the areas of visual perception, visual construction and visual integration. Though not their only functions, these tasks are to a large degree carried out by areas of the parietal lobe.

  • Clock Test.
  • Hooper Visual Organisation Task (VOT).
  • Rey-Osterrieth Complex Figure.

Dementia Specific

Dementia testing is often done by way of testing the cognitive functions that are most often impaired by the disease e.g. memory, orientation, language and problem solving. Tests such as these are by no means conclusive of deficits, but may give a good indication as to the presence or severity of dementia.

  • The Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).
  • Clinical Dementia Rating.
  • Dementia Rating Scale.

Batteries Assessing Multiple Neuropsychological Functions

There are some test batteries which combine a range of tests to provide an overview of cognitive skills. These are usually good early tests to rule out problems in certain functions and provide an indication of functions which may need to be tested more specifically.

  • Barcelona Neuropsychological Test (BNT).
  • Cambridge Neuropsychological Test Automated Battery (CANTAB).
  • Cognistat (The Neurobehavioral Cognitive Status Examination).
  • Cognitive Assessment Screening Instrument (CASI).
  • Cognitive Function Scanner (CFS).
  • Dean-Woodcock Neuropsychology Assessment System (DWNAS).
  • General Practitioner Assessment Of Cognition (GPCOG).
  • Hooper Visual Organisation Test.
  • Luria-Nebraska Neuropsychological battery.
  • MicroCog.
  • Mini mental state examination (MMSE).
  • NEPSY.
  • Repeatable Battery for the Assessment of Neuropsychological Status.
  • Short Parallel Assessments of Neuropsychological Status (SPANS).
  • CDR Computerised Assessment System.

Automated Computerised Cognitive Tests

Traditional cognitive examinations are mostly paper and pen based. As such most of them are time consuming and require special training to be carried out. Today there is a rapidly growing number of automated computerised cognitive tests emerging, for example Brain on Track, Cogstate, CAMCI, CANTAB. Several of these new tests are shoving promising ability to discriminate between healthy individuals and different cognitive difficulties and/or to monitor cognitive impairment over time. Since these tests are easily administered to large groups of people this is opening up possibilities to, for example, regularly screen portions of the population at risk for cognitive decline and early on give adequate support and treatment.

Benefits of Neuropsychological Testing

The most beneficial factor of neuropsychological assessment is that it provides an accurate diagnosis of the disorder for the patient when it is unclear to the psychologist what exactly the patient has. This allows for accurate treatment later on in the process because treatment is driven by the exact symptoms of the disorder and how a specific patient may react to different treatments. The assessment allows the psychologist and patient to understand the severity of the deficit and to allow better decision-making by both parties. It is also helpful in understanding deteriorating diseases because the patient can be assessed multiple times to see how the disorder is progressing.

On This Day … 30 August

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People (Births)

Victor Skumin

Victor Andreevich Skumin (born 30 August 1948) is a Russian and Soviet scientist, psychiatrist, philosopher and writer.

After graduating from the Kharkiv National Medical University in 1973, in 1976, he became a psychotherapist in Kiev Institute of Cardiovascular Surgery. In 1978, he described a new disease, the Skumin syndrome. He introduced a method of psychotherapy and self-improvement based on optimistic autosuggestion for psychological rehabilitation of cardiosurgical patients (1979).

From 1980 to 1990, he was professor of psychotherapy at the Kharkiv Medical Academy of Post-graduate Education. The main result of his scientific activity was the discovery of the “syndrome of the neurotic phantom of somatic disease” and a “concept of the mental constituent of a chronic somatic disease”.

From 1990 to 1994, Skumin held positions as chaired professor of psychology and pedagogy, and of physical education and Health life at the Kharkiv State Academy of Culture. In 1994, he was elected to the post of the President-founder of the World Organisation of Culture of Health (Moscow). In 1995, Skumin became the first editor-in-chief of the journal To Health via Culture. He is known for inventing a popular term “Culture of Health” (1968).

Besides psychiatry and psychology, Skumin writes on healthy lifestyle, yoga, and philosophy. He co-authored series of illustrated books and articles on Agni Yoga, Roerichism, Russian cosmism, transhumanism, and New Age. He wrote books of fiction and lyrics for several songs.

On This Day … 29 August

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People (Births)

  • 1935 – László Garai, Hungarian psychologist and scholar.

Laszlo Garai

László Garai (born 29 August 1935) is a scholar of psychology: studies theoretical psychology, social psychology and economic psychology.

Early Life

Garai was born in Budapest. He graduated in philosophy and psychology from the Faculty of Arts of Budapest University (1959).

He obtained his Candidate degree from the Hungarian Academy of Sciences with a thesis on a specifically human basic need.

He obtained his Doctor of Science degree from the Hungarian Academy of Science with a thesis on social identity and paradoxes of its psychic elaboration.

Professional Work

László Garai started his career as editor at the Encyclopaedia Department of the Hungarian academic publishing house Akadémiai Kiadó. After the defence of his thesis above on specifically basic human need, he concluded this research as a fellow of the Institute for Philosophy of the Hungarian Academy of Sciences (1964-1971). According to his hypothesis, a paradoxical need for a needfree activity is specific for humans and substantial for their other needs. The structure of the hypothesized need is isomorphic with that of the work considered as a “specifically human basic activity” and defined as that of arranging in one and the same structure ends and means. The hypothesis is based on the activity theory of Alexei Leontiev.

He won a Keldysh Scholarship (post doctoral scholarship founded by Keldysh, president of the USSR Academy of Sciences, to support joint Soviet-Hungarian academic research projects) to the Department of scientific discoveries’ psychology in the Institute for History of Natural Sciences and Technology in the Soviet Academy of Sciences (Moscow, 1969-1970)). There Garai studied simultaneous scientific discoveries (such as that of Bolyai and Lobachevsky).

In 1970, Garai founded in the Institute for Psychology of the Hungarian Academy of Sciences a research unit that became the first in Hungary research team of economic psychology and a centre of Vygotskian theoretical research. head of that department (1971-1979) and research advisor (1998-2002). He worked at the Laboratoire Européen de Psychologie Sociale (Paris, 1971, 1973 and 1977) and directed psycho-economic research supported by the National Scientific Research Foundation (1990-2005).

Garai was a member of the advisory board of the Hungarian Ministry of Finance. He is on the editorial board of the Journal of Russian and East European Psychology.

On This Day … 28 August

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People (Births)

  • 1903 – Bruno Bettelheim, Austrian-American psychologist and author (d. 1990).

People (Deaths)

  • 1757 – David Hartley, English psychologist and philosopher (b. 1705).

Bruno Bettelheim

Bruno Bettelheim (28 August 1903 to 13 March 1990) was an Austrian-born psychologist, scholar, public intellectual and author who spent most of his academic and clinical career in the United States. An early writer on autism, Bettelheim’s work focused on the education of emotionally disturbed children, as well as Freudian psychology more generally. In the US, he later gained a position as professor at the University of Chicago and director of the Sonia Shankman Orthogenic School for Disturbed Children, and after 1973 taught at Stanford University.

Bettelheim’s ideas, which grew out of those of Sigmund Freud, theorised that children with behavioural and emotional disorders were not born that way, and could be treated through extended psychoanalytic therapy, treatment that rejected the use of psychotropic drugs and shock therapy. During the 1960s and 1970s he had an international reputation in such fields as autism, child psychiatry, and psychoanalysis.

Much of his work was discredited after his death due to fraudulent academic credentials, allegations of abusive treatment of patients under his care, accusations of plagiarism, and lack of oversight by institutions and the psychological community.

David Hartley

David Hartley FRS (baptised 21 June 1705 to 28 August 1757) was an English philosopher and founder of the Associationist school of psychology.

What is Quazepam?

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Introduction

Quazepam (marketed under brand names Doral, Dormalin) is a relatively long-acting benzodiazepine derivative drug developed by the Schering Corporation in the 1970s.

Quazepam is indicated for the treatment of insomnia including sleep induction and sleep maintenance. Quazepam induces impairment of motor function and has relatively (and uniquely) selective hypnotic and anticonvulsant properties with considerably less overdose potential than other benzodiazepines (due to its novel receptor-subtype selectively). Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture.

Brief History

It was patented in 1970 and came into medical use in 1985.

Medical Uses

Quazepam is used for short-term treatment of insomnia related to sleep induction or sleep maintenance problems and has demonstrated superiority over other benzodiazepines such as temazepam. It had a fewer incidence of side effects than temazepam, including less sedation, amnesia, and less motor-impairment. Usual dosage is 7.5 to 15 mg orally at bedtime.

Quazepam is effective as a premedication prior to surgery.

Side Effects

Quazepam has fewer side effects than other benzodiazepines and less potential to induce tolerance and rebound effects. There is significantly less potential for quazepam to induce respiratory depression or to adversely affect motor coordination than other benzodiazepines. The different side effect profile of quazepam may be due to its more selective binding profile to type 1 benzodiazepine receptors.

  • Ataxia.
  • Daytime somnolence.
  • Hypokinesia.
  • Cognitive and performance impairments.

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.

Tolerance and Dependence

Tolerance may occur to quazepam but more slowly than seen with other benzodiazepines such as triazolam. Quazepam causes significantly less drug tolerance and less withdrawal symptoms including less rebound insomnia upon discontinuation compared to other benzodiazepines. Quazepam may cause less rebound effects than other type1 benzodiazepine receptor selective nonbenzodiazepine drugs due to its longer half-life. Short-acting hypnotics often cause next day rebound anxiety. Quazepam due to its pharmacological profile does not cause next day rebound withdrawal effects during treatment.

No firm conclusions can be drawn, however, whether long-term use of quazepam does not produce tolerance as few, if any, long-term clinical trials extending beyond 4 weeks of chronic use have been conducted. Quazepam should be withdrawn gradually if used beyond 4 weeks of use to avoid the risk of a severe benzodiazepine withdrawal syndrome developing. Very high dosage administration over prolonged periods of time, up to 52 weeks, of quazepam in animal studies provoked severe withdrawal symptoms upon abrupt discontinuation, including excitability, hyperactivity, convulsions and the death of two of the monkeys due to withdrawal-related convulsions. More monkeys died, however, in the diazepam-treated monkeys. In addition it has now been documented in the medical literature that one of the major metabolites of quazepam, N-desalkyl-2-oxoquazepam (N-desalkylflurazepam), which is long-acting and prone to accumulation, binds unselectively to benzodiazepine receptors, thus quazepam may not differ all that much pharmacologically from other benzodiazepines.

Special Precautions

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

Quazepam and its active metabolites are excreted into breast milk.

Accumulation of one of the active metabolites of quazepam, N-desalkylflurazepam, may occur in the elderly. A lower dose may be required in the elderly.

Elderly

Quazepam is more tolerable for elderly patients compared to flurazepam due to its reduced next day impairments. However, another study showed marked next day impairments after repeated administration due to accumulation of quazepam and its long-acting metabolites. Thus the medical literature shows conflicts on quazepam’s side effect profile. A further study showed significant balance impairments combined with an unstable posture after administration of quazepam in test subjects. An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilised. Compared with the benzodiazepines including quazepam, the nonbenzodiazepine sedative/hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative/hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

Interactions

The absorption rate is likely to be significantly reduced if quazepam is taken in the fasted state reducing the hypnotic effect of quazepam. If 3 or more hours have passed since eating food then some food should be eaten before taking quazepam.

Pharmacology

Quazepam is a trifluoroalkyl type of benzodiazepine. Quazepam is unique amongst benzodiazepines in that it selectively targets the GABAA α1 subunit receptors which are responsible for inducing sleep. Its mechanism of action is very similar to zolpidem and zaleplon in its pharmacology and can successfully substitute for zolpidem and zaleplon in animal studies.

Quazepam is selective for type I benzodiazepine receptors containing the α1 subunit, similar to other drugs such as zaleplon and zolpidem. As a result, quazepam has little or no muscle relaxant properties. Most other benzodiazepines are unselective and bind to type1 GABAA receptors and type2 GABAA receptors. Type1 GABAA receptors include the α1 subunit containing GABAA receptors which are responsible for hypnotic properties of the drug. Type 2 receptors include the α2, α3 and α5 subunits which are responsible for anxiolytic action, amnesia and muscle relaxant properties. Thus quazepam may have less side effects than other benzodiazepines but, it has a very long half-life of 25 hours which reduces its benefits as a hypnotic due to likely next day sedation. It also has two active metabolites with half-lives of 28 and 79 hours. Quazepam may also cause less drug tolerance than other benzodiazepines such as temazepam and triazolam perhaps due to its subtype selectivity. The longer half-life of quazepam may have the advantage however, of causing less rebound insomnia than shorter acting subtype selective nonbenzodiazepines. However, one of the major metabolites of quazepam, the N-desmethyl-2-oxoquazepam (aka N-desalkylflurazepam), binds unselectively to both type1 and type2 GABAA receptors. The N-desmethyl-2-oxoquazepam metabolite also has a very long half-life and likely contributes to the pharmacological effects of quazepam.

Pharmacokinetics

Quazepam has an absorption half-life of 0.4 hours with a peak in plasma levels after 1.75 hours. It is eliminated both renally and through faeces. The active metabolites of quazepam are 2-oxoquazepam and N-desalkyl-2-oxoquazepam. The N-desalkyl-2-oxoquazepam metabolite has only limited pharmacological activity compared to the parent compound quazepam and the active metabolite 2-oxoquazepam. Quazepam and its major active metabolite 2-oxoquazepam both show high selectivity for the type1 GABAA receptors. The elimination half-life range of quazepam is between 27 and 41 hours.

Mechanism of Action

Quazepam modulates specific GABAA receptors via the benzodiazepine site on the GABAA receptor. This modulation enhances the actions of GABA, causing an increase in opening frequency of the chloride ion channel which results in an increased influx of chloride ions into the GABAA receptors. Quazepam, unique amongst benzodiazepine drugs selectively targets type1 benzodiazepine receptors which results reduced sleep latency in promotion of sleep. Quazepam also has some anticonvulsant properties.

EEG and Sleep

Quazepam has potent sleep inducing and sleep maintaining properties. Studies in both animals and humans have demonstrated that EEG changes induced by quazepam resemble normal sleep patterns whereas other benzodiazepines disrupt normal sleep. Quazepam promotes slow wave sleep. This positive effect of quazepam on sleep architecture may be due to its high selectivity for type1 benzodiazepine receptors as demonstrated in animal and human studies. This makes quazepam unique in the benzodiazepine family of drugs.

Drug Misuse

Refer to Benzodiazepine Use Disorder.

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

What is Ramelteon?

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Introduction

Ramelteon, sold under the brand name Rozerem among others, is a sleep agent medication that selectively binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus (SCN), instead of binding to GABAA receptors, such as with drugs like zolpidem.

It appears to speed the onset of sleep and alter the total amount of sleep a person gets. It is approved by the US Food and Drug Administration (FDA) for long-term use.

Ramelteon does not show any appreciable binding to GABAA receptors, which are associated with anxiolytic, myorelaxant, and amnesic effects.

Brief History

Ramelteon was approved for use in the United States in July 2005.

Medical Uses

Ramelteon is approved in the United States for the treatment of insomnia characterised by difficulty with sleep onset.

A systematic review, published in 2014, concluded “ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo.”

Mechanism of Action

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors, and high selectivity for human MT1 and MT2 receptors compared to the MT3 receptor.

The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opioids. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel.

The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17-25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20-100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.

Adverse Effects

Ramelteon has not been shown to produce dependence and has shown no potential for abuse, and the withdrawal and rebound insomnia that is typical with GABA modulators is not present in ramelteon.

Six percent of ramelteon-treated patients in clinical trials discontinued due to an adverse event, compared with two percent in the placebo arms. The most frequent adverse events leading to discontinuation were somnolence, dizziness, nausea, fatigue, headache, and insomnia. The US official Prescribing Information warns of rare cases of anaphylactic reactions, abnormal thinking, worsening of depression or suicidal thinking in patients with pre-existing depression, and decreased testosterone and increased prolactin levels. It also notes that ramelteon is not recommended for use in patients with severe sleep apnoea.

In mice treated with ramelteon for two years, increases in liver and testicular tumours were observed, but only at doses at least 20 times greater than the recommended human dose on a milligram/kilogram basis.

Drug Interactions

Ramelteon has been evaluated for potential drug interactions with the following medications and showed no significant effects: omeprazole, theophylline, dextromethorphan, and midazolam, digoxin and warfarin. There were no clinically meaningful effects when ramelteon was co-administered with any of these drugs.

A drug interaction study showed that there were no clinically meaningful effects or an increase in adverse events when ramelteon and the SSRI Prozac (fluoxetine) were co-administered. When co-administered with ramelteon, fluvoxamine (strong CYP1A2 inhibitor) increased AUC approximately 190-fold, and the Cmax increased approximately 70-fold, compared to ramelteon administered alone. Ramelteon and fluvoxamine should not be co-administered.

Ramelteon has significant drug-drug interaction with the following drugs: amiodarone, ciprofloxacin, fluvoxamine, ticlopidine.

Ramelteon should be administered with caution in patients taking other CYP1A2 inhibitors, strong CYP3A4 inhibitors such as ketoconazole, and strong CYP2C9 inhibitors such as fluconazole.

Efficacy may be reduced when ramelteon is used in combination with potent CYP enzyme inducers such as rifampin, since ramelteon concentrations may be decreased.

What is Schema Therapy?

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Introduction

Schema therapy was developed by Jeffrey E. Young for use in treatment of personality disorders and chronic DSM Axis I disorders, such as when patients fail to respond or relapse after having been through other therapies (for example, traditional cognitive behavioural therapy, CBT). Schema therapy is an integrative psychotherapy combining theory and techniques from previously existing therapies, including CBT, psychoanalytic object relations theory, attachment theory, and Gestalt therapy.

Concepts

Four main theoretical concepts in schema therapy are early maladaptive schemas (or simply schemas), coping styles, modes, and basic emotional needs:

  1. In cognitive psychology, a schema is an organised pattern of thought and behaviour. It can also be described as a mental structure of preconceived ideas, a framework representing some aspect of the world, or a system of organizing and perceiving new information. In schema therapy, a schema specifically refers to an early maladaptive schema, defined as a pervasive self-defeating or dysfunctional theme or pattern of memories, emotions, and physical sensations, developed during childhood or adolescence and elaborated throughout one’s lifetime. Often they have the form of a belief about the self or the world. For instance, a person with an Abandonment schema could be hypersensitive (have an “emotional button” or “trigger”) about their perceived value to others, which in turn could make them feel sad and panicky in their interpersonal relationships.
  2. Coping styles are a person’s behavioural responses to schemas. There are three potential coping styles. In “avoidance” the person tries to avoid situations that activate the schema. In “surrender” the person gives into the schema, doesn’t try to fight against it, and changes their behaviour in expectation that the feared outcome is inevitable. In “counterattack”, also called “overcompensation”, the person puts extra work into not allowing the schema’s feared outcome to happen. These maladaptive coping styles (overcompensation, avoidance, or surrender) very often wind up reinforcing the schemas. Continuing the Abandonment example: having imagined a threat of abandonment in a relationship and feeling sad and panicky, a person using an avoidance coping style might then behave in ways to limit the closeness in the relationship to try to protect themselves from being abandoned. The resulting loneliness or even actual loss of the relationship could easily reinforce the person’s Abandonment schema. Another example can be given for the Defectiveness schema: A person using an avoidance coping style might avoid situations that make them feel defective, or might try to numb the feeling with addictions or distractions. A person using a surrender coping style might tolerate unfair criticism without defending themselves. A person using the counterattack/overcompensation coping style might put extra effort into being superhuman.
  3. Modes are mind states that cluster schemas and coping styles into a temporary “way of being” that a person can shift into occasionally or more frequently. For example, a Vulnerable Child mode might be a state of mind encompassing schemas of Abandonment, Defectiveness, Mistrust/Abuse and a coping style of surrendering (to the schemas).
  4. If a patient’s basic emotional needs are not met in childhood, then schemas, coping styles, and modes can develop. Some basic needs that have been identified are: connection, mutuality, reciprocity, flow, and autonomy. For example, a child with unmet needs around connection – perhaps due to parental loss to death, divorce, or addiction – might develop an Abandonment schema.

The goal of schema therapy is to help patients meet their basic emotional needs by helping the patient learn how to:

  • Heal schemas by diminishing the intensity of emotional memories comprising the schema and the intensity of bodily sensations, and by changing the cognitive patterns connected to the schema; and
  • Replace maladaptive coping styles and responses with adaptive patterns of behaviour.

Techniques used in schema therapy including limited reparenting and Gestalt therapy psychodrama techniques such as imagery re-scripting and empty chair dialogues (Refer to techniques in schema therapy, below).

There is a growing literature of outcome studies on schema therapy, where schema therapy has shown impressive results (Refer to outcome studies on schema therapy, below).

Early Maladaptive Schemas

Refer to List of Maladaptive Schemas.

Early maladaptive schemas are self-defeating emotional and cognitive patterns established from childhood and repeated throughout life. They may be made up of emotional memories of past hurt, tragedy, fear, abuse, neglect, unmet safety needs, abandonment, or lack of normal human affection in general. Early maladaptive schemas can also include bodily sensations associated with such emotional memories. Early maladaptive schemas can have different levels of severity and pervasiveness: the more severe the schema, the more intense the negative emotion when the schema is triggered and the longer it lasts; the more pervasive the schema, the greater the number of situations that trigger it.

Schema Domains

Schema domains are five broad categories of unmet needs into which are grouped 18 early maladaptive schemas identified by Young, Klosko & Weishaar (2003):

  • Disconnection/Rejection includes 5 schemas:
    • Abandonment/Instability.
    • Mistrust/Abuse.
    • Emotional Deprivation.
    • Defectiveness/Shame.
    • Social Isolation/Alienation.
  • Impaired Autonomy and/or Performance includes 4 schemas:
    • Dependence/Incompetence.
    • Vulnerability to Harm or Illness.
    • Enmeshment/Undeveloped Self.
    • Failure.
  • Impaired Limits includes 2 schemas:
    • Entitlement/Grandiosity.
    • Insufficient Self-Control and/or Self-Discipline.
  • Other-Directedness includes 3 schemas:
    • Subjugation.
    • Self-Sacrifice.
    • Approval-Seeking/Recognition-Seeking.
  • Over-vigilance/Inhibition includes 4 schemas:
    • Negativity/Pessimism.
    • Emotional Inhibition.
    • Unrelenting Standards/Hypercriticalness.
    • Punitiveness.

Schema Modes

Schema modes are momentary mind states which every human being experiences at one time or another. A schema mode consists of a cluster of schemas and coping styles. Life situations that a person finds disturbing or offensive, or arouse bad memories, are referred to as “triggers” that tend to activate schema modes. In psychologically healthy persons, schema modes are mild, flexible mind states that are easily pacified by the rest of their personality. In patients with personality disorders, schema modes are more severe, rigid mind states that may seem split off from the rest of their personality.

Identified Schema Modes

Young, Klosko & Weishaar (2003) identified 10 schema modes grouped into four categories. The four categories are: Child modes, Dysfunctional Coping modes, Dysfunctional Parent modes, and the Healthy Adult mode. The four Child modes are: Vulnerable Child, Angry Child, Impulsive/Undisciplined Child, and Happy Child. The three Dysfunctional Coping modes are: Compliant Surrenderer, Detached Protector, and Overcompensator. The two Dysfunctional Parent modes are: Punitive Parent and Demanding Parent.

Angry ChildThis is fuelled mainly by feelings of victimisation or bitterness, leading towards negativity, pessimism, jealousy, and rage. While experiencing this schema mode, a patient may have urges to yell, scream, throw/break things, or possibly even injure themselves or harm others. The Angry Child schema mode is enraged, anxious, frustrated, self-doubting, feels unsupported in ideas and vulnerable.
Impulsive ChildThis is the mode where anything goes. Behaviours of the Impulsive Child schema mode may include reckless driving, substance abuse, cutting oneself, suicidal thoughts, gambling, or fits of rage, such as punching a wall when “triggered” or laying blame of circumstantial difficulties upon innocent people. Unsafe sex, rash decisions to run away from a situation without resolution, tantrums perceived by peers as infantile, and so forth are a mere few of the behaviours which a patient in this schema mode might display. Impulsive Child is the rebellious and careless schema mode.
Detached ProtectorThis is based in escape. Patients in Detached Protector schema mode withdraw, dissociate, alienate, or hide in some way. This may be triggered by numerous stress factors or feelings of being overwhelmed. When a patient with insufficient skills is in a situation involving excessive demands, it can trigger a Detached Protector response mode. Stated simply, patients become numb in order to protect themselves from the harm or stress of what they fear is to come, or to protect themselves from fear of the unknown in general.
Abandoned ChildThis is the mode in which a patient may feel defective in some way, thrown aside, unloved, obviously alone, or may be in a “me against the world” mindset. The patient may feel as though peers, friends, family, and even the entire world have abandoned them. Behaviours of patients in Abandoned Child mode may include (but are not limited to) falling into major depression, pessimism, feeling unwanted, feeling unworthy of love, and perceiving personality traits as irredeemable flaws. Rarely, a patient’s self-perceived flaws may be intentionally withheld on the inside; when this occurs, instead of showing one’s true self, the patient may appear to others as “egotistical”, “attention-seeking”, selfish, distant, and may exhibit behaviours unlike their true nature. The patient might create a narcissistic alter-ego/persona in order to escape or hide the insecurity from others. Due to fear of rejection, of feeling disconnected from their true self and poor self-image, these patients, who truly desire companionship/affection, may instead end up pushing others away.
Punitive ParentThis is identified by beliefs of a patient that they should be harshly punished, perhaps due to feeling “defective”, or making a simple mistake. The patient may feel that they should be punished for even existing. Sadness, anger, impatience, and judgement are directed to the patient and from the patient. The Punitive Parent has great difficulty in forgiving themselves even under average circumstances in which anyone could fall short of their standards. The Punitive Parent does not wish to allow for human error or imperfection, thus punishment is what this mode seeks.
Healthy AdultThis is the mode that schema therapy aims to help a patient achieve as the long-lasting state of well-being. The Healthy Adult is comfortable making decisions, is a problem-solver, thinks before acting, is appropriately ambitious, sets limits and boundaries, nurtures self and others, forms healthy relationships, takes on all responsibility, sees things through, and enjoys/partakes in enjoyable adult activities and interests with boundaries enforced, takes care of their physical health, and values themselves. In this schema mode the patient focuses on the present day with hope and strives toward the best tomorrow possible. The Healthy Adult forgives the past, no longer sees themselves as a victim (but as a survivor), and expresses all emotions in ways which are healthy and cause no harm.

Techniques in Schema Therapy

Treatment plans in schema therapy generally encompass three basic classes of techniques: cognitive, experiential, and behavioural (in addition to the basic healing components of the therapeutic relationship). Cognitive strategies expand on standard CBT techniques such as listing pros and cons of a schema, testing the validity of a schema, or conducting a dialogue between the “schema side” and the “healthy side”. Experiential and emotion focused strategies expand on standard Gestalt therapy psychodrama and imagery techniques. Behavioural pattern-breaking strategies expand on standard behaviour therapy techniques, such as role playing an interaction and then assigning the interaction as homework. One of the most central techniques in schema therapy is the use of the therapeutic relationship, specifically through a process called “limited reparenting”.

Specific techniques often used in schema therapy include flash cards with important therapeutic messages, created in session and used by the patient between sessions, and the schema diary – a template or workbook that is filled out by the patient between sessions and that records the patient’s progress in relation to all the theoretical concepts in schema therapy.

Schema Therapy and Psychoanalysis

From an integrative psychotherapy perspective, limited reparenting and the experiential techniques, particularly around changing modes, could be seen as actively changing what psychoanalysis has described as object relations. Historically, mainstream psychoanalysis tended to reject active techniques – such as Fritz Perls’ Gestalt therapy work or Franz Alexander’s “corrective emotional experience” – but contemporary relational psychoanalysis (led by analysts such as Lewis Aron, and building on the ideas of earlier unorthodox analysts such as Sándor Ferenczi) is more open to active techniques. It is notable that in a head to head comparison of a psychoanalytic object relations treatment (Otto F. Kernberg’s transference focused psychotherapy) and schema therapy, the latter has been demonstrated to be more effective in treating Borderline Personality Disorder.

Outcome Studies on Schema Therapy

Schema Therapy vs Transference Focused Psychotherapy Outcomes

Dutch investigators, including Josephine Giesen-Bloo and Arnoud Arntz (the project leader), compared schema therapy (also known as schema focused therapy or SFT) with transference focused psychotherapy (TFP) in the treatment of borderline personality disorder. 86 patients were recruited from four mental health institutes in the Netherlands. Patients in the study received two sessions per week of SFT or TFP for three years. After three years, full recovery was achieved in 45% of the patients in the SFT condition, and in 24% of those receiving TFP. One year later, the percentage fully recovered increased to 52% in the SFT condition and 29% in the TFP condition, with 70% of the patients in the SFT group achieving “clinically significant and relevant improvement”. Moreover, the dropout rate was only 27% for SFT, compared with 50% for TFP.

Patients began to feel and function significantly better after the first year, with improvement occurring more rapidly in the SFT group. There was continuing improvement in subsequent years. Thus investigators concluded that both treatments had positive effects, with schema therapy clearly more successful.

Less Intensive Outpatient, Individual Schema Therapy

Dutch investigators, including Marjon Nadort and Arnoud Arntz, assessed the effectiveness of schema therapy in the treatment of borderline personality disorder when utilised in regular mental health care settings. A total of 62 patients were treated in eight mental health centres located in the Netherlands. The treatment was less intensive along a number of dimensions including a shift from twice weekly to once weekly sessions during the second year. Despite this, there was no lessening of effectiveness with recovery rates that were at least as high and similarly low dropout rates.

Pilot Study of Group Schema Therapy for Borderline Personality Disorder

Investigators Joan Farrell, Ida Shaw and Michael Webber at the Indiana University School of Medicine Centre for BPD Treatment & Research tested the effectiveness of adding an eight-month, 30-session schema therapy group to treatment-as-usual (TAU) for borderline personality disorder (BPD) with 32 patients. The dropout rate was 0% for those patients who received group schema therapy in addition to TAU and 25% for those who received TAU alone. At the end of treatment, 94% of the patients who received group schema therapy in addition to TAU compared to 16% of the patients receiving TAU alone no longer met BPD diagnostic criteria. The schema therapy group treatment led to significant reductions in symptoms and global improvement in functioning. The large positive treatment effects found in the group schema therapy study suggest that the group modality may augment or catalyse the active ingredients of the treatment for BPD patients. As of 2014, a collaborative randomised controlled trial is under way at 14 sites in six countries to further explore this interaction between groups and schema therapy.