What is Adinazolam?

Introduction

Adinazolam (marketed under the brand name Deracyn) is a tranquiliser of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring.

It possesses anxiolytic, anticonvulsant, sedative, and antidepressant properties. Adinazolam was developed by Dr. Jackson B. Hester, who was seeking to enhance the antidepressant properties of alprazolam, which he also developed. Adinazolam was never approved by the US Food and Drug Administration (FDA) and never made available to the public market, however it has been sold as a designer drug.

Side Effects

Overdose may include muscle weakness, ataxia, dysarthria and particularly in children paradoxical excitement, as well as diminished reflexes, confusion and coma may ensue in more severe cases.

A human study comparing the subjective effects and abuse potential of adinazolam (30 mg and 50 mg) with diazepam, lorazepam and a placebo showed that adinazolam causes the most “mental and physical sedation” and the greatest “mental unpleasantness”.

Pharmacodynamics and Pharmacokinetics

Adinazolam binds to peripheral-type benzodiazepine receptors that interact allosterically with GABA receptors as an agonist to produce inhibitory effects.

Metabolism

Adinazolam was reported to have active metabolites in the August 1984 issue of The Journal of Pharmacy and Pharmacology. The main metabolite is N-desmethyladinazolam. NDMAD has an approximately 25-fold high affinity for benzodiazepine receptors as compared to its precursor, accounting for the benzodiazepine-like effects after oral administration. Multiple N-dealkylations lead to the removal of the dimethylaminomethyl side chain, leading to the difference in its potency. The other two metabolites are alpha-hydroxyalprazolam and estazolam. In the August 1986 issue of that same journal, Sethy, Francis and Day reported that proadifen inhibited the formation of N-desmethyladinazolam.

What is Imipramine?

Introduction

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

It is also effective in treating anxiety and panic disorder. The drug is also used to treat bedwetting. Imipramine is taken by mouth.

Common side effects of imipramine include dry mouth, drowsiness, dizziness, low blood pressure, rapid heart rate, urinary retention, and electrocardiogram changes. Overdose of the medication can result in death. Imipramine appears to work by increasing levels of serotonin and norepinephrine and by blocking certain serotonin, adrenergic, histamine, and cholinergic receptors.

Imipramine was discovered in 1951 and was introduced for medical use in 1957. It was the first TCA to be marketed. Imipramine and the other TCAs have decreased in use in recent decades, due to the introduction of the selective serotonin reuptake inhibitors (SSRIs), which have fewer side effects and are safer in overdose.

Brief History

The parent compound of imipramine, 10,11-dihydro-5H-dibenz[b,f]azepine (dibenzazepine), was first synthesized in 1899, but no pharmacological assessment of this compound or any substituted derivatives was undertaken until the late 1940s. Imipramine was first synthesized in 1951, as an antihistamine. The antipsychotic effects of chlorpromazine were discovered in 1952, and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia. The medication was tested in several hundred patients with psychosis, but showed little effectiveness. However, imipramine was serendipitously found to possess antidepressant effects in the mid-1950s following a case report of symptom improvement in a woman with severe depression who had been treated with it. This was followed by similar observations in other patients and further clinical research. Subsequently, imipramine was introduced for the treatment of depression in Europe in 1958 and in the United States in 1959. Along with the discovery and introduction of the monoamine oxidase inhibitor iproniazid as an antidepressant around the same time, imipramine resulted in the establishment of monoaminergic drugs as antidepressants.

In the late 1950s, imipramine was the first TCA to be developed (by Ciba). At the first international congress of neuropharmacology in Rome, September 1958 Dr Freyhan from the University of Pennsylvania discussed as one of the first clinicians the effects of imipramine in a group of 46 patients, most of them diagnosed as “depressive psychosis”. The patients were selected for this study based on symptoms such as depressive apathy, kinetic retardation and feelings of hopelessness and despair. In 30% of all patients, he reported optimal results, and in around 20%, failure. The side effects noted were atropine-like, and most patients suffered from dizziness. Imipramine was first tried against psychotic disorders such as schizophrenia, but proved ineffective. As an antidepressant, it did well in clinical studies and it is known to work well in even the most severe cases of depression. It is not surprising, therefore, that imipramine may cause a high rate of manic and hypomanic reactions in hospitalised patients with pre-existing bipolar disorder, with one study showing that up to 25% of such patients maintained on Imipramine switched into mania or hypomania. Such powerful antidepressant properties have made it favourable in the treatment of treatment-resistant depression.

Before the advent of SSRIs, its sometimes intolerable side-effect profile was considered more tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released TCAs. Since the 1990s, it has no longer been used as commonly, but is sometimes still prescribed as a second-line treatment for treating major depression . It has also seen limited use in the treatment of migraines, ADHD, and post-concussive syndrome. Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome. In paediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis.

Medical Uses

Imipramine is used in the treatment of depression and certain anxiety disorders. It is similar in efficacy to the antidepressant drug moclobemide. It has also been used to treat nocturnal enuresis because of its ability to shorten the time of delta wave stage sleep, where wetting occurs. In veterinary medicine, imipramine is used with xylazine to induce pharmacologic ejaculation in stallions. Blood levels between 150-250 ng/mL of imipramine plus its metabolite desipramine generally correspond to antidepressant efficacy.

Available Forms

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

Contraindications

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

Side Effects

Those listed in italics below denote common side effects.

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

Overdose

Refer to Tricyclic Antidepressant Overdose.

Pharmacology

Pharmacodynamics

Imipramine affects numerous neurotransmitter systems known to be involved in the aetiology of depression, anxiety, attention-deficit hyperactivity disorder (ADHD), enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.

The mechanisms of imipramine’s actions include, but are not limited to, effects on:

  • Serotonin: very strong reuptake inhibition.
  • Norepinephrine: strong reuptake inhibition.
    • Desipramine has more affinity to norepinephrine transporter than imipramine.
  • Dopamine:
    • Imipramine blocks D2 receptors.
    • Imipramine, and its metabolite desipramine, have no appreciable affinity for the dopamine transporter (Ki = 8,500 and >10,000 nM, respectively).
  • Acetylcholine:
    • Imipramine is an anticholinergic, specifically an antagonist of the muscarinic acetylcholine receptors.
    • Thus, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the “dementing” effects of anticholinergics increases the potential of imipramine to cause hallucinations, confusion and delirium in this population.
  • Epinephrine:
    • Imipramine antagonises adrenergic receptors, thus sometimes causing orthostatic hypotension.
  • Sigma receptor:
    • Activity on sigma receptors is present, but it is very weak (Ki = 520 nM) and it is about half that of amitriptyline (Ki = 300 nM).
  • Histamine:
    • Imipramine is an antagonist of the histamine H1 receptors.
  • BDNF:
    • BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis.
    • It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours.
    • Chronic imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promoter, and also reduced expression of hippocampal HDAC5.

Pharmacokinetics

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

Chemistry

Imipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include desipramine (N-desmethylimipramine), clomipramine (3-chloroimipramine), trimipramine (2′-methylimipramine or β-methylimipramine), and lofepramine (N-(4-chlorobenzoylmethyl)desipramine). Imipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of imipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H24N2 with a molecular weight of 280.407 g/mol. The drug is used commercially mostly as the hydrochloride salt; the embonate (pamoate) salt is used for intramuscular administration and the free base form is not used. The CAS Registry Number of the free base is 50-49-7, of the hydrochloride is 113-52-0, and of the embonate is 10075-24-8.

Society and Culture

Generic Names

Imipramine is the English and French generic name of the drug and its INN, BAN, and DCF, while imipramine hydrochloride is its USAN, USP, BANM, and JAN. Its generic name in Spanish and Italian and its DCIT are imipramina, in German is imipramin, and in Latin is imipraminum. The embonate salt is known as imipramine pamoate.

Brand Names

Imipramine is marketed throughout the world mainly under the brand name Tofranil. Imipramine pamoate is marketed under the brand name Tofranil-PM for intramuscular injection.

Availability

Imipramine is available for medical use widely throughout the world, including in the United States, the United Kingdom, elsewhere in Europe, Brazil, South Africa, Australia, and New Zealand.

What is Interpersonal and Social Rhythm Therapy?

Introduction

Interpersonal and social rhythm therapy (IPSRT) is an intervention for people with bipolar disorder (BD).

Its primary focus is stabilising the circadian rhythm disruptions that are common among people with bipolar disorder. IPSRT draws upon principles from interpersonal psychotherapy, an evidence-based treatment for depression and emphasizes the importance of daily routine (rhythm).

IPSRT was developed by Ellen Frank, PhD at the University of Pittsburgh who published a book on her theories: Treating Bipolar Disorder, a Clinician’s Guide Interpersonal and Social Rhythm Therapy. Her research on IPSRT has shown that, in combination with medication, solving interpersonal problems and maintaining regular daily rhythms of sleeping, waking, eating, and exercise can increase quality of life, reduce mood symptoms, and help prevent relapse in people with BD.

Social Zeitgeber Hypothesis

Zeitgebers (“time givers”) are environmental cues that synchronize biological rhythms to the 24-hour light/dark cycle. As the sun is a physical zeitgeber, social factors are considered social zeitgebers. These include personal relationships, social demands, or life tasks that entrain circadian rhythms. Disruptions in circadian rhythms can lead to somatic and cognitive symptoms, as seen in jet lag or during daylight saving time. Individuals diagnosed with, or at risk for, mood disorders may be especially sensitive to these disruptions and thus, vulnerable to episodes of depression or mania when circadian rhythm disruptions occur.

Changes in daily routines place stress on the body’s maintenance of sleep-wake cycles, appetite, energy, and alertness, all of which are affected during mood episodes. For example, depressive symptoms include disturbed sleep patterns (sleeping too much or difficulty falling asleep), changes in appetite, fatigue, and slowed movement or agitation. Manic symptoms include decreased need for sleep, excessive energy, and increase in goal-directed activity. When the body’s rhythms becomes desynchronised, it can result in episodes of depression and mania.

Aims of Treatment

Goals of IPSRT are to stabilise social rhythms (e.g. eating meals with other people) while improving the quality of interpersonal relationships and satisfaction with social roles. Stabilising social rhythms helps to protect against disruptions of biological rhythms; individuals are more likely to maintain a rhythm when other people are involved to hold them accountable.

Interpersonal work can involve addressing unresolved grief experiences including grief for the lost healthy self, negotiating a transition in a major life role, and resolving a role dispute with a significant other. These experiences can be disruptive to social rhythms and thus, serve as targets of treatment to prevent the onset and recurrence of mood episodes seen in bipolar disorder.

Phases of Treatment

IPSRT typically proceeds in four phases:

  1. The initial phase involves a review of the patient’s mental health history in order to elucidate patterns in the associations between social routine disruptions, interpersonal problems and affective episodes. Psychoeducation about BD and the importance of stable routines to mood maintenance is provided. Additionally, The Interpersonal Inventory is used to assess the quality of the patient’s interpersonal relationships. One of four interpersonal problem areas is chosen to focus on:
    • Grief (e.g. loss of loved one, loss of healthy self).
    • Role transitions (e.g. married-to-divorced, parenthood).
    • Role disputes (e.g. conflict with spouse or parents).
    • Interpersonal deficits (e.g. persistent social isolation).
      • The Social Rhythm Metric (SRM) is used to assess the regularity of social routines.
      • Target and actual time of the following activities are tracked on a daily basis: got out of bed; first contact with another person; started work, school, or housework; ate dinner; and went into bed.
      • The intensity of involvement with other people is also rated: 0 = alone, 1 = others present, 2 = others actively involved, and 3 = others very stimulating.
      • Finally, mood is rated on a scale of -5 to +5 at the end of each day.
  2. The intermediate phase focuses on bringing regularity to social rhythms and intervening in the interpersonal problem area of interest.
    • SRM is heavily used to assess amount of activity being engaged in and the impact of activity on mood. The regularity (or irregularity) of activities is examined, and the patient and therapist collaboratively plan how to stabilise the daily routine by making incremental behavioural modifications until a regular target time at which these activities are done is achieved.
    • Sources of interpersonal distress are explored, and individuals in the patient’s life who destabilise routine, along with those who are supportive, are identified. Frequency and intensity of social interactions, as well as other social rhythms (e.g. time at which returning home from school/work and then interacting with family), are discussed.
  3. The maintenance phase aims to reinforce the techniques learned earlier in treatment in order to maintain social rhythms and positive interpersonal relationships.
    • Discussion of early warning signs of episodes are reviewed.
    • Symptomatic and functional change is monitored at each session by asking the patient to rate their mood and note any shifts in routine using the SRM.
  4. The final phase involves termination in which sessions are gradually reduced in frequency.

Interpersonal Strategies

Once the interpersonal problem area of focus is chosen, the following strategies may be used:

  1. Grief:
    • This refers to symptoms resulting from incomplete mourning or unresolved feelings about the death of an important person.
    • This can also refer to grief for the loss of a healthy self (i.e. the person before the illness or the person one could have become, if not for BD).
    • Strategies include encouraging expression of painful feelings about lost hopes, ruined relationships, interrupted careers, and passed opportunities.
    • This is followed by encouragement to develop new relationships, establish new, more realistic goals, and focus on future opportunities.
  2. Interpersonal role disputes:
    • This refers to any close relationship in which there are nonreciprocal expectations, such as in marital conflict and arguments with parental figures.
    • Strategies include learning how to be more patient, tolerant, and accepting of limitations in self and others.
    • This, in turn, can lead to fewer critical and argumentative instincts.
  3. Role transition:
    • This refers to any major life role change, such as new employment, graduation, retirement, marriage, divorce, and giving birth.
    • This can also refer to the loss of previously pleasurable hypomania.
    • Strategies can include noting the negative consequences of hypomania and encouraging the identification of rewarding life goals as suitable alternatives.
  4. Interpersonal deficits:
    • This refers to a long-standing history of impoverished or contentious social relationships, leading to an overall feeling of dissatisfaction.
    • Strategies include identifying the common thread in the multiple disputes across one’s life and possibly working to restore “burnt bridges”.

Social Rhythm Strategies

Individuals with BD benefit from a higher level of stability in their sleep and daily routines than those with no history of affective illness. It is important to identify situations in which routines can be thrown off balance, whether by excessive activity and overstimulation or lack of activity and under-stimulation. Once destabilizing triggers are identified, reasonable goals for change are established. Specific strategies include:

  1. Encouraging proper sleep hygiene to introduce regularity to sleep-wake cycle.
    • Establish a regular wake and sleep time.
    • Avoid caffeine or other stimulants.
    • Use the bed only for sleep and sex, not for watching TV, doing homework, reading etc.
    • Align sunlight exposure with wake time to help set circadian clock.
  2. Maintaining regular meal times throughout the day.
    • Plan ahead by meal prepping the day before.
    • Include snack times if needed to encourage consistent eating habits.
  3. Encouraging medication adherence and establishing a regular schedule.
    • Use alarms on phone as reminders for when to take pills.
    • Use daily pillboxes to keep track of which pills to take at certain times.
  4. Monitoring frequency and intensity of social interactions using Social Rhythm Metric.
    • Note time at which interactions happen and adjust accordingly to establish regularity.
  5. Minimising overstimulation of social interactions.
    • Avoid frequent parties or events.
    • Use recovery days as needed.
  6. Addressing under-stimulation with behavioural activation.
    • Engage in activities that are pleasurable and that give one a sense of mastery.
    • Focus on small, manageable goals that can lead to engagement in other activities (e.g. start jogging to get in shape prior to joining a basketball team).
  7. Identifying interpersonal sources of stabilizing and destabilising influence.
    • Spend time with those who are supportive and stabilising.
    • Reduce time with those who are disruptive.

Evidence of IPSRT Efficacy

In a randomized controlled trial, those who received IPSRT during the acute treatment phase went longer without a new affective episode (depression or mania) than those who received intensive clinical management. Participants in the IPSRT group also had higher regularity of social rhythms at the end of acute treatment, which was associated with reduced likelihood of relapse during maintenance phase. Additionally, those who received IPSRT showed more rapid improvement in occupational functioning than those assigned to intensive clinical management. However, at the end of two years of maintenance treatment, there were no differences between treatment groups.

IPSRT was studied as one of three intensive psychosocial treatments in the NIMH-funded Systematic Treatment Enhancement Programme for Bipolar Disorder. STEP-BD was a long-term outpatient study investigating the benefits of psychotherapies in conjunction with pharmacotherapy in treating episodes of depression and mania, as well as preventing relapse in people with bipolar disorder. Patients were 1.58 times more likely to be well in any study month if they received intensive psychotherapy (cognitive-behavioural therapy, family focused therapy, or IPSRT) than if they received collaborative care in addition to pharmacotherapy. They also had significantly higher year-end recovery rates and shorter times to recovery.

In a trial conducted by a separate research group, 100 participants aged 15-36 years with bipolar I disorder, bipolar II disorder, and bipolar disorder not otherwise specified were randomised to IPSRT (n = 49) or specialist supportive care (n = 51). Both groups experienced improvement in depressive symptoms, social functioning, and manic symptoms, but there were no significant differences between the groups.

Adolescents

IPSRT was adapted to be delivered to adolescents with BD. In an open trial (N=12), feasibility and acceptability of IPSRT-A were high; 11/12 participants completed treatment, 97% of sessions were attended, and adolescent-rated satisfaction scores were high. IPSRT-A participants experienced significant decreases in manic, depressive, and general psychiatric symptoms over the 20 weeks of treatment. Participants’ global functioning increased significantly as well.

In an open trial aimed at prevention, adolescents (N=13) who were identified as high risk for bipolar disorder, due to having a first-degree relative with BD, received IPSRT. Significant changes in sleep/circadian patterns (i.e. less weekend sleeping in and oversleeping) were observed. Families reported high satisfaction with IPSRT, yet, on average, participants attended about half of scheduled sessions. Missed sessions were primarily associated with parental BD illness severity.

Group Therapy

IPSRT was adapted for a group therapy setting; administered over 16 sessions, in a semi-structured format. Patients (N=22) made interpersonal goals, reflected on how they managed their illness, and empathised with fellow group members. Patients were encouraged to react to each other from their own experience, express their feelings about what was said, and to give constructive feedback. Patients spent significantly less time depressed in the year following treatment than they did in the year prior to treatment.

In another small trial, patients with BD who experiencing a depressive episode (N = 9) received six IPSRT-G sessions across two weeks. Topics of discussion in group included defining interpersonal focus area, defining target times for daily routines, discussing grief and medication adherence, addressing interpersonal disputes and role transitions, and reviewing IPSRT strategies and relapse prevention. Depressive symptoms improved significantly at the end of the treatment; improvements were maintained 10 weeks following treatment end.

What is Lofepramine?

Introduction

Lofepramine, sold under the brand names Gamanil, Lomont, and Tymelyt among others, is a tricyclic antidepressant (TCA) which is used to treat depression.

The TCAs are so named as they share the common property of having three rings in their chemical structure. Like most TCAs lofepramine is believed to work in relieving depression by increasing concentrations of the neurotransmitters norepinephrine and serotonin in the synapse, by inhibiting their reuptake. It is usually considered a third-generation TCA, as unlike the first- and second-generation TCAs it is relatively safe in overdose and has milder and less frequent side effects.

Lofepramine is not available in the United States, Canada, Australia or New Zealand, although it is available in Ireland, Japan, South Africa and the United Kingdom, among other countries.

Brief History

Lofepramine was developed by Leo Läkemedel AB. It first appeared in the literature in 1969 and was patented in 1970. The drug was first introduced for the treatment of depression in either 1980 or 1983.

Depression

In the United Kingdom, lofepramine is licensed for the treatment of depression which is its primary use in medicine.

Lofepramine is an efficacious antidepressant with about 64% patients responding to it.

Contraindications

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

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

And in those being treated with amiodarone or terfenadine.

Pregnancy and Lactation

Lofepramine use during pregnancy is advised against unless the benefits clearly outweigh the risks. This is because its safety during pregnancy has not been established and animal studies have shown some potential for harm if used during pregnancy. If used during the third trimester of pregnancy it can cause insufficient breathing to meet oxygen requirements, agitation and withdrawal symptoms in the infant. Likewise its use by breastfeeding women is advised against, except when the benefits clearly outweigh the risks, due to the fact it is excreted in the breast milk and may therefore adversely affect the infant. Although the amount secreted in breast milk is likely too small to be harmful.

Side Effects

The most common adverse effects (occurring in at least 1% of those taking the drug) include agitation, anxiety, confusion, dizziness, irritability, abnormal sensations, like pins and needles, without a physical cause, sleep disturbances (e.g. sleeplessness) and a drop in blood pressure upon standing up. Less frequent side effects include movement disorders (like tremors), precipitation of angle closure glaucoma and the potentially fatal side effects paralytic ileus and neuroleptic malignant syndrome.

Dropout incidence due to side effects is about 20%.

Side effects with unknown frequency include (but are not limited to):

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

Withdrawal

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

Overdose

Refer to Tricyclic Antidepressant Overdose.

Compared to other TCAs, lofepramine is considered to be less toxic in overdose. Its treatment is mostly a matter of trying to reduce absorption of the drug, if possible, using gastric lavage and monitoring for adverse effects on the heart.

Interactions

Lofepramine is known to interact with:

  • Alcohol. Increased sedative effect.
  • Altretamine. Risk of severe drop in blood pressure upon standing.
  • Analgesics (painkillers). Increased risk of ventricular arrhythmias.
  • Anticoagulants (blood thinners). Lofepramine may inhibit the metabolism of certain anticoagulants leading to a potentially increased risk of bleeding.
  • Anticonvulsants. Possibly reduce the anticonvulsant effect of antiepileptics by lowering the seizure threshold.
  • Antihistamines. Possible increase of antimuscarinic (potentially increasing risk of paralytic ileus, among other effects) and sedative effects.
  • Antimuscarinics. Possible increase of antimuscarinic side-effects.
  • Anxiolytics and hypnotics. Increased sedative effect.
  • Apraclonidine. Avoidance advised by manufacturer of apraclonidine.
  • Brimonidine. Avoidance advised by manufacturer of brimonidine.
  • Clonidine. Lofepramine may reduce the antihypertensive effects of clonidine.
  • Diazoxide. Enhanced hypotensive (blood pressure-lowering) effect.
  • Digoxin. May increase risk of irregular heart rate.
  • Disulfiram. May require a reduction of lofepramine dose.
  • Diuretics. Increased risk of reduced blood pressure on standing.
  • Cimetidine, diltiazem, verapamil. May increase concentration of lofepramine in the blood plasma.
  • Hydralazine. Enhanced hypotensive effect.
  • Monoamine oxidase inhibitors (MAOIs). Advised not to be started until at least 2 weeks after stopping MAOIs. MAOIs are advised not to be started until at least 1-2 weeks after stopping TCAs like lofepramine.
  • Moclobemide. Moclobemide is advised not to be started until at least one week after treatment with TCAs is discontinued.
  • Nitrates. Could possibly reduce the effects of sublingual tablets of nitrates (failure to dissolve under tongue owing to dry mouth).
  • Rifampicin. May accelerate lofepramine metabolism thereby decreasing plasma concentrations of lofepramine.
  • Ritonavir. May increase lofepramine concentration in the blood plasma.
  • Sodium nitroprusside. Enhanced hypotensive effect.
  • Thyroid hormones. Effects on the heart of lofepramine may be exacerbated.

Pharmacology

Pharmacodynamics

Lofepramine is a strong inhibitor of norepinephrine reuptake and a moderate inhibitor of serotonin reuptake. It is a weak-intermediate level antagonist of the muscarinic acetylcholine receptors.

Lofepramine has been said to be a prodrug of desipramine, although there is also evidence against this notion.

Pharmacokinetics

Lofepramine is extensively metabolised, via cleavage of the p-chlorophenacyl group, to the TCA, desipramine, in humans. However, it is unlikely this property plays a substantial role in its overall effects as lofepramine exhibits lower toxicity and anticholinergic side effects relative to desipramine while retaining equivalent antidepressant efficacy. The p-chlorophenacyl group is metabolised to p-chlorobenzoic acid which is then conjugated with glycine and excreted in the urine. The desipramine metabolite is partly secreted in the faeces. Other routes of metabolism include hydroxylation, glucuronidation, N-dealkylation and N-oxidation.

Chemistry

Lofepramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include imipramine, desipramine, clomipramine, and trimipramine. Lofepramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine. Unlike other tertiary amine TCAs, lofepramine has a bulky 4-chlorobenzoylmethyl substituent on its amine instead of a methyl group. Although lofepramine is technically a tertiary amine, it acts in large part as a prodrug of desipramine, and is more similar to secondary amine TCAs in its effects. Other secondary amine TCAs besides desipramine include nortriptyline and protriptyline. The chemical name of lofepramine is N-(4-chlorobenzoylmethyl)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine and its free base form has a chemical formula of C26H27ClN2O with a molecular weight of 418.958 g/mol. The drug is used commercially mostly as the hydrochloride salt; the free base form is not used. The CAS Registry Number of the free base is 23047-25-8 and of the hydrochloride is 26786-32-3.

Society and Culture

Generic Names

Lofepramine is the generic name of the drug and its INN and BAN, while lofepramine hydrochloride is its USAN, BANM, and JAN. Its generic name in French and its DCF are lofépramine, in Spanish and Italian and its DCIT are lofepramina, in German is lofepramin, and in Latin is lofepraminum.

Brand Names

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

Availability

In the United Kingdom, lofepramine is marketed (as the hydrochloride salt) in the form of 70 mg tablets and 70 mg/5 mL oral suspension.

Research

Fatigue

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

What is Loxapine?

Introduction

Loxapine, sold under the brand names Loxitane and Adasuve (inhalation only) among others, is a typical antipsychotic medication used primarily in the treatment of schizophrenia.

The drug is a member of the dibenzoxazepine class and structurally related to clozapine. Several researchers have argued that loxapine may behave as an atypical antipsychotic.

Loxapine may be metabolised by N-demethylation to amoxapine, a tricyclic antidepressant.

Medical Uses

The US Food and Drug Administration (FDA) has approved loxapine inhalation powder for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.

A brief review of loxapine found no conclusive evidence that it was particularly effective in patients with paranoid schizophrenia. A subsequent systematic review considered that the limited evidence did not indicate a clear difference in its effects from other antipsychotics.

Available Forms

Loxapine can be taken by mouth as a capsule or a liquid oral concentrate. It is also available as an intramuscular injection and as a powder for inhalation.

Side Effects

Loxapine can cause side effects that are generally similar to that of other medications in the typical antipsychotic class of medications. These include, e.g. gastrointestinal problems (like constipation and abdominal pain), cardiovascular problems (like tachycardia), moderate likelihood of drowsiness (relative to other antipsychotics), and movement problems (i.e. extrapyramidal symptoms (EPS)). At lower dosages its propensity for causing EPS appears to be similar to that of atypical antipsychotics. Although it is structurally similar to clozapine, it does not have the same risk of agranulocytosis (which, even with clozapine, is less than 1%); however, mild and temporary fluctuations in blood leukocyte levels can occur. Abuse of loxapine has been reported.

The inhaled formulation of loxapine carries a low risk for a type of airway adverse reaction called bronchospasm that is not thought to occur when loxapine is taken by mouth.

Pharmacology

Mechanism of Action

Loxapine is a “mid-potency” typical antipsychotic. However, unlike most other typical antipsychotics, it has significant potency at the 5HT2A receptor (6.6 nM), which is similar to atypical antipsychotics like clozapine (5.35 nM). The higher likelihood of EPS with loxapine, compared to clozapine, may be due to its high potency for the D2 receptor.

Pharmacokinetics

Loxapine is metabolised to amoxapine, as well as its 8-hydroxy metabolite (8-hydroxyloxapine). Amoxapine is further metabolized to its 8-hydroxy metabolite (8-hydroxyamoxapine), which is also found in the blood of people taking loxapine. At steady-state after taking loxapine by mouth, the relative amounts of loxapine and its metabolites in the blood is as follows: 8-hydroxyloxapine > 8-hydroxyamoxapine > loxapine.

The pharmacokinetics of loxapine change depending on how it is given. Intramuscular injections of loxapine lead to higher blood levels and area under the curve of loxapine than when it is taken by mouth.

Chemistry

Loxapine is a dibenzoxazepine and is structurally related to clozapine.

What is Haloperidol?

Introduction

Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication.

Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations in alcohol withdrawal. It may be used by mouth or injection into a muscle or a vein. Haloperidol typically works within 30 to 60 minutes. A long-acting formulation may be used as an injection every four weeks in people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.

Haloperidol may result in a movement disorder known as tardive dyskinesia which may be permanent. Neuroleptic malignant syndrome and QT interval prolongation may occur. In older people with psychosis due to dementia it results in an increased risk of death. When taken during pregnancy it may result in problems in the infant. It should not be used in people with Parkinson’s disease.

Haloperidol was discovered in 1958 by Paul Janssen. It was made from pethidine (meperidine). It is on the World Health Organisation’s (WHO’s) List of Essential Medicines. It is the most commonly used typical antipsychotic. In 2017, it was the 296th most commonly prescribed medication in the United States, with more than one million prescriptions.

Refer to Haloperidol Decanoate.

Brief History

Haloperidol was discovered by Paul Janssen. It was developed in 1958 at the Belgian company Janssen Pharmaceutica and submitted to the first of clinical trials in Belgium later that year.

Haloperidol was approved by the US Food and Drug Administration (FDA) on 12 April 1967; it was later marketed in the US and other countries under the brand name Haldol by McNeil Laboratories.

Medical Uses

Haloperidol is used in the control of the symptoms of:

  • Acute psychosis, such as drug-induced psychosis caused by LSD, psilocybin, amphetamines, ketamine, and phencyclidine, and psychosis associated with high fever or metabolic disease.
    • Some evidence, however, has found haloperidol to worsen psychosis due to psilocybin.
  • Adjunctive treatment of alcohol and opioid withdrawal.
  • Agitation and confusion associated with cerebral sclerosis.
  • Alcohol-induced psychosis.
  • Hallucinations in alcohol withdrawal.
  • Hyperactive delirium (to control the agitation component of delirium).
  • Hyperactivity, aggression.
  • Otherwise uncontrollable, severe behavioral disorders in children and adolescents.
  • Schizophrenia.
  • Therapeutic trial in personality disorders, such as borderline personality disorder.
  • Treatment of intractable hiccups.
  • Treatment of neurological disorders, such as tic disorders such as Tourette syndrome, and chorea.
  • Treatment of severe nausea and emesis in postoperative and palliative care, especially for palliating adverse effects of radiation therapy and chemotherapy in oncology.

Haloperidol was considered indispensable for treating psychiatric emergency situations, although the newer atypical drugs have gained a greater role in a number of situations as outlined in a series of consensus reviews published between 2001 and 2005.

In a 2013 comparison of 15 antipsychotics in schizophrenia, haloperidol demonstrated standard effectiveness. It was 13-16% more effective than ziprasidone, chlorpromazine, and asenapine, approximately as effective as quetiapine and aripiprazole, and 10% less effective than paliperidone.

Pregnancy and Lactation

Data from animal experiments indicate haloperidol is not teratogenic, but is embryotoxic in high doses. In humans, no controlled studies exist. Reports in pregnant women revealed possible damage to the foetus, although most of the women were exposed to multiple drugs during pregnancy. In addition, reports indicate neonates exposed to antipsychotic drugs are at risk for extrapyramidal and/or withdrawal symptoms following delivery, such as agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Following accepted general principles, haloperidol should be given during pregnancy only if the benefit to the mother clearly outweighs the potential foetal risk.

Haloperidol is excreted in breast milk. A few studies have examined the impact of haloperidol exposure on breastfed infants and in most cases, there were no adverse effects on infant growth and development.

Other Considerations

During long-term treatment of chronic psychiatric disorders, the daily dose should be reduced to the lowest level needed for maintenance of remission. Sometimes, it may be indicated to terminate haloperidol treatment gradually. In addition, during long-term use, routine monitoring including measurement of BMI, blood pressure, fasting blood sugar, and lipids, is recommended due to the risk of side effects.

Other forms of therapy (psychotherapy, occupational therapy/ergotherapy, or social rehabilitation) should be instituted properly. PET imaging studies have suggested low doses are preferable. Clinical response was associated with at least 65% occupancy of D2 receptors, while greater than 72% was likely to cause hyperprolactinaemia and over 78% associated with extrapyramidal side effects. Doses of haloperidol greater than 5 mg increased the risk of side effects without improving efficacy. Patients responded with doses under even 2 mg in first-episode psychosis. For maintenance treatment of schizophrenia, an international consensus conference recommended a reduction dosage by about 20% every 6 months until a minimal maintenance dose is established.

Depot forms are also available; these are injected deeply intramuscularly at regular intervals. The depot forms are not suitable for initial treatment, but are suitable for patients who have demonstrated inconsistency with oral dosages.

The decanoate ester of haloperidol (haloperidol decanoate, trade names Haldol decanoate, Halomonth, Neoperidole) has a much longer duration of action, so is often used in people known to be noncompliant with oral medication. A dose is given by intramuscular injection once every two to four weeks. The IUPAC name of haloperidol decanoate is [4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl] decanoate.

Topical formulations of haloperidol should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives.

Adverse Effects

As haloperidol is a high-potency typical antipsychotic, it tends to produce significant extrapyramidal side effects. According to a 2013 meta-analysis of the comparative efficacy and tolerability of 15 antipsychotic drugs it was the most prone of the 15 for causing extrapyramidal side effects.

With more than 6 months of use 14 percent of users gain weight. Haloperidol may be neurotoxic.

  • Common (>1% incidence):
    • Extrapyramidal side effects including:
      • Akathisia (motor restlessness).
      • Dystonia (continuous spasms and muscle contractions).
      • Muscle rigidity.
      • Parkinsonism (characteristic symptoms such as rigidity).
    • Hypotension:
    • Anticholinergic side effects such as (These adverse effects are less common than with lower-potency typical antipsychotics, such as chlorpromazine and thioridazine):
      • Blurred vision.
      • Constipation.
      • Dry mouth.
    • Somnolence (which is not a particularly prominent side effect, as is supported by the results of the aforementioned meta-analysis).
  • Unknown frequency:
    • Anaemia.
    • Headache.
    • Increased respiratory rate.
    • Orthostatic hypotension.
    • Prolonged QT interval.
    • Visual disturbances.
  • Rare (<1% incidence):
    • Acute hepatic failure.
    • Agitation.
    • Agranulocytosis.
    • Anaphylactic reaction.
    • Anorexia.
    • Bronchospasm.
    • Cataracts.
    • Cholestasis.
    • Confusional state.
    • Depression.
    • Dermatitis exfoliative.
    • Dyspnoea.
    • Oedema.
    • Extrasystoles.
    • Face oedema.
    • Gynecomastia.
    • Hepatitis.
    • Hyperglycaemia.
    • Hypersensitivity.
    • Hyperthermia.
    • Hypoglycaemia.
    • Hyponatremia.
    • Hypothermia.
    • Increased sweating.
    • Injection site abscess.
    • Insomnia.
    • Itchiness.
    • Jaundice.
    • Laryngeal oedema.
    • Laryngospasm.
    • Leukocytoclastic vasculitis.
    • Leukopenia.
    • Liver function test abnormal.
    • Nausea.
    • Neuroleptic malignant syndrome.
    • Neutropenia.
    • Pancytopenia.
    • Photosensitivity reaction.
    • Priapism.
    • Psychotic disorder.
    • Pulmonary embolism.
    • Rash.
    • Retinopathy.
    • Seizure.
    • Sudden death.
    • Tardive dyskinesia.
    • Thrombocytopenia.
    • Torsades de pointes.
    • Urinary retention.
    • Urticaria.
    • Ventricular fibrillation.
    • Ventricular tachycardia.
    • Vomiting.

Contraindications

  • Pre-existing coma, acute stroke.
  • Severe intoxication with alcohol or other central depressant drugs.
  • Known allergy against haloperidol or other butyrophenones or other drug ingredients.
  • Known heart disease, when combined will tend towards cardiac arrest.

Special Cautions

  • A multiple-year study suggested this drug and other neuroleptic antipsychotic drugs commonly given to people with Alzheimer’s with mild behavioural problems often make their condition worse and its withdrawal was even beneficial for some cognitive and functional measures.
  • Elderly patients with dementia-related psychosis: analysis of 17 trials showed the risk of death in this group of patients was 1.6 to 1.7 times that of placebo-treated patients.
    • Most of the causes of death were either cardiovascular or infectious in nature.
    • It is not clear to what extent this observation is attributed to antipsychotic drugs rather than the characteristics of the patients.
    • The drug bears a boxed warning about this risk.
  • Impaired liver function, as haloperidol is metabolised and eliminated mainly by the liver.
  • In patients with hyperthyroidism, the action of haloperidol is intensified and side effects are more likely.
  • IV injections: risk of hypotension or orthostatic collapse.
  • Patients at special risk for the development of QT prolongation (hypokalaemia, concomitant use of other drugs causing QT prolongation).
  • Patients with a history of leukopenia: a complete blood count should be monitored frequently during the first few months of therapy and discontinuation of the drug should be considered at the first sign of a clinically significant decline in white blood cells.
  • Pre-existing Parkinson’s disease or dementia with Lewy bodies.

Interactions

  • Amiodarone: Q-Tc interval prolongation (potentially dangerous change in heart rhythm).
  • Amphetamine and methylphenidate: counteracts increased action of norepinephrine and dopamine in patients with narcolepsy or ADD/ADHD.
  • Epinephrine: action antagonised, paradoxical decrease in blood pressure may result.
  • Guanethidine: antihypertensive action antagonised.
  • Levodopa: decreased action of levodopa.
  • Lithium: rare cases of the following symptoms have been noted: encephalopathy, early and late extrapyramidal side effects, other neurologic symptoms, and coma.
  • Methyldopa: increased risk of extrapyramidal side effects and other unwanted central effects.
  • Other central depressants (alcohol, tranquilizers, narcotics): actions and side effects of these drugs (sedation, respiratory depression) are increased.
    • In particular, the doses of concomitantly used opioids for chronic pain can be reduced by 50%.
  • Other drugs metabolised by the CYP3A4 enzyme system: inducers such as carbamazepine, phenobarbital, and rifampicin decrease plasma levels and inhibitors such as quinidine, buspirone, and fluoxetine increase plasma levels.
  • Tricyclic antidepressants: metabolism and elimination of tricyclics significantly decreased, increased toxicity noted (anticholinergic and cardiovascular side effects, lowering of seizure threshold).

Discontinuation

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

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

Overdose

Symptoms

Symptoms are usually due to side effects. Most often encountered are:

  • Anticholinergic side effects (dry mouth, constipation, paralytic ileus, difficulties in urinating, decreased perspiration).
  • Coma in severe cases, accompanied by respiratory depression and massive hypotension, shock.
  • Hypotension or hypertension.
  • Rarely, serious ventricular arrhythmia (torsades de pointes), with or without prolonged QT-time.
  • Sedation.
  • Severe extrapyramidal side effects with muscle rigidity and tremors, akathisia, etc.

Treatment

Treatment is mostly symptomatic and involves intensive care with stabilisation of vital functions. In early detected cases of oral overdose, induction of emesis, gastric lavage, and the use of activated charcoal can be tried. In the case of a severe overdose, antidotes such as bromocriptine or ropinirole may be used to treat the extrapyramidal effects caused by haloperidol, acting as dopamine receptor agonists. ECG and vital signs should be monitored especially for QT prolongation and severe arrhythmias should be treated with antiarrhythmic measures.

Prognosis

In general, the prognosis of overdose is good, provided the person has survived the initial phase. An overdose of haloperidol can be fatal.

Pharmacology

Haloperidol is a typical butyrophenone type antipsychotic that exhibits high affinity dopamine D2 receptor antagonism and slow receptor dissociation kinetics. It has effects similar to the phenothiazines. The drug binds preferentially to D2 and α1 receptors at low dose (ED50 = 0.13 and 0.42 mg/kg, respectively), and 5-HT2 receptors at a higher dose (ED50 = 2.6 mg/kg). Given that antagonism of D2 receptors is more beneficial on the positive symptoms of schizophrenia and antagonism of 5-HT2 receptors on the negative symptoms, this characteristic underlies haloperidol’s greater effect on delusions, hallucinations and other manifestations of psychosis. Haloperidol’s negligible affinity for histamine H1 receptors and muscarinic M1 acetylcholine receptors yields an antipsychotic with a lower incidence of sedation, weight gain, and orthostatic hypotension though having higher rates of treatment emergent extrapyramidal symptoms.

Haloperidol acts on these receptors: (Ki)

  • D1 (silent antagonist) – Unknown efficiency.
  • D5 (silent antagonist) – Unknown efficiency.
  • D2 (inverse agonist) – 0.7 nM.
  • D3 (inverse agonist) – 0.2 nM.
  • D4 (inverse agonist) – 5–9 nM.
  • σ1 (irreversible inactivation by haloperidol metabolite HPP+) – 3 nM.
  • σ2 (agonist): 54 nM.
  • 5HT1A receptor agonist – 1927 nM.
  • 5HT2A (silent antagonist) – 53 nM.
  • 5HT2C (silent antagonist) – 10,000 nM.
  • 5HT6 (silent antagonist) – 3666 nM.
  • 5HT7 (irreversible silent antagonist) – 377.2 nM.
  • H1 (silent antagonist) – 1,800 nM.
  • M1 (silent antagonist) – 10,000 nM.
  • α1A (silent antagonist) – 12 nM.
  • α2A (silent antagonist) – 1130 nM.
  • α2B (silent antagonist) – 480 nM.
  • α2C (silent antagonist) – 550 nM.
  • NR1/NR2B subunit containing NMDA receptor (antagonist; ifenprodil site): IC50 – 2,000 nM.

Pharmacokinetics

By Mouth

The bioavailability of oral haloperidol ranges from 60-70%. However, there is a wide variance in reported mean Tmax and T1/2 in different studies, ranging from 1.7 to 6.1 hours and 14.5 to 36.7 hours respectively.

Intramuscular Injections

The drug is well and rapidly absorbed with a high bioavailability when injected intramuscularly. The Tmax is 20 minutes in healthy individuals and 33.8 minutes in patients with schizophrenia. The mean T1/2 is 20.7 hours. The decanoate injectable formulation is for intramuscular administration only and is not intended to be used intravenously. The plasma concentrations of haloperidol decanoate reach a peak at about six days after the injection, falling thereafter, with an approximate half-life of three weeks.

Intravenous Injections

The bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds. The T1/2 is 14.1 to 26.2 hours. The apparent volume of distribution is between 9.5 and 21.7 L/kg. The duration of action is four to six hours.

Therapeutic Concentrations

Plasma levels of five to 15 micrograms per litre are typically seen for therapeutic response (Ulrich S, et al. Clin Pharmacokinet. 1998). The determination of plasma levels is rarely used to calculate dose adjustments but can be useful to check compliance.

The concentration of haloperidol in brain tissue is about 20-fold higher compared to blood levels. It is slowly eliminated from brain tissue, which may explain the slow disappearance of side effects when the medication is stopped.

Distribution and Metabolism

Haloperidol is heavily protein bound in human plasma, with a free fraction of only 7.5 to 11.6%. It is also extensively metabolised in the liver with only about 1% of the administered dose excreted unchanged in the urine. The greatest proportion of the hepatic clearance is by glucuronidation, followed by reduction and CYP-mediated oxidation, primarily by CYP3A4.

Society and Culture

Cost

Haloperidol is relatively inexpensive, being up to 100 fold less expensive than newer antipsychotics.

Brand Names

Haloperidol is the INN, BAN, USAN, AAN approved name.

It is sold under the tradenames Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol (Germany), Einalon S, Eukystol, Haldol (common tradename in the US and UK), Halol, Halosten, Keselan, Linton, Peluces, Serenace and Sigaperidol.

Veterinary Use

Haloperidol is also used on many different kinds of animals for nonselective tranquilisation and diminishing behavioural arousal, in veterinary and other settings including captivity management.

What is Phenelzine?

Introduction

Phenelzine, sold under the brand name Nardil, among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class which is used as an antidepressant and anxiolytic. Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use. It is taken by mouth.

In June 2020, the Therapeutic Goods Administration (TGA) reported that the availability of phenelzine was discontinued in Australia due to global issues with the manufacture of the active pharmaceutical ingredient. However, unapproved phenelzine products may be accessed through alternative pathways, such as the Special Access Scheme (SAS) administered by the TGA. In October 2020, The TGA authorized two sponsors to supply an overseas-registered brand of phenelzine in Australia. In May 2020, the Specialist Pharmacy Service in the UK reported the unavailability of phenelzine from the sole supplier. In July 2020, supplies of unlicensed phenelzine 15mg capsule specials became available for UK patients. In February 2021, Phenelzine again became available in Australia as a subsidised medication through the Pharmaceutical Benefits Scheme.

Brief History

Synthesis of phenelzine was first described by Emil Votoček and Otakar Leminger in 1932.

Indications

Phenelzine is used primarily in the treatment of major depressive disorder (MDD). Patients with depressive symptomology characterised as “atypical”, “nonendogenous”, and/or “neurotic” respond particularly well to phenelzine. The medication is also useful in patients who do not respond favourably to first and second-line treatments for depression, or are “treatment-resistant”. In addition to being a recognised treatment for major depressive disorder, phenelzine is effective in treating dysthymia, bipolar depression (BD), panic disorder (PD), social anxiety disorder, bulimia, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). Phenelzine showed promise in a phase II clinical trial from March 2020 in treating prostate cancer.

Pharmacology

Pharmacodynamics

Phenelzine is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It inhibits both of the respective isoforms of MAO, MAO-A and MAO-B, and does so almost equally, with slight preference for the former. By inhibiting MAO, phenelzine prevents the breakdown of the monoamine neurotransmitters serotonin, melatonin, norepinephrine, epinephrine, and dopamine, as well as the trace amine neuromodulators such as phenethylamine, tyramine, octopamine, and tryptamine. This leads to an increase in the extracellular concentrations of these neurochemicals and therefore an alteration in neurochemistry and neurotransmission. This action is thought to be the primary mediator in phenelzine’s therapeutic benefits.

Phenelzine and its metabolites also inhibit at least two other enzymes to a lesser extent, of which are alanine transaminase (ALA-T), and γ-Aminobutyric acid transaminase (GABA-T), the latter of which is not caused by phenelzine itself, but by a phenelzine metabolite phenylethylidenehydrazine (PEH). By inhibiting ALA-T and GABA-T, phenelzine causes an increase in the alanine and GABA levels in the brain and body. GABA is the major inhibitory neurotransmitter in the mammalian central nervous system, and is very important for the normal suppression of anxiety, stress, and depression. Phenelzine’s action in increasing GABA concentrations may significantly contribute to its antidepressant, and especially, anxiolytic/antipanic properties, the latter of which have been considered superior to those of other antidepressants. As for ALA-T inhibition, though the consequences of disabling this enzyme are currently not well understood, there is some evidence to suggest that it is this action of the hydrazines (including phenelzine) which may be responsible for the occasional incidence of hepatitis and liver failure.

Phenelzine has also been shown to metabolise to phenethylamine (PEA). PEA acts as a releasing agent of norepinephrine and dopamine, and this occurs in the same manner as amphetamine (very similar in structure) by being taken up into vesicles, and displacing, and causing the release of those monoamines (though with markedly different pharmacokinetics such as a far shorter duration of action). Although this is indeed the same mechanism to which some (but not all) of amphetamine’s effects are attributable to, this is not all that uncommon a property among phenethylamines in general, many of which do not have psychoactive properties comparable to amphetamine. Amphetamine is different in that it binds with high affinity to the reuptake pumps of dopamine, norepinephrine, and serotonin, which phenethylamine and related molecules may as well to some extent, but with far less potency, such that it is basically insignificant in comparison. And, often being metabolized too quickly or not having the solubility to enable it to have a psychostimulant effect in humans. Claims that phenethylamine has comparable or roughly similar effects to psychostimulants such as amphetamine when administered are misconstrued. Phenethylamine does not have any obvious, easily discernible, reliably induced effects when administered to humans. Phenelzine’s enhancement of PEA levels may contribute further to its overall antidepressant effects to some degree. In addition, phenethylamine is a substrate for MAO-B, and treatment with MAOIs that inhibit MAO-B such as phenelzine have been shown to consistently and significantly elevate its concentrations.

Phenelzine usually requires six to eight weeks of treatment, and a minimum dose of 60 mg/day, to achieve therapeutic effects. The reason for the delay in therapeutic effect is not fully understood, but it is believed to be due to many factors, including achieving steady-state levels of MAO inhibition and the resulting adaptations in mean neurotransmitter levels, the possibility of necessary desensitisation of autoreceptors which normally inhibit the release of neurotransmitters like serotonin and dopamine, and also the upregulation of enzymes such as serotonin N-acetyltransferase. Typically, a therapeutic response to MAOIs is associated with an inhibition of at least 80-85% of monoamine oxidase activity.

Pharmacokinetics

Phenelzine is administered orally in the form of phenelzine sulfate and is rapidly absorbed from the gastrointestinal tract. Time to peak plasma concentration is 43 minutes and half-life is 11.6 hours. Unlike most other drugs, phenelzine irreversibly disables MAO, and as a result, it does not necessarily need to be present in the blood at all times for its effects to be sustained. Because of this, upon phenelzine treatment being ceased, its effects typically do not actually wear off until the body replenishes its enzyme stores, a process which can take as long as 2-3 weeks.

Phenelzine is metabolised primarily in the liver and its metabolites are excreted in the urine. Oxidation is the primary routine of metabolism, and the major metabolites are phenylacetic acid and parahydroxyphenylacetic acid, recovered as about 73% of the excreted dose of phenelzine in the urine over the course of 96 hours after single doses. Acetylation to N2-acetylphenelzine is a minor pathway. Phenelzine may also interact with cytochrome P450 enzymes, inactivating these enzymes through formation of a heme adduct. Two other minor metabolites of phenelzine, as mentioned above, include phenylethylidenehydrazine and phenethylamine.

Adverse Effects

Common side effects of phenelzine may include dizziness, blurry vision, dry mouth, headache, lethargy, sedation, somnolence, insomnia, anorexia, weight gain or loss, nausea and vomiting, diarrhoea, constipation, urinary retention, mydriasis, muscle tremors, hyperthermia, sweating, hypertension or hypotension, orthostatic hypotension, paraesthesia, hepatitis, and sexual dysfunction (consisting of loss of libido and anorgasmia). Rare side effects usually only seen in susceptible individuals may include hypomania or mania, psychosis and acute liver failure, the last of which is usually only seen in people with pre-existing liver damage, old age, long-term effects of alcohol consumption, or viral infection.

Interactions

The MAOIs have certain dietary restrictions and drug interactions. The amount of such restrictions and interactions is far less than previously thought, and MAOIs are generally safe medications when administered correctly. Hypertensive crisis is generally a rare occurrence while taking MAOIs, yet may result from the overconsumption of tyramine-containing foods. As a result, patients on phenelzine and other MAOIs must avoid excess quantities of certain foods that contain tyramine such as aged cheeses and cured meats, among others. Serotonin syndrome may result from an interaction with certain drugs which increase serotonin activity such as selective serotonin reuptake inhibitors, serotonin releasing agents, and serotonin agonists. Several deaths have been reported due to drug interaction-related serotonin syndrome such as the case of Libby Zion.

As is the case with other MAOIs, there is a concern regarding phenelzine and the use of both local and general anesthetics. Anyone taking phenelzine should inform their dentist before proceeding with dental surgery, and surgeon in any other contexts.

Phenelzine has also been linked to vitamin B6 deficiency. Transaminases such as GABA-transaminase have been shown to be dependent upon vitamin B6 and may be involved in a potentially related process, since the phenelzine metabolite phenylethylidenehydrazine (PEH) is a GABA transaminase inhibitor. Both phenelzine and vitamin B6 are rendered inactive upon these reactions occurring. For this reason, it may be recommended to supplement with vitamin B6 while taking phenelzine. The pyridoxine form of B6 is recommended for supplementation, since this form has been shown to reduce hydrazine toxicity from phenelzine and, in contrast, the pyridoxal form has been shown to increase the toxicity of hydrazines.

What is Play Therapy?

Introduction

Play therapy refers to a range of methods of capitalising on children’s natural urge to explore and harnessing it to meet and respond to the developmental and later also their mental health needs.

It is also used for forensic or psychological assessment purposes where the individual is too young or too traumatised to give a verbal account of adverse, abusive or potentially criminal circumstances in their life.

Play therapy is extensively acknowledged by specialists as an effective intervention in complementing children’s personal and inter-personal development. Play and play therapy are generally employed with children aged six months through late adolescence and young adulthood. They provide a contained way for them to express their experiences and feelings through an imaginative self-expressive process in the context of a trusted relationship with the care giver or therapist. As children’s and young people’s experiences and knowledge are typically communicated through play, it is an essential vehicle for personality and social development.

In recent years play therapists in the western hemisphere, as a body of health professionals, are usually members or affiliates of professional training institutions and tend to be subject to codes of ethical practice.

Play as Therapy

According to Jean Piaget, “play provides the child with the live, dynamic, individual language indispensable for the expression of [the child’s] subjective feelings for which collective language alone is inadequate.” Play helps a child develop a sense of true self and a mastery over her/his innate abilities resulting in a sense of worth and aptitude. During play, children are driven to meet the essential need of exploring and affecting their environment. Play also contributes in the advancement of creative thinking. Play likewise provides a way for children to release strong emotions. During play, children may play out challenging life experiences by re-engineering them, thereby discharging emotional states, with the potential of integrating every experience back into stability and gaining a greater sense of mastery

General

Play therapy is a form of psychotherapy which uses play as the main mode of communication especially with children, and people whose speech capacity may be compromised, to determine and overcome psychosocial challenges. It is aimed at helping patients towards better growth and development, social integration, decreased aggression, emotional modulation, social skill development, empathy, and trauma resolution. Play therapy also assists with sensorimotor development and coping skills.

Diagnostic Tool

Play therapy can also be used as a tool for diagnosis. A play therapist observes a client playing with toys (play-houses, soft toys, dolls, etc.) to determine the cause of the disturbed behaviour. The objects and patterns of play, as well as the willingness to interact with the therapist, can be used to understand the underlying rationale for behaviour both inside and outside of therapy session. Caution, however, should be taken when using play therapy for assessment and/or diagnostic purposes.

According to the psychodynamic view, people (especially children) will engage in play behaviour to work through their interior anxieties. According to this viewpoint, play therapy can be used as a self-regulating mechanism, as long as children are allowed time for “free play” or “unstructured play.” However, some forms of therapy depart from non-directiveness in fantasy play, and introduce varying amounts of direction, during the therapy session.

An example of a more directive approach to play therapy, for example, can entail the use of a type of desensitisation or relearning therapy, to change troubling behaviours, either systematically or through a less structured approach. The hope is that through the language of symbolic play, such desensitisation may take place, as a natural part of the therapeutic experience, and lead to positive treatment outcomes.

Origins

Children’s play has been recorded in artefacts at least since antiquity. In eighteenth-century Europe, Rousseau (1712-1778) wrote, in his book Emile, about the importance of observing play as a way to learn about and understand children.

From Education to Therapeutics

During the 19th century, European educationalists began to address play as an integral part of childhood education. They include Friedrich Fröbel, Rudolf Steiner, Maria Montessori, L.S. Vygotsky, Margaret Lowenfeld, and Hans Zulliger.

Hermine Hug-Hellmuth formalised play as therapy by providing children with toys to express themselves and observed play to analyse the child. In 1919, Melanie Klein began to use play as a means of analysing children under the age of six. She believed that child’s play was essentially the same as free association used with adults, and that as such, it was provide access to the child’s unconscious. Anna Freud (1946, 1965) used play as a means to facilitate an attachment to the therapist and supposedly gain access to the child’s psyche.

Arguably, the first documented case, describing a proto-therapeutic use of play, was in 1909 when Sigmund Freud published his work with “Little Hans”, a five-year-old child suffering from a horse phobia. Freud saw him once briefly and recommended his father take note of Hans’ play to provide observations which might assist the child. The case of “Little Hans” was the first case where a child’s difficulty was adduced to emotional factors.

Models

Play therapy can be divided into two basic types: non-directive and directive. Non-directive play therapy is a non-intrusive method in which children are encouraged to play in the expectation that this will alleviate their problems as perceived by their care-givers and other adults. It is often classified as a psychodynamic therapy. In contrast, directed play therapy is a method that includes more structure and guidance by the therapist as children work through emotional and behavioural difficulties through play. It often contains a behavioural component and the process includes more prompting by the therapist. Both types of play therapy have received at least some empirical support.] On average, play therapy treatment groups, when compared to control groups, improve by .8 standard deviations.

Jessie Taft (1933), (Otto Rank’s American translator), and Frederick H. Allen (1934) developed an approach they entitled relationship therapy. The primary emphasis is placed on the emotional relationship between the therapist and the child. The focus is placed on the child’s freedom and strength to choose.

Virginia Axline, a child therapist from the 1950s applied Carl Rogers’ work to children. Rogers had explored the work of the therapist relationship and developed non-directive therapy, later called Client-Centred Therapy. Axline summarized her concept of play therapy in her article, ‘Entering the child’s world via play experiences’ and stated, “A play experience is therapeutic because it provides a secure relationship between the child and the adult, so that the child has the freedom and room to state himself in his own terms, exactly as he is at that moment in his own way and in his own time”. Axline also wrote Dibs in Search of Self, which describes a series of play therapy sessions over a period of a year.

Non-directive Play Therapy

Non-directive play therapy, may encompass child psychotherapy and unstructured play therapy. It is guided by the notion that if given the chance to speak and play freely in appropriate therapeutic conditions, troubled children and young people will be helped towards resolving their difficulties. Non-directive play therapy is generally regarded as mainly non-intrusive. The hallmark of non-directive play therapy is that it has minimal constraints apart from the frame and thus can be used at any age. These approaches to therapy may originate from Margaret Lowenfeld, Anna Freud, Donald Winnicott, Michael Fordham, Dora Kalff, all of them child specialists or even from the adult therapist, Carl Rogers’ non-directive psychotherapy and in his characterisation of “the optimal therapeutic conditions”. Virginia Axline adapted Carl Rogers’s theories to child therapy in 1946 and is widely considered the founder of this therapy. Different techniques have since been established that fall under the realm of non-directive play therapy, including traditional sandplay therapy, play therapy using provided toys and Winnicott’s Squiggle and Spatula games. Each of these forms is covered briefly below.

Using toys in non-directive play therapy with children is a method used by child psychotherapists and play therapists. These approaches are derived from the way toys were used in Anna Freud’s theoretical orientation. The idea behind this method is that children will be better able to express their feelings toward themselves and their environment through play with toys than through verbalisation of their feelings. Through this experience children may be able to achieve catharsis, gain more stability and enjoyment in their emotions, and test their own reality. Popular toys used during therapy are animals, dolls, hand puppets, soft toys, crayons, and cars. Therapists have deemed such objects as more likely to open imaginative play or creative associations, both of which are important in expression.

Sandplay

Play therapy using a tray of sand and miniature figures is attributed to Dr. Margaret Lowenfeld, a paediatrician interested in child psychology who pioneered her “World Technique” in 1929, drawn from the writer H. G. Wells and his Floor Games published in 1911. Dora Kalff, who studied with her, combined Lowenfeld’s World Technique with Jung’s idea of the collective unconscious and received Lowenfeld’s permission to name her version of the work “sandplay”. As in traditional non-directive play therapy, research has shown that allowing an individual to freely play with the sand and accompanying objects in the contained space of the sandtray (22.5″ x 28.5″) can facilitate a healing process as the unconscious expresses itself in the sand and influences the sand player. When a client creates “scenes” in the sandtray, little instruction is provided and the therapist offers little or no talk during the process. This protocol emphasises the importance of holding what Kalff referred to as the “free and protected space” to allow the unconscious to express itself in symbolic, non-verbal play. Upon completion of a tray, the client may or may not choose to talk about his or her creation, and the therapist, without the use of directives and without touching the sandtray, may offer supportive response that does not include interpretation. The rationale is that the therapist trusts and respects the process by allowing the images in the tray to exert their influence without interference.

Sandplay therapy can be used during family therapy. The limitations presented by the boundaries of the sandtray can serve as physical and symbolic limitations to families in which boundary distinctions are an issue. Also when a family works together on a sandtray, the therapist may make several observations, such as unhealthy alliances, who works with whom, which objects are selected to be incorporated into the sandtray, and who chooses which objects. A therapist may assess these choices and intervene in an effort to guide the formation of healthier relationships.

Winnicott’s Squiggle and Spatula Games

Donald Winnicott probably first came upon the central notion of play from his collaboration in wartime with the psychiatric social worker, Clare Britton, (later a psychoanalyst and his second wife), who in 1945 published an article on the importance of play for children. By “playing”, he meant not only the ways that children of all ages play, but also the way adults “play” through making art, or engaging in sports, hobbies, humour, meaningful conversation, etc. Winnicott believed that it was only in playing that people are entirely their true selves, so it followed that for psychoanalysis to be effective, it needed to serve as a mode of playing.

Two of the playing techniques Winnicott used in his work with children were the squiggle game and the spatula game. The first involved Winnicott drawing a shape for the child to play with and extend (or vice versa) – a practice extended by his followers into that of using partial interpretations as a ‘squiggle’ for a patient to make use of.

The second involved Winnicott placing a spatula (medical tongue depressor) within the child’s reach for her/him to play with. Winnicott considered that “if he is just an ordinary baby he will notice the attractive object…and he will reach for it….[then] in the course of a little while he will discover what he wants to do with it”. From the child’s initial hesitation in making use of the spatula, Winnicott derived his idea of the necessary ‘period of hesitation’ in childhood (or analysis), which makes possible a true connection to the toy, interpretation or object presented for transference.

Efficacy

Winnicott came to consider that “Playing takes place in the potential space between the baby and the mother-figure….[T]he initiation of playing is associated with the life experience of the baby who has come to trust the mother figure”. “Potential space” was Winnicott’s term for a sense of an inviting and safe interpersonal field in which one can be spontaneously playful while at the same time connected to others. Playing can also be seen in the use of a transitional object, a term Winnicott coined for an object, such as a teddy bear, which may have a quality for a small child of being both real and made-up at the same time. Winnicott pointed out that no one demands that a toddler explain whether his Binky is a “real bear” or a creation of the child’s own imagination, and went on to argue that it was very important that the child be allowed to experience the Binky as being in an undefined, “transitional” status between the child’s imagination and the real world outside the child. For Winnicott, one of the most important and precarious stages of development was in the first three years of life, when an infant grows into a child with an increasingly separate sense of self in relation to a larger world of other people. In health, the child learns to bring his or her spontaneous, real self into play with others; whereas in a False self disorder, the child may find it unsafe or impossible to do so, and instead may feel compelled to hide the true self from other people, and pretend to be whatever they want instead. Playing with a transitional object can be an important early bridge “between self and other”, which helps a child develop the capacity to be creative and genuine in relationships.

Research

Play therapy has been considered to be an established and popular mode of therapy for children for over sixty years. Critics of play therapy have questioned the effectiveness of the technique for use with children and have suggested using other interventions with greater empirical support such as Cognitive behavioural therapy (CBT). They also argue that therapists focus more on the institution of play rather than the empirical literature when conducting therapy Classically, Lebo argued against the efficacy of play therapy in 1953, and Phillips reiterated his argument again in 1985. Both claimed that play therapy lacks in several areas of hard research. Many studies included small sample sizes, which limits the generalisability, and many studies also only compared the effects of play therapy to a control group. Without a comparison to other therapies, it is difficult to determine if play therapy really is the most effective treatment. Recent play therapy researchers have worked to conduct more experimental studies with larger sample sizes, specific definitions and measures of treatment, and more direct comparisons.

Outside of the psychoanalytic child psychotherapy field, which is well annotated, research is comparatively lacking in other, or random applications, on the overall effectiveness of using toys in non-directive play therapy. Dell Lebo found that out of a sample of over 4,000 children, those who played with recommended toys vs. non-recommended or no toys during non-directive play therapy were no more likely to verbally express themselves to the therapist. Examples of recommended toys would be dolls or crayons, while example of non-recommended toys would be marbles or a checkers board game. There is also ongoing controversy in choosing toys for use in non-directive play therapy, with choices being largely made through intuition rather than through research. However, other research shows that following specific criteria when choosing toys in non-directive play therapy can make treatment more efficacious. Criteria for a desirable treatment toy include a toy that facilitates contact with the child, encourages catharsis, and lead to play that can be easily interpreted by a therapist.

Several meta analyses have shown promising results about the efficacy of non-directive play therapy. Meta analysis by authors LeBlanc and Ritchie, 2001, found an effect size of 0.66 for non-directive play therapy. This finding is comparable to the effect size of 0.71 found for psychotherapy used with children, indicating that both non-directive play and non-play therapies are almost equally effective in treating children with emotional difficulties. Meta analysis by authors Ray, Bratton, Rhine and Jones, 2001, found an even larger effect size for nondirective play therapy, with children performing at 0.93 standard deviations better than non-treatment groups. These results are stronger than previous meta-analytic results, which reported effect sizes of 0.71, 0.71, and 0.66. Meta analysis by authors Bratton, Ray, Rhine, and Jones, 2005, also found a large effect size of 0.92 for children being treated with non-directive play therapy. Results from all meta-analyses indicate that non-directive play therapy has been shown to be just as effective as psychotherapy used with children and even generates higher effect sizes in some studies

Predictors of Effectiveness

There are several predictors that may also influence the effectiveness of play therapy with children. The number of sessions is a significant predictor in post-test outcomes, with more sessions being indicative of higher effect sizes. Although positive effects can be seen with the average 16 sessions, there is a peak effect when a child can complete 35-40 sessions. An exception to this finding is children undergoing play therapy in critical-incident settings, such as hospitals and domestic violence shelters. Results from studies that looked at these children indicated a large positive effect size after only 7 sessions, which provides the implication that children in crisis may respond more readily to treatment. Parental involvement is also a significant predictor of positive play therapy results. This involvement generally entails participation in each session with the therapist and the child. Parental involvement in play therapy sessions has also been shown to diminish stress in the parent-child relationship when kids are exhibiting both internal and external behaviour problems. Despite these predictors which have been shown to increase effect sizes, play therapy has been shown to be equally effective across age, gender, and individual vs. group settings.

Directive Play Therapy

In the 1930s David Levy developed a technique he called release therapy. His technique emphasized a structured approach. A child, who had experienced a specific stressful situation, would be allowed to engage in free play. Subsequently, the therapist would introduce play materials related to the stress-evoking situation allowing the child to re-enact the traumatic event and release the associated emotions.

In 1955, Gove Hambidge expanded on Levy’s work emphasizing a “structured play therapy” model, which was more direct in introducing situations. The format of the approach was to establish rapport, recreate the stress-evoking situation, play out the situation and then free play to recover.

Directive play therapy is guided by the notion that using directives to guide the child through play will cause a faster change than is generated by nondirective play therapy. The therapist plays a much bigger role in directive play therapy. Therapists may use several techniques to engage the child, such as engaging in play with the child themselves or suggesting new topics instead of letting the child direct the conversation himself. Stories read by directive therapists are more likely to have an underlying purpose, and therapists are more likely to create interpretations of stories that children tell. In directive therapy games are generally chosen for the child, and children are given themes and character profiles when engaging in doll or puppet activities. This therapy still leaves room for free expression by the child, but it is more structured than nondirective play therapy. There are also different established techniques that are used in directive play therapy, including directed sandtray therapy and cognitive behavioural play therapy.

Directed sandtray therapy is more commonly used with trauma victims and involves the “talk” therapy to a much greater extent. Because trauma is often debilitating, directed sandplay therapy works to create change in the present, without the lengthy healing process often required in traditional sandplay therapy. This is why the role of the therapist is important in this approach. Therapists may ask clients questions about their sandtray, suggest them to change the sandtray, ask them to elaborate on why they chose particular objects to put in the tray, and on rare occasions, change the sandtray themselves. Use of directives by the therapist is very common. While traditional sandplay therapy is thought to work best in helping clients access troubling memories, directed sandtray therapy is used to help people manage their memories and the impact it has had on their lives.

Filial therapy, developed by Bernard and Louise Guerney, was an innovation in play therapy during the 1960s. The filial approach emphasizes a structured training program for parents in which they learn how to employ child-centred play sessions in the home. In the 1960s, with the advent of school counsellors, school-based play therapy began a major shift from the private sector. Counsellor-educators such as Alexander (1964); Landreth; Muro (1968); Myrick and Holdin (1971); Nelson (1966); and Waterland (1970) began to contribute significantly, especially in terms of using play therapy as both an educational and preventive tool in dealing with children’s issues.

Roger Phillips, in the early 1980s, was one of the first to suggest that combining aspects of CBT with play interventions would be a good theory to investigate. Cognitive behavioural play therapy was then developed to be used with very young children between two and six years of age. It incorporates aspects of Beck’s cognitive therapy with play therapy because children may not have the developed cognitive abilities necessary for participation in straight cognitive therapy. In this therapy, specific toys such as dolls and stuffed animals may be used to model particular cognitive strategies, such as effective coping mechanisms and problem-solving skills. Little emphasis is placed on the children’s verbalisations in these interactions but rather on their actions and their play. Creating stories with the dolls and stuffed animals is a common method used by cognitive behavioural play therapists to change children’s maladaptive thinking.

Efficacy

The efficacy of directive play therapy has been less established than that of nondirective play therapy, yet the numbers still indicate that this mode of play therapy is also effective. In 2001 meta analysis by authors Ray, Bratton, Rhine, and Jones, direct play therapy was found to have an effect size of .73 compared to the .93 effect size that nondirective play therapy was found to have. Similarly in 2005 meta analysis by authors Bratton, Ray, Rhine, and Jones, directive therapy had an effect size of 0.71, while nondirective play therapy had an effect size of 0.92. Although the effect sizes of directive therapy are statistically significantly lower than those of nondirective play therapy, they are still comparable to the effect sizes for psychotherapy used with children, demonstrated by Casey, Weisz, and LeBlanc. A potential reason for the difference in the effect size may be due to the number of studies that have been done on nondirective vs. directive play therapy. Approximately 73 studies in each meta analysis examined nondirective play therapy, while there were only 12 studies that looked at directive play therapy. Once more research is done on directive play therapy, there is potential that effect sizes between nondirective and directive play therapy will be more comparable.

Application of Electronic Games

The prevalence and popularity of video games in recent years has created a wealth of psychological studies centred around them. While the bulk of those studies have covered video game violence and addiction, some mental health practitioners in the West, are becoming interested in including such games as therapeutic tools. These are by definition “directive” tools since they are internally governed by algorithms. Since the introduction of electronic media into popular Western culture, the nature of games has become “increasingly complex, diverse, realistic, and social in nature.” The commonalities between electronic and traditional play (such as providing a safe space to work through strong emotions) infer similar benefits. Video games have been broken into two categories: “serious” games, or games developed specifically for health or learning reasons, and “off-the-shelf” games, or games without a clinical focus that may be re-purposed for a clinical setting. Use of electronic games by clinicians is a new practice, and unknown risks as well as benefits may arise as the practice becomes more mainstream.

Research

Most of the current research relating to electronic games in therapeutic settings is focused on alleviating the symptoms of depression, primarily in adolescents. However, some games have been developed specifically for children with anxiety and Attention deficit hyperactivity disorder (ADHD), The same company behind the latter intends to create electronic treatments for children on the autism spectrum, and those living with Major depressive disorder, among other disorders. The favoured approach for mental health treatment is through CBT. While this method is effective, it is not without its limitations: for example, boredom with the material, patients forgetting or not practicing techniques outside of a session, or the accessibility of care. It is these areas that therapists hope to address through the use of electronic games. Preliminary research has been done with small groups, and the conclusions drawn warrant studying the issue in greater depth.

Role-playing games (RPGs) are the most common type of electronic game used as part of therapeutic interventions. These are games where players assume roles, and outcomes depend on the actions taken by the player in a virtual world. Psychologists are able to gain insights into the elements of the capability of the patient to create or experiment with an alternate identity. There are also those who underscore the ease in the treatment process since playing an RPG as a treatment situation is often experienced as an invitation to play, which makes the process safe and without risk of exposure or embarrassment. The most well-known and well-documented RPG-style game used in treatment is SPARX. Taking place in a fantasy world, SPARX users play through seven levels, each lasting about half an hour, and each level teaching a technique to overcome depressive thoughts and behaviours. Reviews of the study have found the game treatment comparable to CBT-only therapy. However one review noted that SPARX alone is not more effective than standard CBT treatment. There are also studies that found role-playing games, when combined with the Adlerian Play Therapy (AdPT) techniques, lead to increased psychosocial development. ReachOutCentral is geared toward youth and teens, providing gamified information on the intersection of thoughts, feelings, and behaviour. An edition developed specifically to aid clinicians, ReachOutPro, offers more tools to increase patients’ engagement.

Other Applications

Biofeedback (sometimes known as applied psychophysiological feedback) media is more suited to treating a range of anxiety disorders. Biofeedback tools are able to measure heart rate, skin moisture, blood flow, and brain activity to ascertain stress levels, with a goal of teaching stress management and relaxation techniques. The development of electronic games using this equipment is still in its infancy, and thus few games are on the market. The Journey to Wild Divine’s developers have asserted that their products are a tool, not a game, though the three instalments contain many game elements. Conversely, Freeze Framer’s design is reminiscent of an Atari system. Three simplistic games are included in Freeze Framer’s 2.0 model, using psychophysiological feedback as a controller. The effectiveness of both pieces of software saw significant changes in participants’ depression levels. A biofeedback game initially designed to assist with anxiety symptoms, Relax to Win, was similarly found to have broader treatment applications. Extended Attention Span Training (EAST), developed by NASA to gauge the attention of pilots, was remodelled as an ADHD aid. Brain waves of participants were monitored during play of commercial video games available on PlayStation, and the difficulty of the games increased as participants’ attention waned. The efficacy of this treatment is comparable to traditional ADHD intervention.

Several online-only or mobile games (Re-Mission, Personal Investigator, Treasure Hunt, and Play Attention) have been specifically noted for use in alleviating disorders other than those for anxiety and mood. Re-Mission 2 especially targets children, the game having been designed with the knowledge that today’s western youth are immersed in digital media. Mobile applications for anxiety, depression, relaxation, and other areas of mental health are readily available in the Android Play Store and the Apple App Store. The proliferation of laptops, mobile phones, and tablets means one can access these apps at any time, in any place. Many of them are low-cost or even free, and the games do not need to be complex to be of benefit. Playing a three-minute game of Tetris has the potential to curb a number of cravings, a longer play time could reduce flashback symptoms from posttraumatic stress disorder, and an initial study found that a visual-spatial game such as Tetris or Candy Crush, when played closely following a traumatic event, could be used as a “‘therapeutic vaccine” to prevent future flashbacks.

Efficacy

While the field of allowing electronic media a place in a therapist’s office is new, the equipment is not necessarily so. Most western children are familiar with modern PCs, consoles, and handheld devices even if the practitioner is not. An even more recent addition to interacting with a game environment is virtual reality equipment, which both adolescent and clinician might need to learn to use properly. The umbrella term for the preliminary studies done with VR is Virtual reality exposure therapy (VRET). This research is based on traditional exposure therapy and has been found to be more effective for participants than for those placed in a wait list control group, though not as effective as in-person treatments. One study tracked two groups – one group receiving a typical, lengthier treatment while the other was treated via shorter VRET sessions – and found that the effectiveness for VRET patients was significantly less at the six-month mark.

In the future, clinicians may look forward to using electronic media as a way to assess patients, as a motivational tool, and facilitate social in-person and virtual interactions. Current data, though limited, points toward combining traditional therapy methods with electronic media for the most effective treatment.

Play Therapy in Literature

In 1953 Clark Moustakas wrote his first book, Children in Play Therapy. In 1956 he compiled Publication of The Self, the result of the dialogues between Moustakas, Abraham Maslow, Carl Rogers, and others, forging the humanistic psychology movement. In 1973 Moustakas continued his journey into play therapy and published his novel The child’s discovery of himself. Moustakas’ work as being concerned with the kind of relationship needed to make therapy a growth experience. His stages start with the child’s feelings being generally negative and as they are expressed, they become less intense, the end results tend to be the emergence of more positive feelings and more balanced relationships.

Parent/Child Play Therapy

Several approaches to play therapy have been developed for parents to use in the home with their own children.

Training in nondirective play for parents has been shown to significantly reduce mental health problems in at-risk preschool children. One of the first parent/child play therapy approaches developed was Filial Therapy (in the 1960s), in which parents are trained to facilitate nondirective play therapy sessions with their own children. Filial therapy has been shown to help children work through trauma and also resolve behaviour problems.

Another approach to play therapy that involves parents is Theraplay, which was developed in the 1970s. At first, trained therapists worked with children, but Theraplay later evolved into an approach in which parents are trained to play with their children in specific ways at home. Theraplay is based on the idea that parents can improve their children’s behaviour and also help them overcome emotional problems by engaging their children in forms of play that replicate the playful, attuned, and empathic interactions of a parent with an infant. Studies have shown that Theraplay is effective in changing children’s behaviour, especially for children suffering from attachment disorders.

In the 1980s, Stanley Greenspan developed Floortime, a comprehensive, play-based approach for parents and therapists to use with autistic children. There is evidence for the success of this program with children suffering from autistic spectrum disorders.

Lawrence J. Cohen has created an approach called Playful Parenting, in which he encourages parents to play with their children to help resolve emotional and behavioural issues. Parents are encouraged to connect playfully with their children through silliness, laughter, and roughhousing.

In 2006, Garry Landreth and Sue Bratton developed a highly researched and structured way of teaching parents to engage in therapeutic play with their children. It is based on a supervised entry level training in child centred play therapy. They named it Child Parent Relationship Therapy. These 10 sessions focus on parenting issues in a group environment and utilises video and audio recordings to help the parents receive feedback on their 30-minute ‘special play times’ with their children.

More recently, Aletha Solter has developed a comprehensive approach for parents called Attachment Play, which describes evidence-based forms of play therapy, including non-directive play, more directive symbolic play, contingency play, and several laughter-producing activities. Parents are encouraged to use these playful activities to strengthen their connection with their children, resolve discipline issues, and also help the children work through traumatic experiences such as hospitalisation or parental divorce.

What is Quetiapine?

Introduction

Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Despite being widely used as a sleep aid due its sedating effect, the benefits of such use do not appear to generally outweigh the side effects. It is taken by mouth.

Common side effects include sleepiness, constipation, weight gain, and dry mouth. Other side effects include low blood pressure with standing, seizures, a prolonged erection, high blood sugar, tardive dyskinesia, and neuroleptic malignant syndrome. In older people with dementia, its use increases the risk of death. Use in the third trimester of pregnancy may result in a movement disorder in the baby for some time after birth. Quetiapine is believed to work by blocking a number of receptors including serotonin and dopamine.

Quetiapine was developed in 1985 and approved for medical use in the United States in 1997. It is available as a generic medication. In 2018, it was the 59th most commonly prescribed medication in the United States, with more than 12 million prescriptions.

Brief History

AstraZeneca submitted a new drug application for a sustained-release version of quetiapine in the United States, Canada, and the European Union in the second half of 2006 for treatment of schizophrenia. AstraZeneca was to retain the exclusive right to market sustained-release quetiapine until 2017. The sustained-release quetiapine is marketed mainly as Seroquel XR. Other marketing names are Seroquel Prolong, Seroquel Depot and Seroquel XL

On 18 May 2007, AstraZeneca announced that the US Food and Drug Administration (FDA) had approved Seroquel XR for acute treatment of schizophrenia. During its 2007 Q2 earnings conference, AstraZeneca announced plans to launch Seroquel XR in the US during August 2007. However, Seroquel XR has become available in US pharmacies only after the FDA had approved Seroquel XR for use as maintenance treatment for schizophrenia, in addition to acute treatment of the illness, on 16 November 2007. The company has not provided a reason for the delay of Seroquel XR’s launch.

Health Canada approved sale of Seroquel XR on 27 September 2007.

In early October 2008, the FDA approved Seroquel XR for the treatment of bipolar depression and bipolar mania. According to AstraZeneca, Seroquel XR is “the first medication approved by the FDA for the once-daily acute treatment of both depressive and manic episodes associated with bipolar.”

On 31 July, 2008, Handa Pharmaceuticals, based in Fremont, California, announced that its abbreviated new drug application (“ANDA”) for quetiapine fumarate extended-release tablets, the generic version of AstraZeneca’s SEROQUEL XR, has been accepted by the FDA.

On 01 December 2008, Biovail announced that the FDA had accepted the company’s ANDA to market its own version of sustained-release quetiapine. Biovail’s sustained-release tablets will compete with AstraZeneca’s Seroquel XR.

On 24 December 2008, AstraZeneca notified shareholders that the FDA had asked for additional information on the company’s application to expand the use of sustained-release quetiapine for treatment of depression.

Medical Uses

Quetiapine is primarily used to treat schizophrenia or bipolar disorder. Quetiapine targets both positive and negative symptoms of schizophrenia.

Schizophrenia

In a 2013 comparison of 15 antipsychotics in effectiveness in treating schizophrenia, quetiapine demonstrated standard effectiveness. It was 13-16% more effective than ziprasidone, chlorpromazine, and asenapine and approximately as effective as haloperidol and aripiprazole.

There is tentative evidence of the benefit of quetiapine versus placebo in schizophrenia; however, definitive conclusions are not possible due to the high rate of attrition in trials (greater than 50%) and the lack of data on economic outcomes, social functioning, or quality of life.

It is debatable whether, as a class, typical or atypical antipsychotics are more effective. Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. While quetiapine has lower rates of extrapyramidal side effects, there is greater sleepiness and rates of dry mouth.

A Cochrane review comparing quetiapine to other atypical antipsychotic agents tentatively concluded that it may be less efficacious than olanzapine and risperidone; produce fewer movement related side effects than paliperidone, aripiprazole, ziprasidone, risperidone and olanzapine; and produce weight gain similar to risperidone, clozapine and aripiprazole. They concluded that it produces suicide attempt, suicide; death; QTc prolongation, low blood pressure; tachycardia; sedation; gynaecomastia; galactorrhoea, menstrual irregularity and white blood cell count at a rate similar to first generation antipsychotics.

Bipolar Disorder

In those with bipolar disorder, quetiapine is used to treat depressive episodes; acute manic episodes associated with bipolar I disorder (as either monotherapy or adjunct therapy to lithium; valproate or lamotrigine); acute mixed episodes; and maintenance treatment of bipolar I disorder (as adjunct therapy to lithium or divalproex).

Major Depressive Disorder

Quetiapine is effective when used by itself and when used along with other medications in major depressive disorder (MDD). However, sedation is often an undesirable side effect.

In the United States, the United Kingdom and Australia (while not subsidised by the Australian Pharmaceutical Benefits Scheme for treatment of MDD), quetiapine is licensed for use as an add-on treatment in MDD.

Alzheimer’s Disease

Quetiapine does not decrease agitation among people with Alzheimer’s. Quetiapine worsens intellectual functioning in the elderly with dementia and therefore is not recommended.

Others

The use of low doses of quetiapine for insomnia, while common, is not recommended; there is little evidence of benefit and concerns regarding adverse effects.

It is sometimes used off-label, often as an augmentation agent, to treat conditions such as Tourette syndrome, musical hallucinations and anxiety disorders.

Quetiapine and clozapine are the most widely used medications for the treatment of Parkinson’s disease psychosis due to their very low extrapyramidal side-effect liability. Owing to the risks associated with clozapine (e.g. agranulocytosis, diabetes mellitus, etc.), clinicians often attempt treatment with quetiapine first, although the evidence to support quetiapine’s use for this indication is significantly weaker than that of clozapine.

Adverse Effects

  • Very common (>10% incidence) adverse effects:
    • Dry mouth.
    • Dizziness.
    • Headache.
    • Somnolence:
      • Drowsiness; of 15 antipsychotics quetiapine causes the 5th most sedation.
      • Extended release (XR) formulations tend to produce less sedation, dose-by-dose than the immediate release formulations.
  • Common (1–10% incidence) adverse effects:
    • High blood pressure.
    • Orthostatic hypotension.
    • High pulse rate.
    • High blood cholesterol.
    • Elevated serum triglycerides.
    • Abdominal pain.
    • Constipation.
    • Increased appetite.
    • Vomiting.
    • Increased liver enzymes.
    • Backache.
    • Asthenia.
    • Insomnia.
    • Lethargy.
    • Tremor.
    • Agitation.
    • Nasal congestion.
    • Pharyngitis.
    • Fatigue.
    • Pain.
    • Dyspepsia (Indigestion).
    • Peripheral oedema.
    • Dysphagia.
    • Extrapyramidal disease:
      • Quetiapine and clozapine are noted for their relative lack of extrapyramidal side effects.
    • Weight gain:
      • SMD 0.43 kg when compared to placebo. Produces roughly as much weight gain as risperidone, less weight gain than clozapine, olanzapine and zotepine and more weight gain than ziprasidone, lurasidone, aripiprazole and asenapine.
      • As with many other atypical antipsychotics, this action is likely due to its actions at the H1 histamine receptor and 5-HT2C receptor.
  • Rare (<1% incidence) adverse effects:
    • Prolonged QT interval.
    • Sudden cardiac death.
    • Syncope.
    • Diabetic ketoacidosis.
    • Restless legs syndrome.
    • Hyponatraemia, low blood sodium.
    • Jaundice, yellowing of the eyes, skin and mucous membranes due to an impaired ability of the body to clear bilirubin, a by product of haem breakdown.
    • Pancreatitis, pancreas swelling.
    • Agranulocytosis, a potentially fatal drop in white blood cell count.
    • Leukopenia, a drop in white blood cell count, not as severe as agranulocytosis.
    • Neutropenia, a drop in neutrophils, the cell of the immune cells that defends the body against bacterial infections.
    • Eosinophilia.
    • Anaphylaxis, a potentially fatal allergic reaction.
    • Seizure.
    • Hypothyroidism, underactive thyroid gland.
    • Myocarditis, swelling of the myocardium.
    • Cardiomyopathy.
    • Hepatitis, swelling of the liver.
    • Suicidal ideation.
    • Priapism:
      • A prolonged and painful erection.
    • Stevens-Johnson syndrome:
      • A potentially fatal skin reaction.
    • Neuroleptic malignant syndrome:
      • A rare and potentially fatal complication of antipsychotic drug treatment.
      • It is characterised by the following symptoms: tremor, rigidity, hyperthermia, tachycardia, mental status changes (e.g. confusion), etc.
    • Tardive Dyskinesia:
      • A rare and often irreversible neurological condition characterised by involuntary movements of the face, tongue, lips and rest of the body.
      • Most commonly occurs after prolonged treatment with antipsychotics.
      • It is believed to be particularly uncommon with atypical antipsychotics, especially quetiapine and clozapine

Both typical and atypical antipsychotics can cause tardive dyskinesia. According to one study, rates are lower with the atypicals at 3.9% as opposed to the typicals at 5.5%. Although quetiapine and clozapine are atypical antipsychotics, switching to these atypicals is an option to minimise symptoms of tardive dyskinesia caused by other atypicals.

Weight gain can be a problem for some, with quetiapine causing more weight gain than fluphenazine, haloperidol, loxapine, molindone, olanzapine, pimozide, risperidone, thioridazine, thiothixene, trifluoperazine, and ziprasidone, but less than chlorpromazine, clozapine, perphenazine, and sertindole.

As with some other anti-psychotics, quetiapine may lower the seizure threshold, and should be taken with caution in combination with drugs such as bupropion.

Discontinuation

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

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

Pregnancy and Lactation

Placental exposure is least for quetiapine compared to other atypical antipsychotics. The evidence is insufficient to rule out any risk to the foetus but available data suggests it is unlikely to result in any major foetal malformations. It is secreted in breast milk and hence quetiapine-treated mothers are advised not to breastfeed.

Abuse Potential

In contrast to most other antipsychotic drugs, which tend to be somewhat aversive and often show problems with patient compliance with prescribed medication regimes, quetiapine is sometimes associated with drug misuse and abuse potential, for its hypnotic and sedative effects. It has a limited potential for misuse, usually only in individuals with a history of polysubstance abuse and/or mental illness, and especially in those incarcerated in prisons or secure psychiatric facilities where access to alternative intoxicants is more limited. To a significantly greater extent than other atypical antipsychotic drugs, quetiapine was found to be associated with drug-seeking behaviours, and to have standardised street prices and slang terms associated with it, either by itself or in combination with other drugs (such as “Q-ball” for the intravenous injection of quetiapine mixed with cocaine). The pharmacological basis for this distinction from other second generation antipsychotic drugs is unclear, though it has been suggested that quetiapine’s comparatively lower dopamine receptor affinity and strong antihistamine activity might mean it could be regarded as more similar to sedating antihistamines in this context. While these issues have not been regarded as sufficient cause for placing quetiapine under increased legal controls, prescribers have been urged to show caution when prescribing quetiapine to individuals with characteristics that might place them at increased risk for drug misuse.

Overdose

Most instances of acute overdosage result in only sedation, hypotension and tachycardia, but cardiac arrhythmia, coma and death have occurred in adults. Serum or plasma quetiapine concentrations are usually in the 1-10 mg/L range in overdose survivors, while postmortem blood levels of 10-25 mg/L are generally observed in fatal cases. Non-toxic levels in postmortem blood extend to around 0.8 mg/kg, but toxic levels in postmortem blood can begin at 0.35 mg/kg.

Pharmacology

Pharmacodynamics

Quetiapine has the following pharmacological actions:

  • Dopamine D1, D2, D3, D4, and D5 receptor antagonist.
  • Serotonin 5-HT1A receptor partial agonist, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor antagonist, and 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptor ligand.
  • α1- and α2-adrenergic receptor antagonist.
  • Histamine H1 receptor antagonist.
  • Muscarinic acetylcholine receptor antagonist.

This means quetiapine is a dopamine, serotonin, and adrenergic antagonist, and a potent antihistamine with some anticholinergic properties. Quetiapine binds strongly to serotonin receptors; the drug acts as partial agonist at 5-HT1A receptors. Serial PET scans evaluating the D2 receptor occupancy of quetiapine have demonstrated that quetiapine very rapidly disassociates from the D2 receptor. Theoretically, this allows for normal physiological surges of dopamine to elicit normal effects in areas such as the nigrostriatal and tuberoinfundibular pathways, thus minimising the risk of side-effects such as pseudo-parkinsonism as well as elevations in prolactin. Some of the antagonised receptors (serotonin, norepinephrine) are actually autoreceptors whose blockade tends to increase the release of neurotransmitters.

At very low doses, quetiapine acts primarily as a histamine receptor blocker (antihistamine) and α1-adrenergic blocker. When the dose is increased, quetiapine activates the adrenergic system and binds strongly to serotonin receptors and autoreceptors. At high doses, quetiapine starts blocking significant amounts of dopamine receptors. Off-label prescriptions, e.g. for chronic insomnia, of low-dose quetiapine is not recommended due to the harmful side-effects.

When treating schizophrenia, antagonism of D2 receptor by quetiapine in the mesolimbic pathway relieves positive symptoms and antagonism of the 5HT2A receptor in the frontal cortex of the brain relieves negative symptoms. Quetiapine has fewer extrapyramidal side effects and is less likely to cause hyperprolactinemia when compared to other drugs used to treat schizophrenia, so is used as a first line treatment.

Pharmacokinetics

Peak levels of quetiapine occur 1.5 hours after a dose. The plasma protein binding of quetiapine is 83%. The major active metabolite of quetiapine is norquetiapine (N-desalkylquetiapine). Quetiapine has an elimination half-life of 6 or 7 hours. Its metabolite, norquetiapine, has a half-life of 9 to 12 hours. Quetiapine is excreted primarily via the kidneys (73%) and in faeces (20%) after hepatic metabolism, the remainder (1%) is excreted as the drug in its unmetabolised form.

Chemistry

Quetiapine is a tetracyclic compound and is closely related structurally to clozapine, olanzapine, loxapine, and other tetracyclic antipsychotics.

Synthesis

The synthesis of quetiapine begins with a dibenzothiazepinone. The lactam is first treated with phosphoryl chloride to produce a dibenzothiazepine. A nucleophilic substitution is used to introduce the sidechain.

Society and Culture

Regulatory Status

In the United States, the FDA has approved quetiapine for the treatment of schizophrenia and of acute manic episodes associated with bipolar disorder (bipolar mania) and for treatment of bipolar depression. In 2009, quetiapine XR was approved as adjunctive treatment of major depressive disorder.

Quetiapine received its initial indication from the FDA for treatment of schizophrenia in 1997. In 2004, it received its second indication for the treatment of mania-associated bipolar disorder. In 2007 and 2008, studies were conducted on quetiapine’s efficacy in treating generalized anxiety disorder and major depression.

Patent protection for the product ended in 2012; however, in a number of regions, the long-acting version remained under patent until 2017.

Lawsuits

In April 2010, the US Department of Justice fined Astra-Zeneca $520 million for the company’s aggressive marketing of Seroquel for off-label uses. According to the Department of Justice, “the company recruited doctors to serve as authors of articles that were ghostwritten by medical literature companies and about studies the doctors in question did not conduct. AstraZeneca then used those studies and articles as the basis for promotional messages about unapproved uses of Seroquel.”

Multiple lawsuits have been filed in relation to quetiapine’s side-effects, in particular, diabetes.

Approximately 10,000 lawsuits have been filed against AstraZeneca, alleging that quetiapine caused problems ranging from slurred speech and chronic insomnia to deaths.

Controversy

In 2004, a young man named Dan Markingson committed suicide in a controversial Seroquel clinical trial at the University of Minnesota while under an involuntary commitment order. A group of University of Minnesota bioethicists charged that the trial involved an alarming number of ethical violations.

Nurofen Plus Tampering Case

In August 2011, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) issued a class-4 drug alert following reports that some batches of Nurofen plus contained Seroquel XL tablets instead.

Following the issue of the Class-4 Drug Alert, Reckitt Benckiser (UK) Ltd received further reports of rogue blister strips in cartons of two additional batches of Nurofen Plus tablets. One of the new batches contained Seroquel XL 50 mg tablets and one contained the Pfizer product Neurontin 100 mg capsules.

Following discussions with the MHRA’s Defective Medicines Report Centre (DMRC), Reckitt Benckiser (UK) Ltd decided to recall all remaining unexpired stock of Nurofen Plus tablets in any pack size, leading to a Class-1 Drug Alert. The contamination was later traced to in-store tampering by a customer.

What is a Typical Antipsychotic?

Introduction

Typical antipsychotics (also known as major tranquilisers, or first generation antipsychotics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia).

Advertisement for Thorazine (chlorpromazine) from the 1950s, reflecting the perceptions of psychosis, including the now-discredited perception of a tendency towards violence, from the time when antipsychotics were discovered.

Typical antipsychotics may also be used for the treatment of acute mania, agitation, and other conditions. The first typical antipsychotics to come into medical use were the phenothiazines, namely chlorpromazine which was discovered serendipitously. Another prominent grouping of antipsychotics are the butyrophenones, an example of which is haloperidol. The newer, second-generation antipsychotics, also known as atypical antipsychotics, have largely supplanted the use of typical antipsychotics as first-line agents due to the higher risk of movement disorders in the latter.

Both generations of medication tend to block receptors in the brain’s dopamine pathways, but atypicals at the time of marketing were claimed to differ from typical antipsychotics in that they are less likely to cause extrapyramidal symptoms (EPS), which include unsteady Parkinson’s disease-type movements, internal restlessness, and other involuntary movements (e.g. tardive dyskinesia, which can persist after stopping the medication). More recent research has demonstrated the side effect profile of these drugs is similar to older drugs, causing the leading medical journal The Lancet to write in its editorial “the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction.” While typical antipsychotics are more likely to cause EPS, atypicals are more likely to cause adverse metabolic effects, such as weight gain and increase the risk for type II diabetes.

Brief History

The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anaesthetic after an initial report in 1952. It was first used in psychiatric institutions because of its powerful tranquilising effect; at the time it was regarded as a non-permanent “pharmacological lobotomy” (Note that “tranquilizing” here only refers to changes in external behaviour, while the experience a person has internally may be one of increased agitation but inability to express it).

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs. In the late 1950s the most widely used term was “neuroleptic”, followed by “major tranquilizer” and then “ataraxic”. The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine. It is derived from the Greek: “νεῦρον” (neuron, originally meaning “sinew” but today referring to the nerves) and “λαμβάνω” (lambanō, meaning “take hold of”). Thus, the word means taking hold of one’s nerves. It was often taken to refer also to common effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and harmful, they were, along with akathisia, considered a reliable sign that the drug was working. These terms have been largely replaced by the term “antipsychotic” in medical and advertising literature, which refers to the medication’s more-marketable effects.

Clinical Uses

Typical antipsychotics block the dopamine 2 receptor (D2) receptor, causing a tranquilising effect. It is thought that 60-80% of D2 receptors need to be occupied for antipsychotic effect. For reference, the typical antipsychotic haloperidol tends to block about 80% of D2 receptors at doses ranging from 2 to 5 mg per day. On the aggregate level, no typical antipsychotic is more effective than any other, though people will vary in which antipsychotic they prefer to take (based on individual differences in tolerability and effectiveness). Typical antipsychotics can be used to treat, e.g. schizophrenia or severe agitation. Haloperidol, due to the availability of a rapid-acting injectable formulation and decades of use, remains the most commonly used tranquilizer for chemical restraint in the emergency department setting (in the interests of hospital staff, not to meet a medical need of the patient).

Adverse Effects

Adverse effects vary among the various agents in this class of medications, but common effects include: dry mouth, muscle stiffness, muscle cramping, tremors, EPS and weight gain. EPS refers to a cluster of symptoms consisting of akathisia, parkinsonism, and dystonia. Anticholinergics such as benztropine and diphenhydramine are commonly prescribed to treat the EPS. 4% of users develop rabbit syndrome while on typical antipsychotics.

There is a risk of developing a serious condition called tardive dyskinesia as a side effect of antipsychotics, including typical antipsychotics. The risk of developing tardive dyskinesia after chronic typical antipsychotic usage varies on several factors, such as age and gender, as well as the specific antipsychotic used. The commonly reported incidence of TD among younger patients is about 5% per year. Among older patients incidence rates as high as 20% per year have been reported. The average prevalence is approximately 30%. There are few treatments that have consistently been shown to be effective for the treatment of tardive dyskinesia, though an VMAT2 inhibitor like valbenazine may help. The atypical antipsychotic clozapine has also been suggested as an alternative antipsychotic for patients experiencing tardive dyskinesia. Tardive dyskinesia may reverse upon discontinuation of the offending agent or it may be irreversible, withdrawal may also make tardive dyskinesia more severe.

Neuroleptic malignant syndrome, or NMS, is a rare, but potentially fatal side effect of antipsychotic treatment. NMS is characterized by fever, muscle rigidity, autonomic dysfunction, and altered mental status. Treatment includes discontinuation of the offending agent and supportive care.

The role of typical antipsychotics has come into question recently as studies have suggested that typical antipsychotics may increase the risk of death in elderly patients. A retrospective cohort study from the New England Journal of Medicine on 01 December 2005 showed an increase in risk of death with the use of typical antipsychotics that was on par with the increase shown with atypical antipsychotics. This has led some to question the common use of antipsychotics for the treatment of agitation in the elderly, particularly with the availability of alternatives such as mood stabilising and antiepileptic drugs.

Potency

Traditional antipsychotics are classified as high-potency, mid-potency, or low-potency based on their potency for the D2 receptor as noted in the table below.

PotencyExamplesAdverse Effect Profile
HighFluphenazine and HaloperidolMore extrapyramidal side effects (EPS) and less antihistaminic effects (e.g. sedation), alpha adrenergic antagonism (e.g. orthostatic hypotension), and anticholinergic effects (e.g. dry mouth).
MediumPerphenazine and LoxapineIntermediate D2 affinity, with more off-target effects than high-potency agents.
LowChlorpromazineLess risk of EPS but more antihistaminic effects, alpha adrenergic antagonism, and anticholinergic effects.

Prochlorperazine (Compazine, Buccastem, Stemetil) and Pimozide (Orap) are less commonly used to treat psychotic states, and so are sometimes excluded from this classification.

A related concept to D2 potency is the concept of “chlorpromazine equivalence”, which provides a measure of the relative effectiveness of antipsychotics. The measure specifies the amount (mass) in milligrams of a given drug that must be administered in order to achieve desired effects equivalent to those of 100 milligrams of chlorpromazine. Another method is “defined daily dose” (DDD), which is the assumed average dose of an antipsychotic that an adult would receive during long-term treatment. DDD is primarily used for comparing the utilization of antipsychotics (e.g. in an insurance claim database), rather than comparing therapeutic effects between antipsychotics. Maximum dose methods are sometimes used to compare between antipsychotics as well. It is important to note that these methods do not generally account for differences between the tolerability (i.e. the risk of side effects) or the safety between medications.

Below is list of typical antipsychotics organised by potency.

  • Low potency:
    • Chlorpromazine.
    • Chlorprothixene.
    • Levomepromazine.
    • Mesoridazine.
    • Periciazine.
    • Promazine.
    • Thioridazine (withdrawn by brand-name manufacturer and most countries, and since discontinued).
  • Medium potency:
    • Loxapine.
    • Molindone.
    • Perphenazine.
    • Thiothixene.
  • High potency:
    • Droperidol.
    • Flupentixol.
    • Fluphenazine.
    • Haloperidol.
    • Pimozide.
    • Prochlorperazine.
    • Thioproperazine.
    • Trifluoperazine.
    • Zuclopenthixol.

Long-Acting Injectables

Some typical antipsychotics have been formulated as a long-acting injectable (LAI), or “depot”, formulation. Depot injections are also used on persons under involuntary commitment to force compliance with a court treatment order when the person would refuse to take daily oral medication. This has the effect of dosing a person who doesn’t consent to take the drug. The United Nations Special Rapporteur On Torture has classified this as a human rights violation and cruel or inhuman treatment.

The first LAI antipsychotics (often referred to as simply “LAIs”) were the typical antipsychotics fluphenazine and haloperidol. Both fluphenazile and haloperidol are formulated as decanoates, referring to the attachment of a decanoic acid group to the antipsychotic molecule. These are then dissolved in an organic oil. Together, these modifications prevent the active medications from being released immediately upon injection, attaining a slow release of the active medications (note, though, that the fluphenazine decanoate product is unique for reaching peak fluphenazine blood levels within 24 hours after administration). Fluphenazine decanoate can be administered every 7 to 21 days (usually every 14 to 28 days), while haloperidol decanoate can be administered every 28 days, though some people receive more or less frequent injections. If a scheduled injection of either haloperidol decanoate or fluphenazine decanoate is missed, recommendations for administering make-up injectable dose(s) or providing antipsychotics to be taken by mouth vary by, e.g. how long ago the last injection was and how many previous injections the person has received (i.e. if steady state levels of the medication have been reached or not).

Both of the typical antipsychotic LAIs are inexpensive in comparison to the atypical LAIs. Doctors usually prefer atypical LAIs over typical LAIs due to the differences in adverse effects between typical and atypical antipsychotics in general.