Biological treatments

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CHAPTER 13 Biological treatments

Darryl Bassett, David J. Castle

Psychopharmacology

Medications in psychiatry are used not only to reduce symptoms and modify maladaptive behaviour, but also to facilitate psychological therapies of various kinds. Many patients with mental disorders are significantly more vigilant and more anxious about changes in bodily sensations than other people. Thus, ‘side effects’ tend to be more often identified and more often found to be poorly tolerable. However, tolerance usually improves with persistence and patients should be advised of this. It is essential that patients are made aware of common side effects as well as the risk of less common ones (particularly when potentially very serious or life-threatening). The majority of patients find being aware of potential problems and their management reassuring.

This chapter outlines medications which may be prescribed or encountered in clinical practice. Clinical tips are included and common uses of medications are summarised. Less commonly used medications are included as a resource, should they be encountered in clinical practice.

Drug interactions

Most medications are metabolised, at least to some extent, in the liver by the cytochrome P450 enzyme group (CYP enzymes) and this includes most psychotropic medications. A number of psychotropic medications inhibit or induce isoenzymes of this enzyme group creating potentially significant changes in the blood levels of other medications. Inhibition will promote increased levels and induction will promote decreased levels. These effects need to be considered in the prescribing of medication combinations and must be considered before prescribing. CYP polymorphisms and levels vary from person to person, and also over different racial groups. Genetic testing is now available to determine the profile of these polymorphisms if there are specific clinical indications (see Tables 13.1, 13.2 and 13.3).

TABLE 13.1 CYP isoenzyme inhibition by antidepressants

image

TABLE 13.2 Drugs metabolised by cytochrome P450 (CYP) isoenzymes

TABLE 13.3 Inducers or inhibitors of the cytochrome P450 isoenzymes

Some specific examples are noted below. Pharmacists can be very helpful with advice, computerised prescribing programs include warnings about potential interactions, and the internet site ‘MedWatch’ is very useful.

Cigarette smoking induces CYP1A2 and therefore blood levels of some medications (e.g. clozapine) may be lower in smokers than expected.

ABC membrane transport proteins (ATP-bound cassette membrane proteins) are heavily involved in the regulation of transport of multiple substances across cell membranes, including the gut, blood-brain barrier, placenta, kidneys and other organs. P-glycoprotein (Pgp) is one such membrane transport protein which has a significant role in the regulation of transport of medications and other substances and therefore pharmacokinetics (including drug interactions). Most psychotropic medications cross the blood-brain barrier by passive diffusion through their lipophilic characteristics, but Pgp can modify transfer against concentration gradients. A number of medications inhibit Pgp and therefore have interactive effects on the action of other medications. Examples of such inhibitors include most selective serotonin reuptake inhibitors (SSRIs) and serotonergic and noradrenergic reuptake inhibitors (SNRIs) (with the currently known exception of desmethylvenlafaxine), atypical antipsychotics such as risperidone and olanzapine (less so paliperidone) and a variety of other medications. The tendency of Pgp to have common substrates with the CYP3A group of enzymes can also cause alterations in the bioavailability of several medications. Finally, various neurological diseases alter Pgp activity at the blood-brain barrier.

The combination of medications is a common and often necessary element of clinical practice in medicine. However, it always requires attention to possible interactions, which can be complex and very significant. At the same time, not all combinations are problematic and many interactions are trivial in effect.

The combination of antidepressants in the treatment of depressive disorders is an area of some controversy and any combinations should be approached cautiously and with attention to relative effects on CYP enzymes and Pgp. Most medications are carried in the blood bound to proteins. As many share the same carrier proteins, competition alters the level of ‘free’ drug and therefore effect. Alterations in the levels of warfarin, for example, are commonly important (Box 13.1).

BOX 13.1 Serotonin syndrome

When medications which markedly increase the level of serotonin at nerve synapses are combined with other medications or substances with similar effects, the increase in serotonin levels can produce the symptoms of a serotonin syndrome.

Common examples include an SSRI with a monoamine oxidase inhibitor (MAOI), an SSRI with lithium (often safe), an SSRI with clomipramine and an SSRI with a ‘triptan’ (e.g. sumatriptan) used to treat migraine. This is characterised by three potential groups of clinical phenomena:

1. cardiovascular: flushing of the skin, increased sweating, tachycardia, and increased or decreased blood pressure
2. neurological: tremor, hyperreflexia, myoclonus, delirium and seizures, and
3. gastrointestinal: nausea, vomiting, diarrhoea and abdominal pains.

The severity of the syndrome may vary from mild to life-threatening.

Absorption

Medication absorption and therefore bioavailability is affected by:

image the pharmaceutical preparation of the medication (e.g. wafer, enteric coated or controlled release)
image the timing in relation to food (which can also affect tolerance)
image the concurrent use of other substances (e.g. antacids), and
image gastrointestinal function (e.g. diarrhoea).

Hepatic and renal dysfunction

Hepatic and/or renal diseases may interfere with medication metabolism and/or excretion.

Age

The very young and the aged exhibit differences in fat/lean body ratios, medication absorption from the gut, hepatic and renal function, and tolerance of side effects from medications (see Chs 16 and 17).

BOX 13.2 Practical notes

The use of herbal remedies, other ‘over-the-counter’ medicines and illicit substances may promote significant interactions with prescribed medications.

Hypericum perforatum (St John’s Wort) has weak antidepressant properties and contains a group of substances which have antidepressant properties. Combination with serotonergic antidepressants can provoke a serotonin syndrome (Box 13.1). Several medicinal herbs either induce or inhibit CYP enzymes. Combination of these with psychotropic medications requires specific enquiry for each case.

Many ‘recreational’ substances may interact seriously with medications and include alcohol, amphetamines (various forms), cocaine and opiates.

Adherence with medication regimes is improved with education about the medications, taking the medications when patients follow other habits (e.g. brushing teeth, after meals or upon retiring to bed), dosette boxes and bubble-packs filled by pharmacists.

Common side effects can be managed as suggested below:

• sedation: take shortly before retiring to bed
• weight gain: a planned, healthy diet with frequent small meals and regular exercise
• dry mouth: frequent sips of water with lemon juice; chewing sugar-free gum; selected types of toothpaste (detergent free); and a variety of artificial saliva substitutes
• orthostatic hypotension: stand gradually in stages, and
• nausea: take medications after food; use antiemetic medications concurrently.

Specific medications

The categories used to classify medications are chosen by the manufacturer when first applying for registration with regulatory authorities. This means that medications may have multiple applications but be ‘known’ by their initial categorisation. Dose ranges given are daily and are suggested for ‘routine’ applications, but exceptions may arise. Side effects listed are those encountered commonly in clinical practice and those which are of particular seriousness. More detailed and comprehensive lists of side effects can be obtained from the ‘References and further reading’ and various printed and electronic prescribing guides.

Most psychotropic medications reduce the seizure threshold, but some have more potent effects than others and will be highlighted in the text.

Anxiolytics

Indications

Anxiolytics are:

image indicated in anxiety of any form
image best used for acute treatment of distressing anxiety and ceased as soon as possible, and
image useful in the first week when introducing antidepressant medications for anxiety or anxious depression.

Mode of action

Benzodiazepines act through activation of GABA receptors (the brain’s ‘braking system’), reducing neuronal arousal generally. Buspirone is a serotonin receptor-1A partial agonist, providing optimal serotonergic activity. Clinical notes on anxiolytics are provided in Box 13.3.

BOX 13.3 Clinical notes on anxiolytics

Diazepam is used frequently in presentations of acute anxiety and is useful for patients to keep for ‘crisis’ situations. Its rapid absorption by mouth, and duration of action lasting several hours, makes diazepam a flexible anxiolytic for all forms of anxiety disorder for short-term relief. Encourage patients to use this sparingly to minimise tolerance, dependence and adverse effects on the process of capacity to learn. Just knowing that the patient has ready access if in crisis can provide the confidence to manage without.

Alprazolam is preferred by many patients for short-term relief of panic attacks, but should not be seen as a substitute for cognitive and behavioural interventions. Clear education about the management of panic attacks is essential, in any event.

Benzodiazepines

These include alprazolam, clonazepam, diazepam, flunitrazepam, lorazepam and oxazepam (see Table 13.4).

TABLE 13.4 Dose ranges, equivalent doses to diazepam, and half-lives of anxiolytics

image

General comments

image Benzodiazepines have anticonvulsant and muscle-relaxing properties in addition to anxiolytic properties, which can be very useful at times.
image Safety in oral overdose is very good.

Adverse effects

image Sedation is the most common side effect.
image Benzodiazepines can interfere with cognition, including memory, balance and reaction times, and may be addictive over time.
image When combined with alcohol or other sedative medications, benzodiazepines amplify sedation and increase the adverse effect upon reaction times, reflexes and cognitive functions generally.
image Use should be intermittent if at all possible, as tolerance develops rapidly and there is significant dependence over time.
image Benzodiazepines suppress respiration in very high concentrations (e.g. with bolus intravenous administration).

Spirodecanediones (buspirone)

General comments

image Start at 5 mg and increase slowly because of dizziness, which usually resolves with time.
image Spirodecanediones are not addictive, are well tolerated over time, do not affect cognition and are easily withdrawn. They are not sedating.

Calcium channel modulators (pregabalin)

General comments

image Pregabalin modulates voltage gated calcium channel activity (binds with protein α2δ) with reductions in release of glutamate, noradrenaline and substance P, plus increased production of GABA.
image Pregabalin is useful in generalised anxiety disorders where other treatment may be inappropriate.
image The prime indication is for neurogenic pain.
image The dose range is 75–600 mg daily in divided doses.

Adverse effects

Adverse effects include:

image sedation
image dizziness
image diplopia, dysarthria and ataxia, and
image oedema.

Antidepressants

General comments

image All antidepressants relieve core symptoms and signs of depressive disorders with biological features (see Ch 6).
image They are also very effective in the treatment of all forms of anxiety disorders and particularly useful in treatment-resistant panic disorder, post-traumatic stress disorder and obsessive-compulsive disorder.
image Response in depressive disorders usually takes at least 1 week to be evident and 2 or more weeks to become significant. Optimal response will take several months.
image Response in anxiety disorders is slower than for depressive disorders (3–4 weeks) and usually requires relatively higher doses. Start with a low dose to minimise aggravation of anxiety early and increase gradually. Concurrent use of a benzodiazepine may be useful early in this treatment.
image Choice of antidepressant is usually initially based upon prominent symptoms (e.g. prominent anxiety might suggest a sedating antidepressant first), response, side effect profile and prescriber preference.
image Inappropriate secretion of antidiuretic hormone (SIADH) may occur and result in hyponatraemia (most commonly with SSRIs and SNRIs). Symptoms may include lethargy, muscle weakness, impaired concentration, and potentially hypotension and cardiac arrhythmias. The effect is usually temporary. It is most common in elderly patients. Fluid restriction for a week or more may be required or the medication may need to be changed.
image The metabolism and therefore pharmacokinetics of most antidepressants are affected by polymorphisms of CYP enzymes (e.g. as found in racial variations). Desmethylvenlafaxine is not.
image The dose ranges, half-lives and common side effects of SSRIs are summarised in Table 13.5.
image Suicide and the use of antidepressant medications has been the subject of intense discussion and research. The current findings of this research are summarised in Box 13.4.
image Clinical notes on the use of antidepressants are summarised in Box 13.5.

TABLE 13.5 Dose ranges, half-lives and common side effects of SSRIs

image

BOX 13.4 Antidepressants and the risk of suicide

• The risk of suicide increases around the time of presentation for treatment and in the early stages of treatment for depression or psychosis with any treatment.
• The highest risk of suicide occurs in the week before treatment.
• Some antidepressants may increase the risk of suicidal behaviour by enhancing impulsivity and aggression in the first 2 weeks of treatment, particularly in children and adolescents (notably males). However, care should be exercised with patients under the age of 25 as a sensible precaution.
• There is no evidence that antidepressants increase the risk of suicide in adults, but there is evidence that using antidepressants may reduce the risk of suicide in adults.
• The increased risk of self-injury and suicidal thinking may be reduced by concurrent use of anxiolytic and antipsychotic medications, and may be less with certain antidepressants (e.g. mirtazapine).

BOX 13.5 Clinical notes on antidepressants

Below are suggestions for the choice of antidepressants in common clinical situations, based upon research and personal experience/preference. The list is not exhaustive and clinical judgment must be used in each case, particularly when there is a past history of antidepressant use. When treating depressive disorders, begin with the lowest manufactured dose and increase after 2 weeks if the response is inadequate. When treating anxiety disorders, begin with half the lowest manufactured dose (where practicable) and combine with an anxiolytic for the first week (except NASAs and TCAs). Anxiety disorders will usually require an increase in dose after 2 weeks to achieve an adequate response. Suggestions are:

• depression (uncomplicated): SSRIs
• depression (anxious): usually SSRIs (particularly citalopram, escitalopram, fluvoxamine and paroxetine); if severe, NASAs and TCAs can be useful
• depression (retarded): fluoxetine, SNRIs, reboxetine and nortriptyline
• depression (premenstrual): SSRIs
• depression (severe): SNRIs, mirtazapine and TCAs
• depression (failing to respond to or intolerant of SSRIs): SNRIs, NASAs and TCAs
• depression (treatment-resistant): higher than usual doses of any antidepressants used; TCAs, MAOIs and bupropion
• depression (psychotic): any antidepressant, but particularly SNRIs or TCAs; always combine with an antipsychotic medication
• generalised anxiety disorder: SSRIs; use SNRIs, NASAs or TCAs if failing to respond to SSRIs
• panic disorder: SSRIs combined with an anxiolytic for the first week to avoid provoking panic attacks; SNRIs, NASAs or TCAs if failing to respond to SSRIs
• post-traumatic stress disorder: SSRIs; use SNRIs, NASAs or TCAs if failing to respond to SSRIs
• obsessive-compulsive disorder: SSRIs; use TCAs (particularly clomipramine) if failing to respond to SSRIs; relatively high doses may be required, and
• social anxiety disorder, agoraphobia: SSRIs; use SNRIs, NASAs or TCAs if failing to respond to SSRIs.

Selective serotonin reuptake inhibitors (SSRIs)

These include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline (see Table 13.5).

General comments

image Consumption after food reduces the intensity of nausea and reduces the risk of gastric erosion.
image There is some evidence of greater efficacy and greater efficiency with an increased dose of escitalopram than with citalopram.
image They are safe in overdose.

Indications

image SSRIs are indicated in depressive and anxiety disorders with significant somatic/melancholic symptoms.

Mode of action

image By reducing the reuptake of serotonin and sometimes noradrenaline after release from pre-synaptic terminals, these medications improve the capacity of the brain to recover optimal function during depressive disorders or severe anxiety. Neurotrophic factor release is strongly enhanced.

Adverse effects

image Nausea is common in the first few days, but it usually improves with time.
image There may be disturbed sleep with initial and/or middle insomnia (unpleasant wakefulness after a period of sleep, followed by further sleep).
image There may be sexual dysfunction, including orgasmic delay and suppression of libido; it improves with time and sexual activity; it is particularly significant for females.
image SSRIs do not interfere with cognition.
image Movement disorders such as restless legs syndrome, periodic limb movement disorder and bruxism may be aggravated.
image Platelet adhesion and function is mildly impaired and may result in bruising, an increase in bleeding time and increased risk of gastric bleeding (clotting factors are not affected).
image Gastro-oesophageal reflux may be aggravated.
image Hyponatraemia may occur (see ‘General comments’ on antidepressants, above).
image Withdrawal should be gradual as discontinuation can be very uncomfortable (e.g. dizziness, light-headedness, insomnia, agitation and irritability); it is worst with paroxetine.
image There may be reduced male fertility.

Serotonergic and noradrenergic reuptake inhibitors (SNRIs)

These include desvenlafaxine, duloxetine and venlafaxine. Details of dose range, half-lives and adverse effects can be found in Table 13.6.

TABLE 13.6 Dose ranges, half-lives and common side effects of other antidepressants

image

Indications

image SNRIs are indicated in depressive and anxiety disorders with significant vegetative symptoms.
image SNRIs are popular in more severe disorders or when response to SSRIs is inadequate.
image Duloxetine can be very helpful in the management of chronic pain; other members of this group can also be of benefit in this regard.

Mode of action

image It is similar to SSRIs but with greater effect upon noradrenaline; duloxetine and desvenlafaxine have significant dual serotonergic/noradrenergic effect at usual doses; venlafaxine requires a relatively high dose (more than 225 mg daily) to achieve a significant noradrenergic effect.

Adverse effects

image There may be similar unwanted effects to SSRIs; side effects with venlafaxine appear clinically more severe than duloxetine and desvenlafaxine.
image Withdrawal should be very gradual, as discontinuation can be very uncomfortable (dizziness, light-headedness, insomnia, agitation and irritability); it appears to be most severe for venlafaxine and less severe for duloxetine and desvenlafaxine.
image Duloxetine may be mildly sedating at first or may be activating.
image Diastolic hypertension may rise; the increase is proportional to the dose; the effects of duloxetine and desvenlafaxine appear less severe than for venlafaxine.
image Hyponatraemia may occur (see ‘General comments’ on antidepressants, above).

Selective noradrenergic reuptake inhibitors (NRIs)

These include reboxetine (see Table 13.6).

General comment

image Use of reboxetine is not accompanied by weight gain.

Indications

image NRIs are indicated in depressive and anxiety disorders with significant somatic/melancholic symptoms.
image NRIs are activating and energising.

Mode of action

image By reducing the reuptake of noradrenaline after release from pre-synaptic terminals, these medications improve the capacity of the brain to recover optimal function during depressive disorders or severe anxiety. Neurotrophic factor release is significantly enhanced.

Adverse effects

image Initial insomnia may occur.
image NRIs may provoke abnormal ejaculation and urinary retention in males; rarely, there is heightened genital arousal in females.
image They can amplify anxiety markedly, particularly early in treatment.
image Withdrawal is best achieved slowly, but is usually not uncomfortable.
image Movement disorders such as restless legs syndrome, periodic limb movement disorder and bruxism may be aggravated.
image Platelet adhesion and function is mildly impaired and may result in bruising and an increase in bleeding time and increased gastric bleeding.

Noradrenaline and specific serotonergic agents (NASAs)

These include mianserin and mirtazapine (see Table 13.6).

General comments

image Mirtazapine is used most commonly, as mianserin carries a higher risk of blood dyscrasia.
image Mianserin is usually more sedating than mirtazapine.
image They are usually well tolerated in elderly patients and this can be an advantage (see Ch 17).

Indications

image NASAs are indicated in depressive disorders with significant somatic/melancholic symptoms and severe anxiety disorders.

Mode of action

image There is inhibition of alpha-2 noradrenergic receptors, thus enhancing noradrenaline and serotonin release.
image There is inhibition of serotonin 2a receptors enhancing noradrenaline and dopamine release.

Adverse effects

image NASAs are very sedating and weight gain can be a significant problem; the effect decreases with increasing dose (reverse of that usually expected).
image There are no or limited adverse effects on sexual function.
image Dry mouth, constipation and sometimes urinary retention can occur.
image Occasionally, unusual and sometimes distressing dreaming may accompany NASAs; withdrawal is usually the optimal management, but they may resolve with persistence.
image There is some evidence of an increased risk of seizures in vulnerable individuals.
image Blood dyscrasia occurs rarely.

Tricyclic antidepressants (TCAs)

These include amitriptyline, nortriptyline, dothiepin, doxepin, imipramine, clomipramine and trimipramine (see Table 13.7).

TABLE 13.7 Dose ranges, half-lives and common side effects of TCAs

image

General comments

image TCAs are very useful if tolerance of SSRIs and SNRIs is poor or those medications have failed to provide optimal response.
image Nortriptyline is a selectively noradrenergic TCA which can be useful when greater activation is required or when there is risk of serotonin syndrome.

Indications

image TCAs are indicated in depressive and anxiety disorders with significant somatic/melancholic symptoms, as well as with chronic pain management.

Mode of action

image By reducing the reuptake of serotonin and noradrenaline after release from pre-synaptic terminals, and by enhancing noradrenaline and dopamine release through inhibition of serotonin 2a receptors, these medications improve the capacity of the brain to recover optimal function during depressive disorders or severe anxiety. Neurotrophic factor release is significantly enhanced, but the mechanism remains uncertain.

Adverse effects

image Dry mouth and constipation are common (muscarinic) side effects. Optimal dosing is usually associated with these effects.
image TCAs are potentially lethal in overdose because of cardiac arrhythmia (impaired ventricular conduction).
image Blurred vision and urinary retention may occur, particularly at higher doses.

Noradrenaline and dopamine reuptake inhibitors

These include bupropion (see Table 13.6).

Indications

image Noradrenaline and dopamine reuptake inhibitors are indicated in depressive disorders and smoking cessation.
image Activating effects can be useful clinically.
image They are sometimes used to counteract sexual dysfunction provoked by serotonergic medications.
image There is some evidence of being less likely to promote manic switching in bipolar disorders than most antidepressants.
image They are used in Australia mostly for treatment-resistant depression because of cost.

Mode of action

image The mechanism is uncertain, but reuptake of noradrenaline and dopamine is reduced.

Adverse effects

image Dry mouth, nausea, sweating, insomnia and dizziness are relatively common.
image Rarely, seizures may occur.

Metabolism

image Bupropion is metabolised to hydroxyl-bupropion by CYP isoenzyme 2B6.

Serotonin receptor antagonists/melatonin receptor agonists

These include agomelatine (see Table 13.6).

Indications

image Serotonin receptor antagonists/melatonin receptor agonists are indicated in depressive and anxiety disorders with significant somatic/melancholic symptoms.
image Agomelatine is not currently registered in Australia, but is currently in use by numerous psychiatrists.
image Agomelatine is currently used for patients with a history of very poor tolerance of other antidepressants.

Mode of action

image They inhibit serotonin 2a receptors with increased noradrenaline and dopamine release.
image There is enhancement of melatonin types 1 and 2 receptors with increased efficiency of sleep induction.

Adverse effects

image While adverse effects similar to those of SSRIs have been reported, the intensity is low and some patients do not report any adverse effects at all.
image Mild increases in liver transaminase levels have been found in some patients, but the clinical significance of these is not clear.

Monoamine oxidase inhibitors (MAOIs)

These include moclobemide, phenelzine and tranylcypromine (see Tables 13.8, 13.9 and 13.10).

TABLE 13.8 Dose ranges, half-lives and common side effects of MAOIs

image

Indications

image MAOIs are indicated in depressive disorders with significant somatic/melancholic symptoms and severe anxiety disorders.
image They are reserved in clinical practice for treatment-resistant depressive and anxiety disorders.
image Moclobemide is best used for relatively mild depressive disorders.

Mode of action

image Inhibition of monoamine oxidase increases the quantities of serotonin, noradrenaline and dopamine available for release from pre-synaptic terminal.

Adverse effects

image Reversible inhibitors of monoamine oxidase type A (RIMAs) are very well tolerated but are often not effective. Their relatively select inhibition of the A type of monoamine oxidase (MAO) is advantageous, as this is found mostly in the brain and much less often in the gut. Consequently, the risk of excessive tyramine absorption from certain foods is very much lower (not absent) and use of the medications much safer and easier.
image MAOIs carry dietary restrictions because of increased tyramine absorption from foods (by reducing destruction by MAO in the bowel).
image Introduction of tyramine in foods or in combination with serotonergic substances can result in rapid and severe hypertension, which can result in a cerebrovascular accident and even death (see Table 13.9).
image Typical early symptoms are:

image very severe headache (often of an ‘exploding’ quality)
image severe neck stiffness
image high temperature
image sweating, and
image tachycardia.

image Treatment can include sedation (e.g. with benzodiazepines), analgesia and vasodilating medications (e.g. phentolamine/diazoxide/nifedipine). General medical intervention with admission to hospital must be obtained urgently if any such symptoms or a rise in blood pressure occurs.
image MAOIs also amplify the effects of monoamines (including noradrenaline, adrenaline and serotonin of any source) and serotonergic medications (including pethidine, lithium and most antidepressants) (see Table 13.10).

TABLE 13.9 MAOI dietary restrictions

High tyramine content: not permitted Moderate tyramine content: limited amounts are safe Low tyramine content: permissible and safe
Aged, matured cheeses (unpasteurised) (e.g. cheddar, camembert, stilton, blue and Swiss)
Smoked or pickled meats, fish or poultry (e.g. herring, sausage and corned beef)
Aged/putrefying meats, fish and poultry (e.g. chicken or beef liver, pâté and game)
Yeast or meat extracts (e.g. ‘Bovril’, marmite and brewers’ yeast, but beware of drinks, soups or stews made with these products). Note: ‘yeast breads’ are safe
Certain wines (e.g. chianti, sherry and vermouth)
Italian broad beans (e.g. fava beans)

Meat extracts (e.g. bouillon and consomme)
Pasteurised light and pale beers (tap beers preferred)
Ripe avocado
Soy sauce and soy milk

Distilled spirits (in moderation) (e.g. vodka, gin, rye and Scotch)
Red and white wines (in moderation—not chianti)
Cheese (e.g. cottage cheese, cream cheese, mozzarella and ricotta)
Beverages containing chocolate and caffeine
Fruits (e.g. figs, raisins, grapes, pineapple and oranges)
Yoghurt and sour cream (commercial preparations)

TABLE 13.10 MAOI dangerous combinations

Amphetamines
Pethidine
Opioids
Lithium
Serotonergic antidepressants
Hypericum perforatum
Tryptophan

Antipsychotics

Indications

image Antipsychotic medications all relieve psychotic symptoms of any cause to some degree. They reduce the intensity of sensory information drawn from the environment, improve the efficiency of reformulation of environmental stimuli and facilitate processing of information and perceptions. They can then gradually improve reality processing and facilitate more appropriate responses to their internal and external environment.
image The efficacy is high in schizophrenia, mania and psychotic depression, but variable (sometimes ineffective) in psychosis secondary to general medical disorders or substance use (including prescribed medications), and in delusional disorders.

Clinical notes on the use of antipsychotics are summarised in Box 13.9 on page 177.

Mode of action

image All antipsychotics increase production of nerve growth factors in the brain (of considerable importance in schizophrenia particularly) and may have other useful effects upon neuronal and glial function.
image All of the current antipsychotics have modulating effects upon dopamine activity in the brain and this is directly related to their beneficial effects upon positive features of psychosis (see Ch 5).
image They appear to have greater effects upon nerve growth factor production than first generation antipsychotics. The most significant benefits have been evident with clozapine, which also has a more potent effect upon positive features of psychosis.
image When present, serotonergic effects positively affect negative features and cognitive functions.

Adverse effects

image The first generation antipsychotics do not appear to have significant benefit upon negative and cognitive features of psychosis (particularly schizophrenia), and can easily provoke a variety of extrapyramidal side effects (Box 13.6).
image Second generation antipsychotics, called ‘atypical antipsychotics’, are much less likely to produce these side effects (although they can occur).
image The second generation antipsychotics have beneficial effects upon negative features of psychosis and cognitive deficits.

BOX 13.6 Extrapyramidal side effects (EPS)

General comments

• Inhibition of dopamine-1 receptors in the substantia nigra and basal ganglia provokes an imbalance of dopaminergic and cholinergic activity. This can produce clinical signs and symptoms usually associated with basal ganglia diseases such as Parkinson’s disease.
• EPS are aggravated by anxiety.
• EPS are much less common with atypical antipsychotic medications, but occur more frequently with risperidone than others in this group, particularly at doses above 4 mg daily. Aripiprazole has a greater tendency to produce akathisia.
• EPS with depot preparations of medications can provide increased risks if severe, because of the long duration of action.

Acute forms of EPS

EPS may include:

• tremor (worst at rest)
• dystonias: involuntary sustained muscle contractions, particularly of the head and neck; very unpleasant and can be painful; may include facial muscles including the tongue
• occulogyric crisis: dystonia, which affects the external ocular muscles
• laryngeal stridor: dystonia, which affects the laryngeal muscles and is potentially very serious
• Parkinsonism: mask-like facial expression; muscle rigidity with tremor (‘cog-wheel rigidity’); shuffling gait (‘festinating gait’); retropulsion; and reduced spontaneous arm swing, and
• akathisia: subjective sensation of very uncomfortable restlessness, which is not relieved by movement (contrast ‘restless legs syndrome’); observation reveals frequent or constant movement and restlessness, which is difficult to resist; the patient tends to walk as much as possible.

Management of acute EPS

• Reduce dose of medication if possible.
• Anticholinergic medication such as benztropine 1–2 mg orally or intramuscularly, or benzhexol 2–5 mg orally, can be given.
• Beta-blockers such as propranolol and benzodiazepines (notably diazepam) are most useful for akathisia.

Neuroleptic malignant syndrome (NMS)

• NMS is a very serious, but rare, neurological reaction to antipsychotic medications characterised by severe hypertonia, high fever, autonomic instability and delirium.
• It is idiosyncratic and unpredictable.
• It develops over hours to days with ‘lead-pipe’ rigidity as an early sign.
• Myolysis and myoglobinuria may occur, which is aggravated by dehydration.
• Creatinine phosphokinase levels rise sharply and can be very high; liver transaminases and neutrophil counts may also rise.
• Admission to a general medical intensive care unit is essential given the life-threatening implications and complex management.
• Subsequent management requires specialist psychiatric care because of the risk of relapse.

Tardive forms (delayed onset; sometimes many years)

These include:

• tardive dyskinesia: mostly orobuccofaciolingual abnormal and involuntary movements; typically chewing movements and/or licking of lips and/or random tongue movements and/or grimacing; may not be distressing to the patient; may be accompanied by more generalised choreoathetosis which can be severe; may be due to other causes (a range of neurological disorders or substances); can arise in schizophrenia without exposure to medications and are more common than expected
• tardive dystonias: late onset dystonias as above, and
• tardive akathisia: late onset akathisia as above.

Management of tardive EPS

• Benzodiazepines may give some relief and change to atypical antipsychotic medications; clozapine in particular can be very helpful.
• Withdrawal or change to an atypical antipsychotic early in the appearance of tardive side effects can promote reversal of the movement disorder.
• It may resolve spontaneously.

Metabolic side effects

These may include:

image weight gain
image hyperlipidaemia, notably hypercholesterolaemia, but sometimes triglyceridaemia
image diabetes mellitus (type 2), and
image metabolic syndrome, which may be a combination of weight gain, diabetes mellitus (type 2), hypertension and hypercholesterolaemia (metabolic complications are spontaneously more common in schizophrenia than with other disorders).

Side effects are most prominent with atypical antipsychotics.

Cardiovascular side effects

These may include:

image postural hypotension (particularly with first generation antipsychotics such as chlorpromazine), and
image cardiac dysrhythmias (rarely).

First generation antipsychotics (neuroleptics)

These include chlorpromazine, fluphenazine, flupenthixol, haloperidol, pericyazine, trifluoperazine and zuclopenthixol (see Tables 13.11 and 13.12). Practical notes regarding the use of first generation antipsychotics are summarised in Box 13.7.

TABLE 13.11 Relative frequency of common adverse effects of antipsychotics at usual therapeutic doses

image

TABLE 13.12 Relative frequency of common adverse effects of depot antipsychotics at usual therapeutic doses (frequency of occurrence of adverse effects, not the intensity with which they occur)

image

BOX 13.7 Practical notes regarding first generation antipsychotics

• Exposure to sunlight when taking chlorpromazine can provoke erythema, which can be uncomfortable and even painful (photosensitivity).
• Cholestatic liver dysfunction can occur, particularly with chlorpromazine.
• Intense heat should be avoided, as temperature regulation may be impaired.
• Assistance with appetite and weight management is invaluable.
• Slow-release intramuscular depot preparations of fluphenazine, flupenthixol, zuclopenthixol and haloperidol are available.
• Extrapyramidal side effects are common (Box 13.6).

BOX 13.8 Clozapine

• Clozapine is used in treatment-resistant schizophrenia, but is increasingly utilised early in treatment if the response to other antipsychotic medications is suboptimal.
• Clozapine carries a significant risk of agranulocytosis and regular monitoring of haematological measures is mandatory.
• In addition, clozapine carries risks of pericarditis/myocarditis (usually acute and very serious), cardiomyopathy (usually chronic and less serious) and epilepsy.
• However, the efficacy of clozapine in schizophrenia and (probably) in bipolar affective disorders is so exceptional that these risks can often be justified in patients with treatment-resistant illness.

BOX 13.9 Clinical notes on antipsychotics

The starting dose will usually be the lowest manufactured dose, with any increase determined by the response over days to weeks.

Second generation antipsychotic medications are currently often used in preference to first generation antipsychotics because of the lower risk of EPS and potential benefits upon negative and cognitive symptoms. Asenapine may have some advantages in the treatment of negative and cognitive symptoms. Weight gain, promotion of diabetes mellitus (type 2), hyperlipidaemias and metabolic syndrome from some of these medications are reasons for caution in practice.

First generation antipsychotics are cheaper than second generation medications and may be preferred for this reason.

Ziprasidone is best absorbed if taken with food.

Antipsychotics may prolong cardiac conduction (QTc interval) and examples include haloperidol, quetiapine, ziprasidone and sertindole. The risk is increased by concurrent use of some antiarrhythmic medications, hypokalaemia, hypomagnesaemia and high dose. If there is any doubt, an electrocardiograph should be performed and serum electrolyte levels checked. If gastrointestinal disorders, including severe food restriction in anorexia nervosa, are present then a serum magnesium should also be obtained. A QTc interval of < 500 ms is considered reasonable, but for safety < 450 ms is preferable.

Intramuscular depot preparations of first and second generation antipsychotics assist with improved treatment adherence (see Table 13.12).

Second generation antipsychotics (atypicals)

These include amisulpride, aripiprazole, asenapine, clozapine (Box 13.8), olanzapine, paliperidone, risperidone, quetiapine, sertindole and ziprasidone (see Tables 13.11 and 13.12). Note that:

image Rapidly disintegrating oral preparations of olanzapine (wafer) and risperidone (tablet) are available.
image Slow-release preparations of risperidone (intramuscular depot), paliperidone (oral, slow-release capsule) and quetiapine (oral, slow-release tablet) are available.
image Asenapine is not yet available in Australia, but has a sublingual preparation and has no significant effects on the QT interval.

Mood stabilisers

This includes lithium.

General comments

image Lithium is the most effective mood stabiliser for bipolar affective disorder and neuroprotective in chronic mood disorder.
image The excretion half-life is 24–30 hours (once a steady state has been established).
image Sampling of blood level should occur 10–12 hours after the last dose so that it is at the start of the excretion phase.
image The therapeutic index is low; aim for blood level between 0.5 and 1.2 millimoles/L; adjust for patient tolerance and efficacy.
image ‘Higher’ blood levels are associated with subtle cognitive impairment (> 0.8 millimoles/L).
image Interactions with other drugs includes potential but rare serotonin syndrome when combined with serotonergic medications (common when combined with MAOIs); combination with anti-inflammatory medications and thiazide diuretics increases the lithium level.
image The dose range is 250–1500 mg daily.

Indications

image Lithium is indicated in the management of bipolar mood disorders, both in acute care and in prophylaxis.
image Onset of action is over several weeks.
image It is most effective in treating mania.
image It is also effective as an augmenting treatment for depressive disorder.
image It exerts an ‘antisuicidal’ effect.
image It may reduce the intensity of aggressive behaviour.

Mode of action

image There is a complex range of effects upon signal transduction in neurons, alteration of some fundamental cell processes, an antiapoptotic effect and an increase in serotonin availability.

Adverse effects

image Lithium may damage the thyroid gland, impeding production and release of thyroid hormones. It is reversible early in the treatment, but may become permanent and require oral thyroid hormone supplements.
image It may make the skin/hair coarse and promote psoriasis.
image It may cause increased urine production (‘nephrogenic diabetes insipidus’). Renal cortical damage can occur and, rarely, renal failure can follow.
image Toxicity can arise easily if poorly monitored. This is characterised by coarse tremor, dysarthria and ataxia; it is promoted by dehydration.

Clinical notes on the use of lithium are summarised in Box 13.10.

BOX 13.10 Clinical notes on lithium

Lithium is the ‘gold standard’ for mood stabilisers, but many patients are wary because of its side effect profile. Careful psychoeducation about its use and advantages is essential.

Anticonvulsants

These include sodium valproate, carbamazepine and lamotrigine.

Indications

image Anticonvulsants are indicated in the management of bipolar mood disorders, both in acute management and in prophylaxis.
image Onset of action is over several weeks.
image They are most effective in treating mania.
image Sodium valproate and carbamazepine are effective in rapid cycling and mixed affective disorders.
image Lamotrigine is effective in bipolar affective disorder (type II) and bipolar spectrum disorders.

Clinical notes on the use of anticonvulsants are summarised in Box 13.11.

BOX 13.11 Clinical notes on anticonvulsants

Sodium valproate is easily introduced at 500 mg daily in most patients and is preferred to carbamazepine in the first instance because of better tolerance and efficacy.

Mode of action

image Sodium valproate and carbamazepine appear similar to lithium in some aspects of mode of action.
image Lamotrigine appears to modulate glutaminergic activity, possibly through its effects on sodium channel activity.

Adverse effects

Adverse effects for sodium valproate, carbamazepine and lamotrigine are:

image sodium valproate (dose 500–1000 mg): tremor, weight gain, alopecia (partial), blurred vision, thrombocytopaenia and hepatotoxicity
image carbamazepine (dose 100–800 mg): skin rash, dizziness, sedation, ataxia, dysarthria, thrombocytopaenia and agranulocytosis, and
image lamotrigine (dose 200–400 mg): serious rash (Stevens-Johnson syndrome; necrotising epidermolysis), headache, dizziness, diplopia and ataxia.

For lamotrigine, introduce 25 mg daily and increase slowly (25 mg daily for 2 weeks; then 50 mg daily for 2 weeks; then 100 mg daily for 2 weeks; then 200 mg daily) with care to check skin regularly for any unusual changes. Most skin changes are harmless and treatment can be resumed, but always withhold lamotrigine until the nature of the skin change has been clarified.

Hypnotics

These include benzodiazepines: flunitrazepam, nitrazepam and temazepam (see Tables 13.13 and 13.4).

TABLE 13.13 Dose ranges, equivalent doses to diazepam, and half-lives of hypnotics

image

General comments

image Side effects are those of any benzodiazepines.
image Temazepam is most commonly used in practice.
image Hypnotics disrupt the sleep cycle with regular use and become addictive.
image Avoid flunitrazepam where possible because of the long duration of action, its potent adverse effect on memory and frequency of abuse (dependency, ‘date-rape drug’).

Indications

image Hypnotics are indicated in distressing insomnia.
image Aim for intermittent and short-term use.

Mode of action

image The mode of action is as for other benzodiazepines.

Adverse effects

image Adverse effects are as for other benzodiazepines.

Imidazopyridines

These include zolpidem (see Table 13.13).

General comments

image There is a minimal effect on the sleep cycle and they appear to have relatively less addictiveness than benzodiazepines.
image An immediate release preparation has little effect on cognition after about 8 hours.
image An ‘extended release’ preparation has little effect on cognition after about 10 hours.

Mode of action

image There is activation of the Ω-1 subset of GABA benzodiazepine receptors with more selective GABA-ergic effect; sedation.
image There is significantly less activation of Ω-2 and Ω-3 subsets of receptor.

Adverse effects

image There may be odd but harmless effects (sleepwalking and hallucinations) if taken too early and in vulnerable individuals; try a low ‘test dose’ and avoid regular use.
image Unusual behaviours are strongly aggravated by concurrent alcohol use.

Cyclopyrrolones

These include zopiclone (see Table 13.13).

General comments

image Cyclopyrrolones are expensive but have similar advantages to zolpidem.
image They are longer acting than zolpidem.
image Some people experience a ‘metallic taste’.
image The mode of action is the same as for zolpidem.

Indoleamines

These include N-acetyl-5-methoxytryptamine (melatonin).

General comments

image Indoleamines are produced endogenously by the pineal gland and are a component of the normal sleep process, provoked by the reduction of ambient light.
image They are given orally in a slow-release formulation, augmenting endogenous melatonin.

Mode of action

image There is activation of the suprachiasmatic nucleus of the hypothalamus (‘biological clock’), with a consequent inhibition of the ventrolateral preoptic nucleus. There is subsequently inhibition of a series of ‘arousal’ nuclei, promoting the induction of the sleep process.

Adverse effects

image Tolerance is usually excellent, but flushing of skin, diarrhoea, migraine and abdominal cramps have been reported.

Other psychotropic medications

Oestrogen supplements

image Oestrogen deficiency in females is associated with an increased risk of depressive disorders; it is commonly observed in the perimenopause.
image Oestrogen supplements facilitate the management of depressive disorders at times of relative deficiency.
image Oestradiol is the only oestrogen which crosses the blood-brain barrier and is therefore effective in the management of disorders involving brain dysfunction.
image Management of schizophrenia in women is also augmented by supplementary oestradiol in doses of 50–100 mg transdermally twice weekly.
image The mechanism of action appears to include modulation of serotonin, dopamine and neurotrophic factor activity in the brain.
image Adverse effects include nausea, increased risk of thromboembolism and enhancement of oestrogen-dependent neoplasia.
image The use of oestrogen in clinical psychiatric practice is still relatively new and routine use in psychiatry has not yet been achieved.

Medications for attention deficit disorders (ADD)

The drugs listed below are used mostly for attention deficit disorders (ADDs), but also for certain forms of brain injury and depressive disorders. Medications for ADDs include:

image dexamphetamine (dose 5–30 mg): improves attention and concentration in ADD; insomnia and reduced appetite are common unwanted effects; it is addictive, but is not usually a problem in ADD (correctly diagnosed); a slow release mix of amphetamine salts is available in other countries
image methylphenidate (dose 10–30 mg): similar to dexamphetamine and is available in sustained-release preparation, and
image atomoxetine (dose 10–120 mg): not addictive, but more limited in efficiency and efficacy than the stimulants.

Clinical notes on the use of medications for ADD are summarised in Box 13.12.

BOX 13.12 Clinical notes about medications for ADD

This is a controversial area because of public concerns about children being given medications (drugs) and the opportunity for abuse (a significant social reality). Their use should be restricted to specialists and carefully considered.

Other stimulants

Modafanil (dose 100–400 mg) may have value in some patients with severe lethargy, apathy or abulia; it is non-addictive, expensive but well tolerated.

Pregnancy and breastfeeding

General comments

image Always seek specialist advice before prescribing a psychotropic medication to a pregnant or breastfeeding woman.
image Between 2% and 4% of all live births have some form of congenital deformity, across populations and cultures.
image No psychotropic medication can be guaranteed safe in pregnancy or during lactation, but relative risks can be defined to some degree (Box 13.13). The fundamental principle is to carefully balance the risks of the patient’s illness against the known risks of the treatment. However, excessive concern over adverse effects upon the fetus can sometimes leave mother and baby at significant risk and the decision about medication should be made carefully. Specialist assistance may be particularly useful.
image All psychotropic medications cross into breast milk, but the concentrations are less than 10% of those in the maternal blood. This means that the risks to the infant are very small. Lithium carries a greater risk because of the possibilities of lithium toxicity and damage to the infant’s thyroid gland, but this risk is also very small.
image Sometimes, mixed formula and breastfeeding or expression of breast milk during ‘troughs’ in medication levels for use later can be helpful, particularly in premature infants.

BOX 13.13 Risks of pharmacological treatment during pregnancy and lactation

Risks include:

• teratogenesis
• abortion
• growth retardation
• intrauterine fetal death
• low birth weight
• the baby developing rash after delivery
• the baby developing delirium after delivery
• withdrawal symptoms, including restlessness and poor feeding after birth
• pulmonary hypertension after birth
• hypotonia (‘floppy-baby’ syndrome), and
• the baby suffering sedation or irritability after birth and with breastfeeding.

Antidepressants during pregnancy and lactation

image The length of exposure to pregnant women without evidence of adverse effects suggests that tricyclic antidepressants are relatively safe in pregnancy.
image Sertraline, fluoxetine, fluvoxamine and citalopram/escitalopram appear to be largely safe in pregnancy, but neonatal hypoglycaemia may occur.
image Paroxetine may be associated with an increase in heart defects and is best avoided.
image SSRIs and particularly venlafaxine/desmethylvenlafaxine can be associated with pulmonary hypertension and discontinuation symptoms after birth. The dose should be progressively reduced before labour begins and can be increased again after delivery.
image Little is known about the safety of duloxetine in pregnancy, but there are no adverse reports at this time.
image Mirtazapine and mianserin appear relatively safe and there is no evidence to suggest that reboxetine has significant problems in pregnancy.
image Bupropion appears relatively safe in pregnancy.

Anxiolytics during pregnancy and lactation

image There is some evidence that benzodiazepines may promote cleft palate deformity when used in the first trimester of pregnancy. The extent of this risk remains uncertain.

Antipsychotics during pregnancy and lactation

image Quetiapine has the advantage of significantly lower transmission across the placenta (greater binding to Pgp than other antipsychotics); risperidone and paliperidone appear next most advantageous, and olanzapine next.
image Most other current antipsychotic medications appear relatively safe in pregnancy.
image Metabolic complications such as increased risk of gestational diabetes mellitus and weight gain need to be considered.
image There is some limited evidence to suggest aripiprazole might be better avoided in pregnancy.

Mood stabilisers during pregnancy and lactation

image Lithium can uncommonly be associated with major deformities of the heart and great vessels, and can also provoke hypotonia (‘floppy-baby’) soon after delivery from lithium toxicity in the infant. Damage to the thyroid gland of the fetus may occur but is rare.
image Carbamazepine and valproate are both associated with serious neural tube defects, as well as other deformities in facial bone development. They should be avoided in pregnancy if at all possible. Folic acid supplements (5 mg daily) during pregnancy help to reduce these risks, but are not fully effective.
image Lamotrigine may increase the risk of deformities if used during pregnancy, but the risk appears small. Folic acid supplements (5 mg daily) during pregnancy help to reduce these risks.

Adjunctive medications and exercise

image Omega-3 fatty acids: there is increasing evidence that supplements containing these fatty acids (e.g. fish oil capsules) may be beneficial in major mood disorders. At least 3000 mg daily is required.
image Supplements of 5000 international units per day of vitamin D may be helpful in patients with vitamin D deficiency, which appears common in major mood disorders.
image N-acetyl cysteine, an amino acid, is converted to glutathione, which is an important antioxidant in the brain. It may enhance the long-term mental state of patients with bipolar disorders and schizophrenia. The recommended dose is 1000 mg twice daily.
image Regular cardiopulmonary and strength exercises are highly advantageous to patients with psychological disorders of all kinds and are particularly valuable in depressive, bipolar and anxiety disorders.
image Folic acid deficiency is destructive to mental state and supplements are essential if deficiency is evident.
image Magnesium and zinc deficiency can be deleterious to mental state and supplements may be appropriate.

Other biological treatments

Electroconvulsive therapy (ECT)

The nature of ECT

image Inducing a generalised seizure has a powerful therapeutic effect upon severe depressive disorders, but not all such seizures are therapeutic.
image A seizure is induced by passing an electric current through the frontal lobes, using a pulsed square-wave form.
image A seizure is necessary but not sufficient to have a therapeutic effect. The extent to which the electrical charge exceeds the threshold for inducing a seizure, specific electrical features of seizure and to some extent transient post-ictal blood pressure and heart rate increases (reflecting increased sympathetic activity) are useful guides to the likely efficacy of treatment.
image The treatment is given under a general anaesthetic to allow muscle relaxation and therefore reduced risk of musculoskeletal injury.
image The electrical stimulus is given either to both sides of the head (bilateral) or one side (unilateral). Unilateral placement reduces cognitive impairment significantly.
image A treatment course will usually require 6–12 treatments to be effective.

Mechanisms of action of ECT

Mechanisms of action of ECT (probably a combination) are:

image an anticonvulsant effect
image inhibition of cerebral activity
image increased and potent release of nerve growth factors (similar to antidepressants)
image increased release of serotonin, noradrenaline and dopamine (similar to antidepressants), and
image hormonal changes, including reduction in corticotrophin-releasing hormone.

Indications for use of ECT

ECT is indicated in:

image severe melancholic depressive disorder, particularly with psychosis and/or catatonia; improvement is almost always very impressive, particularly with catatonia
image severe depression during pregnancy (relatively safer than medications) and puerperium (where a high risk of injury to mother and infant is present)
image severe depression in the elderly (response is usually excellent)
image mania
image schizophrenia with comorbid severe depression, and
image some neurological disorders.

ECT remains the most potent and reliable treatment for severe melancholia and psychotic depression.

Contraindications

ECT is contraindicated in:

image raised intracranial pressure (a total contraindication)
image recent cerebrovascular accident (< 6 weeks)
image anaesthetic risks as for any procedure
image severe cardiovascular disease, including within 10 days of a myocardial infarction, and
image other major medical disorders which might complicate treatment or recovery.

Adverse effects

Adverse effects of ECT include:

image cognitive impairment, notably memory dysfunction; mostly reversible except for events within days of the treatment
image cognitive impairment can be both retrograde and anterograde
image cognitive impairment is reduced by:

image using unilateral electrode placement (over the non-dominant hemisphere)
image using a pulsed square-wave stimulus
image using a pulse width of 0.3–0.5 ms
image spacing treatments in time, and
image giving good education to the patient about the nature and effects of the treatment

image cognitive impairment is aggravated by concurrent use of lithium or MAOIs
image persistent cognitive impairment has been reported as a rare phenomenon and appears related to multiple factors
image musculoskeletal injury from movement during the seizures
image transient cardiac dysrhythmias (mostly harmless unless accompanied by preexisting cardiac pathology)
image persistent seizures: relieved by intravenous anticonvulsants such as diazepam
image headache: common early in treatment and relieved by analgesics, and
image mania: easily relieved by further treatments or medications.

Structural brain injury does not occur, despite many claims to the contrary.

Future developments

Magnetic stimulation therapy

Magnetic stimulation therapy uses a pulsating magnetic field to provoke seizures and may offer equal efficacy with much less cognitive impairment than ECT.

Light therapy

Exposure to bright light each morning can relieve depression in some patients.

Transcranial magnetic stimulation

This treatment uses pulses of magnetic field over the dorsolateral prefrontal cortex to relieve depressive disorders. It remains an experimental but promising development.

References and further reading

Aszalos A. Drug–drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1) II. Clinical Aspects Drug Discovery Today. 2007:838-843. 12(19/20)

Castle D., Copolov D., Wykes T., Mueser K. Pharmacological and psychosocial treatments in schizophrenia. London: Informa UK; 2008.

Dowden J., Allardice J., Ames D., et al. Therapeutic guidelines: psychotropic version. Melbourne: Therapeutic Guidelines; 2008.

Janicak P., Davis J., Preskorn S., et al. Principles and practice of psychopharmacotherapy. Philadelphia: Lippincott Williams and Wilkins; 2006.

Menon S. Psychotropic medication during pregnancy and lactation. Archives of Gynecology and Obstetrics. 2008;277(1):1-13.

Rosenbaum J., Arana G., Hyman S., et al. Handbook of psychiatric drug therapy. Philadelphia: Lippincott Williams and Wilkins; 2005.

Schatzberg A., Nemeroff C. Essentials of clinical psychopharmacology. Washington DC: American Psychiatric Publishing; 2006.

Stahl S. Essential psychopharmacology. The prescriber’s guide. Cambridge: Cambridge University Press; 2005.

Tiller J., Lyndon R., editors. Electroconvulsive therapy. An Australasian guide. Melbourne: Australian Postgraduate Medicine, 2003.

Weiner R., Fink M., Hammersley D., et al. The practice of electroconvulsive therapy: recommendations for treatment, training and privileging. In Task Force Report of the American Psychiatric Association. Washington DC: American Psychiatric Association; 1990.

Wiznen P., Op Den Buijsch R., Drent M., et al. the prevalence and clinical relevance of cytochrome P450 polymorphisms. Alimentary Pharmacology and Therapeutics. 2007;26(Suppl 2):211-219. Review article

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