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Ovid: Oxford Handbook of Psychiatry

Editors: Semple, David; Smyth, Roger; Burns, Jonathan; Darjee, Rajan; McIntosh, Andrew Title: Oxford Handbook of Psychiatry, 1st Edition Copyright ©2005 Oxford University Press > Table of Contents > Chapter 21 – Therapeutic issues Chapter 21 Therapeutic issues P.850
Medication adherence Is adherence important?

  • It has been estimated that only one third of patients prescribed medication actually adhere to the treatment plan and that -80% of psychiatric admissions relate to medication non-adherence. Adherence is a particular problem when the illness runs a chronic course and requires the patient to be on medication for life
  • Patients with schizophrenia who comply with a sufficient dosage of antipsychotic medication have only about one fifth the risk of relapse compared to patients who do not take their medication.
  • There is good evidence that prophylactic lithium treatment of bipolar disorder reduces the likelihood of relapse, as well as the risk of suicide.
  • Continuation of antidepressant treatment for at least six months after symptom resolution significantly reduces the risk of further depressive episodes.

Reasons for non-adherence It is important to realise that the patient may have understandable reasons for being reluctant to take prescribed medication. Uncovering these reasons may help in negotiation and developing strategies to improve the situation.

  • Continued symptoms of the underlying disorder (e.g. delusions, lack of motivation, impaired insight, disorganisation) or comorbid disorders (e.g. substance misuse, personality disorder).
  • Negative attitude towards medication in general (versus other forms of treatment) or stigma associated with being ‘on medication’, particularly where there are external stigmata of treatment such as parkinsonism (‘looking like a zombie’).
  • Unacceptable (or unexpected) side-effects (e.g. weight gain—p. 852, sedation, EPSEs—p. 860, sexual dysfunction—p. 856, perceived loss of ‘good’ symptoms e.g. hypomania).
  • Forgetting (genuine oversight, disorganisation, cognitive impairment).
  • Lack of communication (reasons for medication not fully explained or understood).
  • Failure to obtain (or renew) prescription (through non-attendance, poor communication or poor relationship with responsible prescriber e.g. GP).
  • Belief that the medication is ‘not working’.
  • Feeling well and no longer seeing the need for medication. The ‘reward’ of freedom from side-effects may be immediate, while the ‘punishment’ of relapse may be more distant, not taken seriously, or not directly associated with stopping treatment.

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Strategies to improve adherence Education

  • Promote insight and understanding about the illness and the benefits of treatment.
  • Provide information about the medication, how to take it, possible side-effects, the length of time needed to see benefits, and the potential problems of suddenly stopping.
  • Discuss the reasons for prophylactic or continued treatment, especially when patient feels well (e.g. to reduce risk of relapse and improve long term outcome).
  • Encourage discussion of pros and cons of suggested treatment plan.
  • Encourage openness about potentially embarrassing issues that may lead to non-adherence (e.g. sexual side-effects).
  • Regularly ask about and document side-effects at each review.

Sensible prescribing

  • Simplify drug regime—use single-dose where possible (most psychotropic medications have long half-lives and can be given once daily or are available in slow-release preparations).
  • Minimise side-effects through choice of a medication with lowest potential for side-effects, and using lowest therapeutic dose,
  • If side-effects are problematic, consider a change to an alternative preparation or (where an alternative would be less effective) co-prescribing agents to counter significant problems.
  • Rational medication choice based on individual acceptability of side-effects (e.g. any weight gain may be unacceptable to a young female patient).
  • Clear communication of any changes in regime both to patient and primary care team (including written instructions for patient and direct communication with GP) especially if the primary care physician is main prescriber.
  • Use depot antipsychotic preparations—this may sometimes be requested by the patient, but is more often necessary when the patient lacks insight, or has had significant serious relapses related to non-adherence.
  • Regularly review the need for continued medication.

Practical/behavioural measures

  • Written information to patient, particularly where regime is complex or where change of dose/medication is planned.
  • Establish a regular daily routine for taking medication.
  • Use of Dosette® box.
  • Supervised administration (e.g. by relative/carer, at pharmacy, in day hospital, by CPN).
  • Active monitoring (e.g. tablet count, blood levels—p. 888).

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Weight gain with psychiatric medication General points Weight gain is a significant cause of non-compliance with psychiatric medication, and patients often complain about increases in weight, even when clinicians may regard it as ‘clinically insignificant’. Effects on general health, self-esteem, and social embarrassment should not be overlooked. Antipsychotics Proposed mechanisms Sedation (reduced activity), thirst (anticholinergic S/Es), reduced metabolism, fluid retention, endocrine effects (increased prolactin, altered cortisol, altered insulin secretion), increases in leptin levels (changes in ‘set-point’ weight), and altered neurotransmitters (5-HT2C blockade, histamine affinity, D2 blockade, CCK changes) have all been proposed. Increased risk Female, previous pattern of overeating, narcissistic traits, family or personal history of obesity. Effects of specific agents (see opposite). Management1

  • Routine measurement of baseline weight.
  • Warn patient of possibility.
  • Encourage ‘healthy diet’ (involve dietician if necessary), moderate physical exercise, avoid high-calorie fluids.
  • Use lowest therapeutic dose, introduce medication increases slowly, consider intermittent dosing.
  • Consider adjunctive prescribing (e.g. clozapine plus quetiapine, to allow lowering of clozapine dose).

Antidepressants Proposed mechanisms Reduced metabolism, carbohydrate craving (NB may be a symptom of depression itself), central serotonin mechanisms in regulating food intake (appetite/satiety). Effects of specific agents (see opposite). Management

  • General advice about diet and exercise
  • Use lowest therapeutic dose
  • Consider switching to alternative antidepressant
  • Adjunctive prescribing (e.g. naltrexone, ranitidine at night (may reduce ‘midnight snacks’)).

Lithium2 Proposed mechanisms Increased intake of high calorie drinks, hypothyroidism, increased insulin secretion. Management Counselling and advice about diet and exercise, use of low-calorie drinks, avoidance of salty foods (or adding salt to foods). P.853
Other mood stabilisers Carbamazepine Weight gain due to increased appetite. Valproate Weight gain which may be due to increased serum leptin and insulin. Gabapentin Marked weight gain in some cases (up to 10% above baseline weight). Weight gain with antipsychotics

Antipsychotic Average weight gain (kg)
Pimozide -2.7
Placebo -1.0
Trifluoperazine 0.3
Ziprasodone 0.3
Haloperidol 0.5
Polypharmacy 0.5
Loxapine 0.7
Non-drug controls 0.8
Fluphenazine 1.1
Risperidone 1.7
Quetiapine 2.5
Thioridazine 2.8
Sertindole 2.9
Olanzapine 4.2
Chlorpromazine 4.2
Clozapine 5.7
Perphenazine 5.8
Fenton (2000) Evidence Based Mental Health 3, 58.

Weight changes with antidepressants SSRIs Fluoxetine: weight loss; paroxetine, fluvoxamine: slight weight loss; sertraline: limited weight gain; citalopram: no change TCAs Weight gain (amitriptyline>imipramine>clomipramine) MAOIs/RIMAs Weight loss (tranylcypromine)—rarely weight gain; weight gain (phenelzine>moclobemide) Others Mianserin: mirtazepine; weight gain; reboxetine, trazodone: no change; venlafaxine: weight loss References 1 Baptista T (1999) Body weight gain induced by antipsychotic drugs: mechanisms and management. Acta Psych Scand 101, 3–16. 2 Baptista T (1995) Lithium and body weight gain. Pharmacopsychiatry 28, 35–44. P.854
Hyperprolactinaemia with antipsychotics Essence Secretion of prolactin (PRL) by the pituitary is under inhibitory control via dopamine from the hypothalamus. Blockade of dopamine D2 receptors by conventional antipsychotics (plus risperidone) can raise prolactin levels, leading to symptoms of hyperprolactinaemia in both men (erectile dysfunction, loss of libido, and hypogonadism) and women (amenorrhoea, galactorrhoea, infertility, loss of libido, and possibly osteoporosis). Differential diagnosis Diseases of the pituitary (e.g. prolactin secreting pituitary adenomas) or hypothalamus, severe primary hypothyroidism, liver cirrhosis, end-stage renal disease, stress, high-dose oestrogens, chronic cocaine use, opiates, dopamine depletion (e.g. due to reserpine, tetrabenazine). Investigations

  • Check for signs of chest wall irritation (which can promote galactorrhoea and raise prolactin) and signs of a sellar mass (including checking visual fields).
  • Serum levels of TSH (exclude hypothyroidism), creatinine (exclude renal failure), and PRL (may be raised due to stress, after eating, or post-ictally).

NB Patients may be symptomatic even when PRL in the normal range (i.e. it is the relative increase in PRL that matters, not just the absolute increase).

  • Consider CT/MRI and/or a referral to endocrinology.

Management

  • Exclude other possible aetiologies.
  • Consider a change of medication to a prolactin-sparing antipsychotic (e.g. clozapine, olanzapine, quetiapine) or reduction in dose if the patient’s mental state is stable (monitor closely).
  • If problems persist or medication changes are precluded (or not tolerated), consider referral to endocrinology for consideration of other treatments: hormone replacement, amantadine, bromocriptine, etc.
  • Pre-menopausal women should be advised about resumption of normal menstrual cycle (and return of fertility) when changing antipsychotics, and the use of contraception should be discussed.

NB Asymptomatic hyperprolactinaemia does not warrant (in itself) changes to medication. P.855
P.856
Sexual dysfunction and psychiatric medication The degree of sexual dysfunction experienced by patients taking psychiatric medication may be a major source of distress and a significant reason for non-compliance. Clinicians are notoriously poor at enquiring about these problems, despite reports that patients regard sexual side-effects as the most troublesome of all medication-related problems. Antidepressants Rates of sexual dysfunction seen in clinical practice (commonly delayed ejaculation and orgasmic dysfunction) may be higher than those reported in product information. Clomipramine, SSRIs (paroxetine, sertraline, citalopram, fluoxetine), and venlafaxine appear to be most likely to cause sexual dysfunction of some form (30–60%). Other TCAs show intermediate risk of dysfunction (10–30%). Bupropion and moclobemide appear much less likely to cause problems (≤10%). Mirtazepine appears possibly to have the lowest rates of sexual side-effects1. Problems of reduced libido appear to be associated with SSRIs, whereas TCAs tend to cause (more troublesome) difficulties with sexual performance. Management2

  • ‘Watchful waiting’—to see if symptoms subside.
  • Dose alteration (either up or down) to find effective dose without side-effects.
  • ‘Drug holidays’ or scheduled interruptions in therapy (e.g. weekends).
  • Addition of another agent to counteract the sexual side-effects (combination e.g. mirtazepine, buspirone, bupropion; or ‘as required’ e.g. sildenafil, cyproheptadine, amantadine, yohimbine).
  • Switch to another agent known to have fewer adverse sexual effects (e.g. mirtazepine, bupropion).

Antipsychotics The prevalence of sexual dysfunction associated with antipsychotics ranges from 40–71%, with reports of problems in all groups of antipsychotic medication (usually reduced libido/sexual arousal problems)3.

  • Dysfunction may be related to dopamine blockade, autonomic side-effects, and hyperprolactinaemia.
  • The dose of medication, use of anticholinergics, and comorbid depression are significant associations.
  • Thioridazine can cause ‘dry’ or ‘retrograde’ ejaculation (semen may be present in the urine).
  • Clozapine and quetiapine seem to have the lowest risk of sexual side-effects.

Management

  • Dose reduction where possible.
  • Reduction or discontinuation of drugs with anticholinergic effects.
  • Consider switching to alternative agent (e.g. quetiapine, low-dose olanzapine, clozapine).

P.857
Mood stabilisers Lithium therapy may impair desire and arousal, but does not appear to have a major impact on patient self-satisfaction or subjective sense of pleasure during sexual activity4. Although the occurrence of sexual dysfunction is estimated as 10–30%, it is usually mild, not a source of distress, and does not lead to non-compliance. Carbamazepine and phenytoin both increase prolactin and decrease dehydroepiandrosterone and other adrenal androgen levels, making sexual dysfunction likely. Valproate does not cause these changes, and is associated with a low likelihood of sexual dysfunction. References 1 Gregorian RS, Golden KA, Bahce A, et al. (2002) Antidepressant-induced sexual dysfunction. Annals of Pharmacotherapy 36, 1577–89. 2 Gutierrez MA and Stimmel GL (1999) Management of and counseling for psychotropic drug-induced sexual dysfunction. Pharmacotherapy 19, 823–31. 3 Wirshing DA, Pierre JM, Marder SR, et al. (2002) Sexual side effects of novel antipsychotic medications. Schizophrenia Research 56, 25–30. 4 Aizenberg D, Sigler M, Zemishlany Z, Weizman A (1996) Lithium and male sexual function in affective patients. Clinical Neuropharmacology 19, 515–19. P.858
Priapism Priapism1 is defined as a sustained, painful erection that cannot be relieved by sexual intercourse or masturbation, and that is frequently unrelated to sexual desire. Without intervention, it usually subsides within a few days, but 50–80% of affected men become permanently impotent. Stasis of blood for more than several hours leads to increased blood viscosity, deoxygenation, and, ultimately, irreversible fibrosis of tissue. Thus, priapism is a urologic emergency requiring immediate intervention2. (Clitoral priapism has also been reported and may be associated with either pain and discomfort or increased libido and orgasmic response3.) Trazodone About 30% of reported cases of priapism are drug-induced, with 80% of those cases involving trazodone. Trazodone-induced priapism is rare, occurring in less than 0.1% of patients taking the drug. It typically is seen within the first month of therapy, occurs in all age groups, and may occur even with low daily doses of 50–100mg. Other drugs Antipsychotics (haloperidol, clozapine, zuclopenthixol), SSRIs, bupropion, phenelzine, prazosin, buspirone, phenytoin, and intracavernosal injection of vasoactive drugs. Management In the past, surgical intervention was routine practice, but it resulted in up to 50% of men being permanently impotent. Because trazodone-induced priapism is understood to be due to alpha1-adrenergic blockade, pharmacologic treatment is preferred since it carries no risk of permanent sequelae.

  • Patients must be aware of the possibility of priapism when taking trazodone, and treatment must be given quickly to minimise the risk of permanent impotence.
  • If less than 24hrs’ duration: Intracavernosal irrigation with an alpha1-adrenergic agonist (successfully causes detumescence in most patients).
  • If more than 24hrs’ duration: Corporeal fibrosis is more likely and drug treatment is less effective. Remove blood from the penis and infuse a solution of an alpha1-adrenergic agonist into the corpus cavernosum. Preferred agent: phenylephrine (the most selective and potent alpha1-adrenergic vasoconstrictor); onset of action less than 1 minute and duration of 7–20 minutes; several intermittent injections of 0.1mg/ml solution may be necessary (continuously monitor BP and HR).

Patient counselling Although rare, priapism is a serious medical emergency that requires immediate intervention. Since most patients would not attribute the prolonged erection to trazodone, patient counselling about its possibility is necessary for all men beginning therapy with the drug. They should be advised to report prolonged or painful erections to their doctor immediately. References 1 “Priapus”, the son of Zeus and Aphrodite, was a god with an enormous penis who symbolized the earth’s fertility. 2 Banos JE, Bosch F, Farre M (1989) Drug-induced priapism. Its aetiology, incidence and treatment. Med Toxicol Adverse Drug Exp. 4, 46–58. 3 Patel AG, Mukherji K, Lee A (1996) Priapism associated with psychotropic drugs. British Journal of Hospital Medicine 55, 315–319. P.859
P.860
Antipsychotic-induced parkinsonism Essence A frequent adverse effect found in full form in at least 20% of patients treated with antipsychotic medication. Generally occurs within 4 wks of treatment and is a major cause of non-compliance. Examination (p. 214) is generally sufficient to detect the onset of symptoms and should be carried out frequently in the first 3 mths of treatment. Monitoring may help establish the minimally effective dose of antipsychotic needed by individual patients, reducing discomfort and improving compliance. Symptoms/signs Characterised by tremor, rigidity, and bradykinesia; the presentation is similar to that of idiopathic Parkinson’s disease (p. 170), although bradykinesia may be less prominent and symptoms are always bilateral. Pathophysiology D2 receptor blockade in the nigrostriatal pathway. Differential diagnosis Many drugs have been associated with parkinsonism (see opposite) and some may increase the likelihood of problems (e.g. prednisolone). Other differentials include: idiopathic Parkinson’s disease, dementia (e.g. DLB), negative symptoms of schizophrenia, psychomotor retardation (e.g. in depression). Treatment Several strategies may be used, including:

  • Dose reduction.
  • Switching to another antipsychotic agente e.g. olanzapine, quetiapine, risperidone (<8mg/day), clozapine.
  • Use of anticholinergic agents (e.g. biperiden, procyclidine, orphenadrine, trihexphenidyl) or amantadine.

NB Anticholinergic agents are often used in younger patients. However, older patients may not be able to tolerate the side-effects of blurred vision, dry mouth, constipation, urinary retention, and particularly cognitive impairment. This has led to the use of amantadine, which is better tolerated, or more frequent use of the newer antipsychotics, especially when patients already have early signs of Parkinson’s disease.

  • When treatment is by depot, there is some evidence that pipothiazine palmitate, flupenthixol, or zuclopenthixol decanoate may be better tolerated. Risperidone depot is also now available, and may be considered as another option.

Follow-up

  • If anticholinergics have been used, the need for continued treatment ought to be kept under review.
  • Their slow withdrawal should be attempted after the acute phase of treatment, or following any lowering of antipsychotic dose, as drug-induced parkinsonism tends to resolve over time and additional medication may no longer be needed.

P.861
Drugs reported to cause parkinsonism

  • antidepressants (e.g. SSRIs, MAOIs, TCAs)
  • lithium
  • anticonvulsants (e.g. carbamazepine, valproate)
  • analgesics (e.g. NSAIDs, opiates)
  • drugs of abuse (e.g. cocaine, PCP)
  • cardiovascular drugs (e.g. amiodarone, diazoxide, diltiazem, methyldopa, metirosine, mexilitine, nifedipine, tocainide)
  • GI drugs (e.g. cimetidine, domperidone, metoclopramide, prochlorperazine)
  • anti-infection drugs (e.g. acyclovir, cephaloridine, chloroquine)
  • respiratory drugs (e.g. antihistamines, salbutamol, terbutaline)
  • hormones (e.g. medroxyprogesterone)
  • cytotoxics (e.g. cyclosporin, interferons)
  • others (e.g. cyclizine, ondansetron, levodopa, tetrabenazine)

P.862
Akathisia Essence Akathisia usually occurs in the context of antipsychotic treatment. It may manifest in acute, chronic, withdrawal-related, or tardive (late-onset) forms. It is an unpleasant, distressing side-effect of medication and may be confused with agitation or worsening of psychiatric symptoms. When it is severe, patients may act aggressively, leading to inappropriate increases in antipsychotic medication. Careful assessment, including detailed history and review of medication, is essential. Symptoms/signs Although there is no universally accepted definition of akathisia, the disorder characteristically manifests with:

  • a subjective component—a feeling of inner restlessness (with the drive to engage in motor activity, esp. lower limbs and trunk).
  • an objective component—movements: such as pacing constantly; inability to stand, sit, or lie still; rocking; crossing/uncrossing legs.

Pathophysiology Not yet fully understood. Theories include: dopaminergic/noradrenergic interactions (e.g. inhibition of presynaptic D2 heteroreceptors on NA nerve terminals, with net increase in NA release), imbalance of dopaminergic/cholinergic transmission (causing compensatory increased NA or 5HT release), low serum iron/ferritin. Epidemiology Prevalence ranges reported in schizophrenic patients on antipsychotic medication are quoted as 41% (mild symptoms), 21% (moderate-severe symptoms), up to 24% (for chronic symptoms (inpatient population)). For atypical agents, the reported incidence is up to 6%. Risk factors Use of high-dose and/or high-potency antipsychotics, chronic use of antipsychotics, rapid increase/sudden withdrawal of antipsychotics, use of depot intra-muscular preparations, history of organic brain disease (e.g. dementia, alcoholism, HIV), history of previous akathisia, concomitant use of predisposing drugs (e.g. lithium, SSRIs). Differential diagnosis Anxiety/agitation (primary or secondary to other psychiatric disorders), other withdrawal/discontinuation syndromes, acute confusional states, encephalitis/meningitis, parkinsonism/dystonia/ dyskinesia, serotonergic syndrome (early symptoms), toxicity due to other drugs (e.g. recreational drugs—amphetamine, MDMA, cocaine; antidepressants; antihistamines; sympathomimetics; salicylate), restless legs syndrome, iron deficiency anaemia, endocrine disorders (e.g. thyrotoxicosis, hypo/ hyperglycaemia, phaeochromocytoma). Investigations General blood screen (FBC, LFTs, U&Es, glucose, TFTs) Management

  • Review history/medication to identify possible causative agent(s).
  • Reduce dose or slow increase of potential causative agent.
  • If antipsychotic-related, consider use of lower-potency drug.
  • If symptoms persist consider specific treatment: first line—propranolol, initially 30mg/d (usual range 30–120mg/d); or pindolol, betaxolol, metoprolol.
  • P.863

  • If patient has history of hypotension, diabetes, or associated parkinsonism (or propranolol ineffective) consider use of anticholinergic agents (e.g. benztropine, benzhexol, biperiden, orphenadrine, procyclidine, trihexphenidyl).
  • If ineffective, consider adding or changing to a benzodiazepine (e.g. clonazepam, diazepam, lorazepam).
  • For unresponsive, predominantly anxious/agitated patient (without hypotension) consider clonidine 0.2–0.8 mg/d (may be sedative).
  • Other possible agents include amantadine, buspirone (may also worsen symptoms), cyproheptadine, mianserin (may also worsen symptoms), tryptophan, piracetam, or even iron supplements.

Course/prognosis Most cases will respond to treatment and usually the response will be seen after a few days. Chronic or tardive cases may be more difficult to treat, and it should be borne in mind that therapeutic benefit (e.g. of propranolol) can take up to 3 months. Follow-up

  • Once the akathisia has settled, any specific treatment ought to be kept under review.
  • Slow withdrawal of any additional agent should be attempted after a few weeks (in the case of benzodiazepines) or after several months (for other agents).
  • If akathisia recurs, long-term therapy may be necessary. However, little data exists for agents other than propranolol (although original optimism for long-term benefit has not been borne out) or anticholinergics.
  • The need for continued use of high-dose, high-potency antipsychotics should also be reviewed in the light of any change in the clinical presentation of the primary psychiatric disorder.

Drugs reported to cause akathisia Antipsychotics (usually high-potency) Chlorpromazine (less likely), clozapine (rare), haloperidol, olanzapine, pipothiazine, prochlorperazine, promazine, risperidone (withdrawal), thioridazine (less likely), triuoperazine, trimeprazine, triuoperazine, zuclopenthixol. Antidepressants Amoxapine, citalopram, fluoxetine, fluvoxamine, imipramine (and other TCAs), mianserin, paroxetine, sertraline, venlafaxine (withdrawal). Anxiolytics Alprazolam, buspirone, lorazepam. Others Diltiazem, alpha-interferon, levodopa, lithium, melatonin (withdrawal), metoclopramide, ondansetron, verapamil. P.864
Tardive dyskinesia Essence Late onset (months→years, mean 7yrs) involuntary, repetitive, purposeless movements, occurring with long-term antipsychotic treatment (although also has been reported in untreated schizophrenic patients). Also associated with amoxapine, bupropion, buspirone, clomipramine, doxepin, diphenhydramine, fluoxetine, fluvoxamine, lithium, metoclopramide, and phenytoin. Symptoms/signs Perioral movements are the most common (e.g. tongue, lips, jaw), hence the alternative terms: oral-lingual, orofacial, oro-bucco-facial, or buccal-lingual-masticatory dyskinesia. Other movements may include: axial—trunk twisting, torticollis, retrocollis, shoulder shrugging, pelvic thrusting; limbs—rapid movements of the fingers or legs, hand clenching (and sometimes slower, choreoform movements). Symptoms can be consciously suppressed, worsen with distraction, are exacerbated by stress and antiparkinsonian agents, and disappear during sleep. Pathophysiology Not yet fully understood. Theories include: dopaminergic/cholinergic imbalance, upregulation/supersensitivity of postsynaptic DA receptors in the basal ganglia following chronic blockade, GABA hypofunction leading to enhanced DA transmission. Epidemiology Prevalence is -10% of chronically treated patients but may be as high as 70% in the ‘high risk’ population. Risk factors Chronic use of antipsychotics (particularly in high dose), change/cessation of chronic treatment (especially intermittent treatment), concomitant anticholinergic treatment elderly (over 50), female (♀:♂ = 1.7:1), history of organic brain disease (e.g. dementia, learning disability, epilepsy), previous head injury, alcoholism, comorbid mood disorder, negative symptoms of schizophrenia, diabetes mellitus, history of previous drug-induced akathisia/parkinsonism/dystonias, concomitant use of predisposing drugs (e.g. lithium, antidepressants, stimulants). Differential diagnosis Stereotypies, tic disorders, other causes of dyskinesia (e.g. Parkinson’s disease or use of antiparkinsonian agents), other causes of chorea/athetoid movements (e.g. Sydenham’s/Huntington’s chorea, Wilson’s disease). Management

  • Review history/medication to identify possible causative agent(s).
  • Reduce dose of potential causative agent, to achieve minimum effective dose that adequately controls psychotic symptoms.
  • Anticholinergic agents will exacerbate the problem and should also be slowly reduced and stopped if possible.
  • If residual symptoms can be tolerated, it is best to ‘wait and see’, as TD tends to improve with time, before considering addition of any specific treatment.
  • If residual symptoms are severe, interfere significantly with functional abilities, or may be life-threatening, then temporarily raising the dose of antipsychotic may give immediate relief, whilst addition of a specific treatment may be commenced (dose of antipsychotic should then be reduced again).
  • P.865

  • Specific treatments First line—biogenic amine (DA) depleting agent: Tetrabenazine 12.5mg to start, titrated to 25–75mg/d, max. 200mg/d.
  • Other possible strategies
    • dopamine agonists (e.g. low-dose bromocriptine 0.75–7.5mg/d, L-dopa, amantadine)
    • benzodiazepines (e.g. clonazepam (if dystonia also present))
    • adrenergic agents (e.g. propranolol, clonidine)
    • calcium-channel blockers (e.g. nifedipine (high doses), verapamil, diltiazem)
    • anticonvulsants (e.g. valproate, gabapentin)
    • antioxidants (e.g. vitamin E (efficacy disputed))
    • other (e.g. baclofen, buspirone (high dose), cyproheptadine, insulin, ondansetron, piracetam, progabide, pyridoxine).
  • If the symptoms are severe and non-responsive to other strategies, then consider an alternative antipsychotic—clozapine (reportedly effective in up to 43% of refractory cases), sulpiride, or an ‘atypical’ antipsychotic (e.g. olanzapine, risperidone, quetiapine) ECT has also been (anecdotally) shown to be effective.

Course/prognosis

  • Symptoms may not progress and remission rates are -30%/yr with 50% of sufferers clinically improved after 5yrs, even without treatment.
  • Most cases will respond to treatment although a balance may need to be struck between reduction in dyskinesia vs. control of psychotic symptoms.

Follow-up

  • Residual symptoms should be closely monitored.
  • The need for continued antipsychotic treatment should also be regularly reviewed.
  • Ensure that occurrence of TD and treatment strategy clearly recorded in case-notes.

P.866
Acute dystonic reaction Essence Acute reaction following exposure to antipsychotic medication with sustained, often painful muscular spasms, producing twisted abnormal postures. Aetiology Unknown. Usually occur at a time when blood levels of antipsychotics would be falling. Incidence 3–10% of patients exposed to all antipsychotics (up to 30% with high-potency drugs). Risk factors Previous/family history of dystonia, younger age group1, ♂ > ♀ (most likely due to use of higher doses of antipsychotics in men), liver failure, clinically severe schizophrenia (esp. with marked negative symptoms), use of high-potency antipsychotics (up to 10%; for other agents see opposite). Onset 50% of cases occur within 48hrs, rising to 90% within 5 days. Symptoms/signs Frequency of occurrence of dystonias: neck (30%), tongue (17%), jaw (15%), oculogyric crisis (neck arched and eye rolled back: 6%), opisthotonus (body arching: 3.5%). Usually more generalised in younger patients (may be confused with fits, esp. in children) and more localised (head and neck) in older patients. Course May fluctuate over hours, but most last minutes to hours without treatment. Differential diagnosis May be mistaken for bizarre behaviour motivated by psychotic symptoms or even histrionic personality traits. Management

  • Discontinue suspected agent.
  • Emergency treatment with IM/IV anticholinergic agents (e.g. procyclidine 5mg, benztropine 2mg).
  • Continue use of anticholinergic for 1–2 days, unless antipsychotic clinically needed—then concomitant anticholinergic should be continued, but tapered off over 2–3 weeks (long term treatment may predispose to TD).
  • Alternative treatment includes use of amatadine (fewer SEs than other agents).
  • Routine prophylaxis should be considered for patients with a history of previous drug-induced dystonic reaction.

P.867
Agents reported to cause dystonias Antipsychotics Amoxapine, clozapine (rare/abrupt withdrawal), flupentixol decanoate, haloperidol, loxapine, olanzapine (rare), prochlorperazine, risperidone (rare), trimeprazine, zuclopethixol. Other psychotropics Benztropine (rare), bupropion, buspirone, carbamazepine, cocaine (+ withdrawal), disulfiram (rare), fluoxetine, midazolam, paroxetine, phenelzine, sertraline, TCAs. Other (mostly rare/isolated cases) Amiodarone, azapropazone, diphenhydramine, domperidone, ergotamine, indomethacin, metoclopramide, nifedipine, penicillamine, prochlorperazine, promethazine, propranolol, sumatriptan. References 1 Note—in contrast with most medication side-effects, acute dystonias are more common in the young than the elderly. This may be related to asymptomatic loss of dopaminergic neurons in later life. P.868
Neuroleptic malignant syndrome Essence A rare, life-threatening, idiosyncratic reaction to antipsychotic (and other) medication (see opposite), characterised by: fever, muscular rigidity, altered mental status, and autonomic dysfunction. N.B. If diagnosed in a psychiatric setting, transfer patient to acute medical services where intensive monitoring and treatment are available. Pathophysiology Theories: 2° to DA activity in the CNS— i.e. striatum (rigidity), hypothalamus (thermoregulation)—by blockade of D2-receptors or ↓DA availability; impaired Ca2+ mobilisation in muscle cells leads to rigidity (like malignant hyperthermia1); sympathetic nervous system activation or dysfunction. Epidemiology Incidence 0.07–0.2% (pooled data); ♀:♂ = 2:1. Mortality 5–20%—death usually due to respiratory failure, cardiovascular collapse, myoglobinuric renal failure, arrhythmias, or DIC. Morbidity Rhabdomyolysis, aspiration pneumonia, renal failure, seizures, arrhythmias, DIC, respiratory failure, worsening of primary psychiatric disorder (due to withdrawal of antipsychotics). Symptoms/signs Hyperthermia (>38°C), muscular rigidity, confusion/ agitation/altered level of consciousness, tachycardia, tachypnoea, hyper/ hypotension, diaphoresis/sialorrhea, tremor, incontinence/retention/obstruction, ↑CK/urinary myoglobin, leukocytosis, metabolic acidosis. Risk factors ↑ambient temperature; dehydration; patient agitation or catatonia; rapid antipsychotic initiation/dose escalation; withdrawal of antiparkinsonian medication; use of high-potency agents/depot IM preparations; history of organic brain disease (e.g. dementia, alcoholism), affective disorder, previous NMS; predisposing drugs (e.g. lithium, anticholinergic agents). Differential diagnosis (Lethal) catatonia (see opposite); malignant hyperthermia; encephalitis/meningitis; heat exhaustion; parkinsonism/ acute dystonia; serotonergic syndrome; toxicity due to other drugs (e.g. amphetamine, MDMA, cocaine, antidepressants, antihistamines, sympathomimetics, salicylates); DTs; rhabdomyolysis; septic shock; haemorrhagic stroke; tetanus; phaeochromocytoma; strychnine poisoning. Investigations FBC, blood cultures, LFTs, U&Es, calcium and phosphate levels, serum CK, urine myoglobin, ABGs, coagulation studies, serum/urine toxicology, CXR (if aspiration suspected), ECG; consider head CT (intracranial cause), LP (to exclude meningitis). Management

  • Benzodiazepines for acute behavioural disturbance (p. 896) (NB: Use of restraint and I/M injection may complicate the interpretation of serum CK.)
  • Stop any agents thought to be causative (esp. antipsychotics), or restart antiparkinsonian agents.
  • Supportive measures: oxygen, correct volume depletion/hypotension with IV fluids, reduce the temperature (e.g. cooling blankets, antipyretics, cooled IV fluids, ice packs, evaporative cooling, ice-water enema).
  • P.869

  • Rhabdomyolysis—vigorous hydration and alkalinisation of the urine using IV sodium bicarbonate to prevent renal failure.
  • Pharmacotherapy to reduce rigidity—dantrolene (IV 0.8–2.5mg/kg qds; PO 50–100mg bd), lorazepam (up to 5mg); 2ndline: bromocriptine (PO 2.5–10mg tds, increase to max. 60mg/day), amantidine (PO 100–200mg bd); 3rd line: nifedipine; consider ECT (NB ↑ risk of fatal arrhythmias).

Course May last 7–10 days after stopping oral antipsychotics and up to 21 days after depot antipsychotics (e.g. fluphenazine). Prognosis In the absence of rhabdomyolysis, renal failure, or aspiration pneumonia, and with good supportive care, prognosis is good. Follow-up Monitor closely for residual symptoms. Once symptoms have settled allow 2+wks (if possible) before restarting medication (use low-dose, low-potency, or atypical agents). Consider prophylaxis (bromocriptine). Inform patient about risk of recurrence if given antipsychotic medication. Ensure this is recorded prominently in their medical notes. Drugs reported to cause symptoms characteristic of NMS Antipsychotics Chlorpromazine, clozapine (rarely), flupenthixol, fluphenazine, haloperidol, loxapine, olanzapine, promazine, quetiapine (rarely), risperidone, thioridazine. Antiparkinsonian agents Amantadine (+withdrawal), anticholinergics (withdrawal), levodopa (+withdrawal). Antidepressants Amoxapine, clomipramine, desipramine, phenelzine, trimipramine, venlafaxine. Other Carbamazepine (+withdrawal), ganciclovir, ferrous sulphate, lithium, methylphenidate, metoclopramide, oral contraceptives. Differentiating NMS from catatonia

Feature NMS Catatonia
Patient taking antipsychotics Usually Not usually
Catatonic symptoms:
Echo phenomena Rare Yes
Ambitendency Rare Yes
Posturing Rare Yes
Hyperthermia Usually before stupor Usually before/during severe agitation
Muscle rigidity Yes Yes
Raised WCC Yes No
Raised CK Yes Yes

References 1 A rare disorder associated with exposure to inhaled aesthetics and succinylcholine. Genetic linkage found to chromosome 19. Possibly due to a muscle membrane defect, leading to ↓ intracellular Ca2+ and intense muscle contractions. Temperature rises rapidly (up to 1°C/5mins). P.870
Serotonin syndrome Essence A rare but potentially fatal syndrome occuring in the context of initiation or dose increase of a serotonergic agent, characterised by altered mental state, agitation, tremor, shivering, diarrhoea, hyperreflexia, myoclonus, ataxia, and hyperthermia. Although SSRIs are commonly linked to SS, many other drugs (e.g. amphetamines, MAOIs, TCAs, lithium) have the potential of causing hyperserotonergic symptoms. SS can occur as a result of overdose, drug combinations (including over the counter medications), and rarely with therapeutic doses. Pathophysiology A variety of mechanisms can potentially increase the quantity or activity of serotonin: ↑production of serotonin due to ↑availability of precursors (L-tryptophan–containing substances); ↓metabolism of serotonin (MAOIs, selegiline); ↑release of stored serotonin (amphetamine, cocaine, fenfluramine, MDMA, meperidine); reuptake inhibition (SSRIs, TCAs, SNRIs, NaSSAs, MDMA, dextromethorphan, meperidine, St. John’s Wort); direct stimulation of serotonin receptors (buspirone, LSD); unknown mechanisms (lithium). Epidemiology Incidence -1% for SSRIs (moderate/major symptoms; mild symptoms may be common, but tend to go unreported); mortality <1 in 1000 cases. Symptoms/signs (see opposite) Psychiatric/neurological Confusion, agitation, coma. Neuromuscular Myoclonus, rigidity, tremors (including shivering), hyperreflexia (usually lower rather than upper limbs), ataxia. Autonomic Hyperthermia (may be 2° to prolonged seizure activity, rigidity, or muscular hyperactivity), GI upset (nausea, diarrhoea), mydriasis, tachycardia, hyper/hypotension. Differential diagnosis NMS (see opposite), malignant hyperthermia, infections (encephalitis/meningitis, sepsis), metabolic disturbances, substance abuse (cocaine)/withdrawal/overdose (LSD, PCP). Investigations FBC, U&Es, LFTs, glucose, pH, biochemistry (including calcium, magnesium, phosphate, anion gap), CK, drug toxicology screen, CXR (if evidence of respiratory distress/possible aspiration), ECG monitoring (arrhythmia/conduction problems—prolonged QRS or QTc interval). Treatment

  • If severe, requires immediate transfer to emergency department for supportive treatment and active management.
  • If overdose, consider gastric lavage and/or activated charcoal.
  • IV access—to allow volume correction (dehydration: insensible fluid loss due to hyperthermia) and reduce risk of rhabdomyolysis.
  • Rhabdomyolysis should be dealt with quickly, with emphasis on maintaining a high urine output combined with alkalinisation using sodium bicarbonate (target urine pH of 6). If necessary, reduce the temperature (e.g. cooling blankets, antipyretics, cooled IV fluids, ice packs, evaporative cooling, ice-water enema).
  • P.871

  • Pharmacotherapy Agitation, seizures, and muscular rigidity/ myoclonus best managed using a benzodiazepine (e.g. lorazepam IV (slow) 1–2mg every 30 mins; clonazepam). Serotonin receptor antagonists may be considered in selected cases (e.g. cyproheptadine PO 4–8mg every 2–4 hrs (max 0.5mg/kg/d), chlorpromazine (risk of reduced seizure threshold), mirtazepine, methysergide, propranolol (mild 5HT antagonist)). Antihypertensives are usually unnecessary unless the hypertension is persistent and clinically significant (e.g. nitroglycerin IV 2mg/kg/min).

Course and prognosis Onset is usually acute, However, recurrent mild symptoms may occur for weeks before the appearance of severe symptoms. Most cases resolve without sequelae within 24–36 hours with adequate supportive measures. Following an SSRI overdose, a patient who remains asymptomatic for several hours is unlikely to need further medical management. Sternbach’s diagnostic criteria1

  • Other potential causes excluded (e.g. infection, metabolic, substance abuse, withdrawal).
  • No concurrent antipsychotic dose changes prior to symptom onset.
  • At least three of the following:
    • Agitation/restlessness
    • Sweating
    • Diarrhoea
    • Fever
    • Hyperreflexia
    • Ataxia
    • Mental state changes (confusion, hypomania)
    • Myoclonus
    • Shivering
    • Tremor

Distinguishing SS from NMS Although the clinical presentation of these 2 syndromes is very similar (i.e. autonomic dysfunction, alteration of mental status, rigidity, and hyperthermia), differentiation is very important as specific management may differ (e.g. use of chlorpromazine in SS, which may worsen NMS).

  NMS SS
Associated Rx Antipsychotics Serotonergic agents
(Idiosyncratic/normal dose) (OD/drug combination)
Onset Slow (days to weeks) Rapid
Progression Slow (24–72 hrs) Rapid
Muscle rigidity Severe (‘lead pipe’) Less severe
Activity Bradykinesia Hyperkinesia

References 1 Sternbach H (1991) The serotonin syndrome. AJP 148, 705–13. P.872
SSRI1 withdrawal (discontinuation) syndrome 2 The incidence and prevalence of this syndrome are currently unknown. Rates of occurrence vary from 12–85%, depending both on the SSRI used and the underlying condition being treated. The few available discontinuation studies indicate minor forms of the syndrome may be common and severe forms unusual. There may be less risk with certain drugs (e.g. fluoxetine—perhaps due to longer half-life) and possibly greater risk with paroxetine (perhaps due to cholinergic rebound), although symptoms of discontinuation have been reported with all the SSRIs. Clinical features Neurologic symptoms —most common: dizziness, vertigo, lightheadedness, and gait instability. Somatic complaints —nausea/emesis, fatigue and headache; insomnia. Less frequently reported: shock-like sensations, paraesthesia, visual disturbances, diarrhoea, flu-like symptoms (myalgias and chills). Non-specific symptoms —agitation, impaired concentration, vivid dreams, depersonalisation, irritability, and suicidal thoughts have also been reported. Course and duration Usually develop after 1 month of SSRI treatment, within 2–5 days after SSRI discontinuation or dose reduction. If untreated, duration is variable (one to several weeks) and ranges from mild-moderate intensity in most patients, to extremely distressing in a small number. Aetiology The biological mechanisms underlying this syndrome are not well understood, although an acute decrease in synaptic serotonin in the face of down-regulated or desensitised serotonin receptors has been postulated. Risk factors Appears to be idiosyncratic with no specific associations with age, sex, diagnosis, or dose of SSRI (both low and high doses have been reported). Differential diagnosis The syndrome may be easily confused with recurrence of symptoms after inadequate duration of SSRI treatment, particularly in the anxiety disorders. Other possibilities (e.g. infection, metabolic, withdrawal from drugs of abuse/alcohol) should be excluded. If the syndrome occurs when cross-tapering from one SSRI to another antidepressant, be aware of the possibility of serotonin syndrome (see p. 870). Management

  • Tapering SSRIs may help reduce the risk of developing the syndrome (use of liquid preparations may be helpful in allowing greater flexibility). However, guidelines on the optimum rates of dose reduction are at best empirical (see p. 275) and a cautious approach is advised (slowly over a number of weeks).
  • If severe, re-introduction of the SSRI rapidly resolves the symptoms. However, the syndrome may recur in up to 75% of patients when the same SSRI is later discontinued.
  • P.873

  • Awareness of some of the more unusual symptoms, such as dizziness and shock-like sensations, and education of patients prior to stopping or tapering an SSRI, should prevent unnecessary and expensive medical investigations.
  • When symptoms are mild-moderate and short-lived they can generally be tolerated by the patient, allowing for successful discontinuation of the SSRI.

References 1 The ‘special case’ for differentiating an ‘SSRI discontinuation syndrome’ is debatable, since withdrawal syndromes have been described with most antidepressants including TCAs and SNRIs (venlafaxine)—all with similar symptoms to those described for SSRIs. In general, gradual tapering of antidepressants is recommended and abrupt stopping should be avoided (see p. 274). 2 Zajecka J, Tracy KA, Mitchell S (1997) Discontinuation symptoms after treatment with serotonin reuptake inhibitors: a literature review. Journal of Clinical Psychiatry 58, 291–7 (& suppl. 7). P.874
Hyponatraemia and antidepressants Essence Low serum sodium is a rare, idiosyncratic side-effect of antidepressants which may have serious consequences if undiagnosed. Aetiology Incompletely understood, but probably due to the syndrome of inappropriate secretion of anti-diuretic hormone (SIADH). Risk factors Previous SIADH/history of hyponatraemia; age >80yrs; comorbidity: diabetes mellitus, hypertension, impaired renal function, COAD; other medication (e.g. diuretics). Clinical features Depend upon the severity, duration, and rate of change in serum sodium. May be asymptomatic, or display symptoms and signs (e.g. lethargy, confusion, nausea, weight loss, muscle cramps/ weakness, hypertension, cardiac failure, oedema, seizures). Investigations U&Es (serum Na+<125mmol/l), 24hr urine collection (urinary Na+>20mmol/l and osmolality>100mosml/kg). Alternatively there may be low plasma osmolality (<260mmol/kg) without hypovolaemia, oedema, or diuretics. Differential diagnosis Malignancy e.g. lung small-cell; pancreas; prostate; lymphoma. CNS disorders e.g. meningoencephalitis; abscess; stroke; subarachnoid/subdural haemorrhage; head injury; Guillain-Barré; vasculitis. Respiratory disorders e.g. TB; pneumonia; abscess; aspergillosis. Metabolic disease e.g. porphyria; trauma. Drugs e.g. opiates; chlorpropramide; cytotoxic agents. Management

  • Prevention Baseline U&Es prior to commencing antidepressant, with monitoring for those at high risk (initially monthly, or after any dose change, once treatment dose established—every 3–6mths).
  • Treatment
    • Withdraw suspected agent immediately.
    • If serum Na+ remains <125mmol/l, refer to specialist medical care (to eliminate other possible causes, and to treat more intensively—e.g. with fluid restriction and occasionally with demeclocycline).
    • If serum Na+>125mmol/l, continue to monitor U&Es daily until >135mmol/l.
    • Consider alternative antidepressant (usually from a different class—low dose, gradual increase, close monitoring) or, if treatment urgent, ECT may be an option.

P.875
Paradoxical reactions to benzodiazepines1 Essence Paradoxical or ‘disinhibitory’ reactions to BDZs occur in a minority of patients (less than 1% of general population) and are characterised by acute excitement and altered mental state:

  • increased anxiety
  • vivid dreams
  • hyperactivity
  • sexual disinhibition
  • hostility and rage (‘aggressive dyscontrol’)

Recognition is important as behavioural disturbance may be exacerbated by inappropriate use of higher doses of BDZs. NB Similar types of reaction are described for most CNS depressants (e.g. alcohol, barbiturates). Aetiology Incompletely understood; theories include: ‘release behaviour’ due to loss of frontal lobe inhibition through GABAA mechanism; BDZ related reduction in 5HT neurotransmission; BDZ related reduction in ACh neurotransmission. Risk factors Children, learning disability, history of brain injury, dementia, borderline PD, antisocial PD, history of aggression/poor impulse control, family/personal history of paradoxical reaction, use of high-dose/high-potency BDZs (e.g. alprazolam, clonazepam, flunitrazepam, triazolam), IV/intranasal administration. Management

  • Nurse in safe environment, with constant supervision.
  • Use sedative antipsychotic to treat acute behavioural disturbance if necessary.
  • In extreme cases consider use of IV flumazenil (may require repeated doses).
  • Clearly record occurrence of paradoxical reaction so that future episodes of acute behavioural disturbance are managed appropriately.

References 1 Paton C (2002) Benzodiazepines and disinhibition: a review Psychiatric Bulletin 26, 460–2. P.876
Prescribing in pregnancy Data is limited (and often conflicting) regarding the safety of psychotropic drugs in pregnancy. Many clinicians prefer to use older agents as they have more experience with these compounds. Antipsychotics

  • All drugs carry a moderate risk and should be used with caution, although there is little clear evidence for teratogenicity of most compounds. (Some evidence for increased risk of organ dysgenesis with the phenothiazines.)
  • Depot formulations should be avoided as gradual withdrawal prior to delivery is complicated (and neonatal withdrawal may be more severe).
  • Specific advice from the manufacturer (Novartis) should be sought regarding the use of clozapine (although it does not appear to be a major teratogen).

Antidepressants

  • There is relatively more data establishing the safety of older compounds (e.g. imipramine, amitriptyline). However, serum monitoring and dose adjustment may be necessary.
  • Of the SSRIs, fluoxetine is the most studied with no good evidence of teratogenicity (and only a slight increased possibility of miscarriage—similar to TCAs).

Benzodiazepines

  • Neonatal respiratory depression, hypothermia, hypotonia (‘floppy baby syndrome’) and withdrawal syndromes may occur when BDZs are used close to delivery.
  • High doses and use in the first trimester increase the teratogenic risk.
  • There may be an association between BDZs (esp. diazepam) and increased risk of facial clefts (detailed ultrasonography at 16–18wks indicated).
  • Short-term use and minimum effective dose are advised if BDZs are necessary. Promethazine is often preferred.

Mood stabilisers

  • All commonly used mood stabilisers are teratogenic and, where possible, should be avoided in the first trimester.
  • Lithium has been associated with an increased risk (1:1000) of Epstein’s anomaly (downward displacement of the tricuspid valve into the right ventricle) and detailed ultrasound/foetal echocardiography is indicated at 16–18wks.
    • Relapse rates on discontinuation (50% within 2–10wks) are generally regarded to preclude stopping lithium therapy in pregnancy.
    • Serum monitoring, dosage adjustment, and ensuring adequate hydration are essential (particularly after delivery).
    • Neonatal problems include ‘floppy baby syndrome’, non-toxic goitre, hypothyroidism, nephrogenic diabetes insipidus, and cardiac arrhythmias.
  • P.877

  • Valproate, and to a lesser extent carbamazepine, are associated with neural tube defects (hence folic acid supplementation is recommended for women of child-bearing age—although evidence for benefit is inconclusive). Valproate has recently been associated with increased risk of hypospadias.
    • Detailed ultrasonography should be carried out at 16–18wks, and maternal serum alpha-fetoprotein (AFT) levels measured.
    • There is also an increased risk of neonatal haemorrhage, and vitamin K should be given to mothers in the last month of gestation (and to neonates at birth).
  • Little data is available for gabapentin, lamotrigine, or other newer anticonvulsants and the risk/benefit needs to be carefully considered.

Guiding principles1 For all women of child-bearing age

  • Always consider (and ask about) the possibility of pregnancy.
  • Before starting any medication, a pregnancy test is recommended.
  • Counsel the patient about the necessity of adequate contraception.
  • Advise further consultation if pregnancy is planned.

For a planned conception

  • Discuss the risks/benefits of discontinuation/continuation of medication (e.g. relapse vs. teratogenicity, the possible time it may take to conceive, no decision is risk-free).
  • Avoidance of all drugs during the first trimester is ideal (but often not achievable).

In pregnancy

  • Consider switching to a lower risk drug if possible, use the lowest dose possible, avoid polypharmacy, and monitor closely.
  • Pregnancy may alter the pharmacokinetics of drugs, hence dosages may need to be adjusted (e.g. lithium).
  • Gradual withdrawal of some compounds (e.g. BDZs, TCAs, SSRIs) in the weeks prior to delivery may help avoid ‘withdrawal’ effects in the newborn baby.

References 1 Adapted from Bazire S (2001) Psychotropic Drug Directory 2001/02, p 206. Bath Press, UK. P.878
Prescribing in lactation Absolute contraindications Breastfeeding should be avoided when the mother is concurrently taking MAOIs, lithium, and clozapine, or there is evidence in the infant of renal, hepatic, cardiac, or neurological disorders. General points

  • All psychotropic medication should be regarded as passing into breast milk (to a greater or lesser degree).
  • Of the limited studies examining this problem, the general findings are that levels of most psychotropic drugs in breast milk are relatively low, and infant blood levels may be undetectable.
  • Although infant exposure may be relatively low from breast milk (much lower than in utero exposure if mother was taking medication during pregnancy), there is a risk of both withdrawal symptoms and adverse effects on development.
  • Evidence may be lacking for specific risks, nonetheless caution should be exercised.
  • Monitoring of the infant should include biochemical (renal and liver function tests) and behavioural measures, with the involvement of a paediatrician to ensure development is within normal parameters.

Choice of medication in nursing mothers

  • Where possible, consider non-pharmacological treatments.
  • If medication is necessary, the lowest effective therapeutic dose should be used and polypharmacy should be avoided.
  • A recent review of the topic1 concludes that ‘the findings to date suggest that provided that infants are healthy at the outset it is likely that the benefits of breast-feeding will outweigh potential hazards if their mothers are taking established tricyclic drugs at recommended dose levels. Much less is known about risks associated with SSRI antidepressants or about antipsychotic drugs such as phenothiazines and butyrophenones or mood stabilizers such as carbamazepine’.

Antipsychotics Low doses of chlorpromazine (max. 200mg/day), haloperidol (max. 10mg/day), and trifluoperazine (max. 20mg/day) may be used cautiously, with close monitoring of the infant. Antidepressants Most evidence exists for the TCAs (esp. imipramine and nortriptyline). SSRIs have not been shown to have major adverse effects on the infant. Newer antidepressants should not be used, unless the mother has taken them during the pregnancy. Mood stabilisers Lithium should be avoided. Carbamazepine and valproate may be used cautiously, preferably given as a single dose in slow-release form. Strategies to minimise infant exposure

  • Breastfeeding should be avoided at the time when serum levels in the mother are likely to be at their peak (check drug information for these values).
  • P.879

  • If possible, medication should be given as a single dose before the infant’s longest sleep period.
  • Breastfeeding should occur immediately before taking the next due dose.
  • Alternatively, breast milk may be expressed when serum levels are at their lowest.

References 1 Yoshida K, Smith B, Kumar R (1999) Psychotropic drugs in mothers’ milk: a comprehensive review of assay methods, pharmacokinetics and of safety of breast-feeding. J Psychopharmacol. 13, 64–80. P.880
Prescribing for patients with cardiovascular disease General points In considering a suitable psychotropic drug the main issues revolve around the propensity of that drug to interact with other medications the patient may be taking, to affect blood pressure, or lead to cardiac conduction problems (see opposite). Due to the unpredictability of drug interactions, polypharmacy is best avoided. Specific contraindications BDZs and chlormethiazole in pulmonary insufficiency, disulfiram (Antabuse) and lithium in heart failure or sick sinus syndrome, lofexidine in post-MI patients. Pimozide is best avoided in most conditions. Myocardial infarction Antidepressants Best avoided in the first 2 months; if clinically indicated—SSRIs rather than TCAs, with exception of fluvoxamine and citalopram. If sedation required consider use of a small dose of trazodone at night. Antipsychotics High doses should be avoided; phenothiazines are generally more hypotensive than butyrophenones; clozapine should be used with caution in the 1st yr post MI; of the newer antipsychotics, olanzapine may offer best risk-benefit balance. Heart failure Where possible, hypotensive agents (β-blockers, clozapine, risperidone, TCAs) and drugs causing fluid retention (carbamazepine, lithium) should be avoided. Angina/IHD Avoid hypotensive agents (see above) and those known to cause tachycardia (phenothiazines, clozapine, risperidone). Hypertension Avoid agents that may raise blood pressure (low-dose TCAs, phenothiazines, clozapine, high-dose venlafaxine). Arrhythmias (see opposite) Antidepressants SSRIs should be first choice (but not fluvoxamine or citalopram). Antipsychotics High doses should be avoided; risperidone may be least likely to cause conduction problems. P.881
The QTc question Awareness of QT prolongation, as measured by the corrected QT interval (QTc), has been heightened because of the potential (but relatively rare) risk of fatal arrhythmias (e.g. torsade de pointes), highlighted recently by the withdrawal of thioridazine as a first-line antipsychotic (and now contraindicated in patients with a history of, or at risk of, arrhythmias) and the restricted use of droperidol. QTc is derived by dividing the QT interval by the square root of the cycle length i.e.: Normal QTc is 380–420ms; if prolonged to 450ms—some concern; if >500–520ms—‘at risk’. Causes of prolonged QT interval: acute myocardial ischaemia, myocarditis, bradycardia (e.g. AV block), head injury, hypothermia, electrolyte imbalance (K+↑, Ca2+↓, Mg2+↓), congenital, sotalol, quinidine, antihistamines, macrolides (e.g. erythromycin), amiodarone, antipsychotics (esp. phenothiazines), antidepressants (esp. TCAs). General advice: good practice dictates use of routine ECG prior to commencement of antipsychotic medication (esp. pimozide, zotepine, thioridazine, and other phenothiazines), and regular monitoring, particularly with use of high doses (p. 216). P.882
Prescribing for patients with liver disease General points

  • Almost all psychotropic drugs are metabolised by the liver.
  • Exceptions to this rule include lithium, gabapentin, sulpiride, and amisulpiride, which have minimal (or no) liver metabolism.
  • Most drugs are highly protein-bound (with the exception of citalopram, sulpiride, and amisulpiride) and plasma levels may be increased in liver disease.
  • In liver disease, when using drugs with high 1st pass clearance (e.g. imipramine, amitriptyline, desipramine, doxepin, haloperidol) initial doses should be low.
  • Where possible, phenothiazines (e.g. chlorpromazine) and hydrazine MAOIs (may be hepatotoxic) should be avoided.
  • If in doubt, closely monitor LFTs, particularly during dose changes.

Antidepressants (always start with lowest possible dose)

  • TCAs Best evidence for use of imipramine.
  • SSRIs Some evidence for paroxetine; avoid sertraline.
  • MAOIs When clinically necessary, use 30–50% usual dose.
  • Others Venlafaxine (use 50% usual dose), mirtazepine (cautious use), reboxetine (extensively metabolised, very low starting dose).

Antipsychotics

  • Best evidence for haloperidol (considered ‘drug of choice’), with sulpiride a close second (only 5% liver metabolism).
  • Few problems reported for flupenthixol/zuclopenthixol.
  • Clozapine dose should be kept low (some evidence of hepatotoxicity).
  • Amisulpiride is predominantly excreted by the kidneys, but there is little literature on its use in liver disease.
  • For the newer agents recommendations suggest:
    • Olanzapine (up to 7.5mg) may be safe (but does induce transaminases).
    • Risperidone doses should be kept low (start 0.5mg bd, max 4mg/d).
    • Quetiapine is extensively metabolised (hence start low—25mg).
    • Zotepine should only be used with caution (start 2.5mg bd, max 75mg/d, monitor LFTs weekly for at least 3mths).

Mood stabilisers

  • Lithium is the ‘drug of choice’, with gabapentin as second choice.
  • Valproate is contraindicated in severe liver disease, but may be used with caution in mild-moderate impairment.
  • Similarly caution should be exercised with carbamazepine, and lamotrigine is contraindicated in severe disease.

Anxiolytics

  • Where necessary, use low doses of short-acting BDZs (e.g lorazepam, oxazepam).
  • If chlormethiazole is to be used, the dose should be reduced to -30%.

P.883
P.884
Prescribing for patients with renal impairment General points

  • Renal impairment generally leads to accumulation of drugs (or active metabolites) that are predominantly cleared by the kidney. This will lead to higher serum levels, and increased risk of dose-related side-effects (e.g. postural hypotension, sedation, EPSEs).
  • Hence, all psychotropics should be started at a low (or divided) dose, increased slowly, and carefully monitored (for efficacy and tolerability).
  • When patients are receiving dialysis seek specific advice from manufacturer—dosages should usually be reduced by at least 50% and dosing separated in time from dialysis itself.

Classification of chronic renal failure (CRF) CRF may be classified as mild (GFR 30–50ml/min), moderate (GFR 10–29ml/min), severe (GFR <10ml/min), or end-stage (GFR <5ml/min). See opposite for estimation of GFR. Antidepressants

  • In severe renal failure avoid fluoxetine, venlafaxine, and lofepramine (unless the patient is on dialysis).
  • Otherwise cautious use, beginning low and gradually increasing the dose is advised.
  • No specific therapeutic dose adjustments are necessary for MAOIs (except for isocarboxazid), RIMAs, mianserin, tryptophan, trazodone, or TCAs.

Antipsychotics

  • Lower doses are recommended to avoid dose-related side-effects (particularly with the phenothiazines, which may be best avoided).
  • Clozapine is contraindicated in severe renal impairment.
  • Greater care is necessary with amisulpiride/sulpiride, risperidone, and zotepine.
  • Loxapine appears to have few specific problems.
  • Some authorities recommend haloperidol, but accumulation is possible, so careful monitoring is still necessary.

Mood stabilisers

  • Lithium is relatively contraindiciated in renal failure. However, its use may often be necessary, and dose reduction (e.g. to 50–75% for mild-moderate and 25–50% for severe renal failure) with close monitoring of plasma levels is recommended. In dialysis, 600mg×3/wk (after dialysis) has been shown to maintain therapeutic plasma levels.
  • No specific problems are reported for valproate or carbamazepine, although in severe renal failure, serum levels should be monitored.
  • Gabapentin requires specific dose adjustments and manufacturer’s recommendations should be sought.
  • Lamotrigine should be used cautiously, particularly in severe renal impairment.

P.885
Anxiolytics/hypnotics

  • BDZs (with the exception of chlordiazepoxide) tend to accumulate, with increasing CNS side-effects (particularly sedation)—hence use low doses.
  • Buspirone is contraindicated in moderate-severe renal failure.
  • β-blockers should be started at low dose as they may complicate renal failure by reducing renal blood flow.
  • Zopiclone and zaleplon require no dosage adjustment. However, the half-life of zolpidem may be doubled in renal failure.

Others

  • Anticholinergics, disulfiram—cautious use.
  • Acamprosate—contraindicated if serum creatinine >120µmol/l.
  • Anticholinesterases—no reported problems.

Estimating glomerular filtration rate (GFR) Creatinine clearance is a measure of GFR, the volume of fluid filtered by the glomeruli per minute (ml/min). Normal value is approx. 125ml/min. Urine is collected over a 24-hr period for urinary creatinine (mmol/l), along with a blood sample for serum creatinine (µmol/l). Urine creatinine concentration = u mmol/l Plasma creatinine concentration = pµmol/l 24-hr urine volume = v mls NB Always check the units are correct for each variable in the equation. For an estimate of creatinine clearance* based only on the serum creatinine, the following formula can be used: NB To convert µmol/l to mg/dl, divide µmol/l by 88.4. Footnote *For women, the above estimate should be multiplied by 0.85. P.886
Prescribing for patients with epilepsy General points In considering a suitable psychotropic there are 2 related considerations:

  • The propensity of that drug to interact with other medications the patient may be taking (justifying serum monitoring where possible).
  • The risk of lowering seizure threshold and exacerbating the condition.

As these effects appear dose-related, the daily dose of any drug should be kept as low as possible. Greater caution is necessary when:

  • Other psychotropics are also being given (e.g. regular plus ‘ as required’ antipsychotics).
  • Patients may be withdrawing from CNS depressants (e.g. BDZs, barbiturates, or alcohol).

Antidepressants

  • All TCAs appear to lower seizure threshold, although there appears to be greater risk with amitriptyline and clomipramine.
  • Tetracyclics (maprotiline and amoxapine) also appear pro-convulsant, as does bupropion.
  • The other antidepressants appear less likely to cause problems, and a usual first choice is often an SSRI.

Antipsychotics

  • Greatest risk of seizures is associated with the use of phenothiazines (esp. chlorpromazine), loxapine, zotepine, olanzapine, and particularly clozapine.
  • The risk of seizures with clozapine rises from 1% (at doses <300mg/d), to 2.7% (300–600mg/d), to 4.4% (>600mg/d). EEG changes are seen in up to 75% of people taking clozapine, with -40% showing paroxysmal discharges1. Because of this risk it is quite common to cover high doses of clozapine with concomitant use of valproate. Hence, greater caution is needed when clozapine is used in individuals with epilepsy.
  • Lowest risk is associated with haloperidol, sulpiride, zuclopenthixol, amisulpiride, pimozide, quetiapine, and risperidone.

Mood stabilisers

  • Lithium does cause seizures in overdose. However, therapeutic doses appear safe.
  • If in doubt, anticonvulsants provide useful alternatives. However, clinical efficacy must be weighed against any potential risks of using lithium.

Anxiolytics/hypnotics

  • Generally these drugs are anticonvulsant.
  • Exceptions include buspirone, zolpidem, and β-blockers—although there is no evidence that they are epileptogenic.

P.887
Others

  • Anticholinergics, acamprosate—no reported problems.
  • Disulfiram—caution recommended.
  • Anticholinesterases—care is needed with donepezil and rivastigmine. However, galantamine appears safe.

References 1 Pacia SV and Devinsky O (1994) Clozapine-related seizures: experience with 5,629 patients. Neurology 44, 2247–9. P.888
Plasma level monitoring There are a limited number of drugs with well-established plasma levels that equate with efficacy. Plasma monitoring is a regular procedure only for lithium therapy. However, there may be a number of other reasons for requesting plasma levels (bear in mind that assays for specific drugs may not be locally available and may need special arrangements.) Many psychiatric drugs have marked variations in metabolism, or large numbers of active metabolites, making plasma levels difficult to interpret. Reasons for monitoring

  • Established therapeutic plasma levels (see below).
  • Monitoring of any changes in plasma level that might affect efficacy (e.g. due to drug interactions, inter-current illness, pregnancy, or altered pharmacokinetics over time).
  • Clinical evidence of toxicity (e.g. lithium, anticonvulsants).
  • Where there is doubt about patient compliance (e.g. lack of effect despite adequate or even high-dose treatment).
  • In cases where the patient may be unable to report adverse effects (e.g. children, severe LD, dementia).
  • After overdose, to confirm it is safe to restart medication.
Reference ranges for selected drugs
Lithium (see p. 328) 0.8–1.2mmol/L
(0.6–0.8mmol/L—as an augmentative agent)
Valproate (see p. 332) 50–125mg/L
Carbamazepine (see p. 334) 4–12mg/L
(>7mg/L may be more efficacious in BAD)
Clozapine (see p. 218) 350–500mcg/L (0.35–0.5mg/L)
Nortriptyline 50–150mcg/L

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