Box 23.1 Legal principles applying to unlicensed prescribing \200 Legally unlicensed prescribing would not be held as a breach of the duty of care, if that t reatment was supported by a respected body of medical opinion, as the Bolam test (Bolam v. Friern Hospital Management Committee, 1957) in medical negligence claims asks for proof tha t a body of doctors would act similarly to the doctor in question. According to the case of Bolitho v. City and Hackney Health Authority (1997), medical opinion should also be capabl e of withstanding logical analysis. In unlicensed prescribing this implies that doctors con sider the risks and bene \201 ts of varying treatment options, with due regard to the avai lable evidence. 1 Royal College of Psychiatrists: CR142 (Jan 2007) Use of licensed medicines for unlicensed applica- tions in psychiatric practice. M http://www.rcpsych.ac.uk/ \201 les/pdfversion/c r142.pdf 2 British Association for Psychopharmacology (BAP) Consensus Statement (1997) Chil d and learning disability psychopharmacology. J Psychopathol 11: 291 \200\2234. M http://jo p.sagepub.com/con- tent/11/4/291.full.pdf+html 23_Semple_Chap23.indd 927 12/7/2012 5:12:48 PM CHAPTER 23 Therapeutic issues 928 Plasma level monitoring There are a limited number of drugs with well-established plasma le vels that equate with ef \201 cacy. Plasma monitoring is a regular procedure only for lith ium therapy. However, there may be a number of other reasons for requesting plasma levels ( bear in mind that assays for speci \201 c drugs may not be locally available and may need special arrangements). Many psychiatric drugs have marked variations in metabolism, or larg e numbers of active metabolites, making plasma levels dif \201 cult to interpret. Reasons for monitoring \200 \200 Established therapeutic plasma levels (see Table 23.1). Monitoring of any changes in plasma level that might affect ef \201 cacy (e.g. due to drug interactions, intercurrent illness , pregnancy, or altered pharmacokinetics over time). Clinical evidence of toxicity (e.g. li thium, 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 con \201 rm it is safe to restart medication. \200 Plasma level monitoring of other psychotropics (aripiprazole [and dehy- droaripiprazole], o lanzapine, risperidone [and 9-hydroxy-risperidone], quetiapine, amisulpiride, lamotrigine, sulpiride) is available in the UK1 and could be used in assessing adherence, dose optimizat ion, and if acute poi- soning is suspected. However, it is not advised in routine practice and other ways of establishing treatment adherence are preferred (e.g. meas- urement of ser um prolactin if patient is on risperidone \200\224see b p. 936). Table 23.1 Reference ranges for selected drugs Lithium (see b p. 336) 0.6 \200\2231mmol/L (0.6 \200\2230.8mmol/L \200\224as an augmentative agent) Valproate (see b p. 342) Carbamazepine (see b p. 346) Clozapine (see b p. 210) 50 \200\223100mg/L 4 \200\22312mg/L (>7mg/L may be more ef \201 cacious in bipolar disorder) 350 \200\223500mcg/L (0.35 \200\2230.5mg/L) 1 Toxicology Unit, KingsPath Laboratory, King \200\231s College Hospital, London. M www.kin gspath. co.uk/tests/toxicology/ 23_Semple_Chap23.indd 928 12/7/2012 5:12:48 PM PARADOXICAL REACTIONS TO BENZODIAZEPINES 929 Paradoxical reactions to benzodiazepines1 Essence Paradoxical or \200\230disinhibitory \200\231 reactions to BDZs occur in a minority of patients (less than 1% of general populat ion) and are characterized by acute excitement and altered mental state: \200 \200 \200 \200 \200 Increased anxiety. Vivid dreams. Hyperactivity. Sexual disinhibition. Hostility and rage ( \200\230aggressive dyscontrol \200\231). Recognition is important as behavioral disturbance may be exacerbated by inappropriate use of higher doses of BDZs. Note: similar types of reac- tion are described for most CNS depre ssants (e.g. alcohol, barbiturates). Etiology Incompletely understood; theories include: \200\230release behavior \200\231 due to loss of frontal lobe inhibition through GABAA mechanism; BDZ related reduction in 5-HT n eurotransmission; BDZ related reduction in ACh neurotransmission. Risk factors Children, learning disability, history of brain injury, dementia, borderline P D, antisocial PD, history of aggression/poor impulse control, family/ personal history of p aradoxical reaction, use of high-dose/high-potency BDZs (e.g. alprazolam, clonazepam, \202 unitrazepam, triazolam), IV/intra- nasal administration. Management \200 \200 Nurse in safe environment, with constant supervision. Use sedative antipsychotic to treat a cute behavioral disturbance if necessary. In extreme cases consider use of IV \202 umazen il (may require repeated doses). Clearly record occurrence of paradoxical reaction so futur e episodes of acute behavioral disturbance can be managed appropriately. 1 Paton C (2002) Benzodiazepines and disinhibition: a review. Psychiat Bull 26: 460 \200 \2232. 23_Semple_Chap23.indd 929 12/7/2012 5:12:48 PM CHAPTER 23 Therapeutic issues 930 Weight gain with psychiatric medication General points Weight gain is a signi \201 cant ca use of non-compliance with psychiatric medi- cation, and patients often complain about incr eases in weight, even when clinicians may regard it as \200\230clinically insigni \201 ca nt \200\231. Effects on general health, self-esteem, and social embarrassment should not be overlooked. Antipsychotics Proposed mechanisms Sedation (reduced activity), thirst (anticholinergic sid e-effects), reduced metabolism, \202 uid retention, endocrine effects (increased prolacti n, altered cortisol, altered insulin secretion), increases in leptin levels (changes in \200\230set-point \200\231 weight), and altered neurotransmitters (5-HT2C blockade, hista- mine af \201 nity, D2 blockade, CCK changes) have all been proposed. Increased risk Female, previous pattern of overeating, narcissistic traits, family or perso nal history of obesity. Effects of speci \201 c agents (see Table 23.2). Management1 \200 \200 \200 Routine measurement of baseline weight. Warn patient of possibility. Encourage \200\230hea lthy diet \200\231 (involve dietician if necessary), moderate physical exercise, avoid high -calorie \202 uids. Use lowest therapeutic dose, introduce medication increases slowly, c onsider intermittent dosing. Consider adjunctive prescribing (e.g. clozapine lowering of cl ozapine dose). plus quetiapine, to allow Antidepressants Proposed mechanisms Reduced metabolism, carbohydrate craving (Note: may be a symptom of depression itself), central serotonin mechanisms in regulating food intake (ap petite/satiety). Effects of speci \201 c agents (see Box 23.2). Management \200 \200 \200 \200 General advice about diet and exercise. Use lowest therapeutic dose. Consider switching to alternative antidepressant. Adjunctive prescribing (e.g. naltrexone, ranitidine at night: m ay reduce \200\230midnight snacks \200\231). 23_Semple_Chap23.indd 930 12/7/2012 5:12:48 PM WEIGHT GAIN WITH PSYCHIATRIC MEDICATION 931 Table 23.2 Weight gain with antipsychotics1 Antipsychotic Average weight gain (kg) Pimozide \210\2222.7 Aripiprazole \210\2221.3 Placebo \210\2221.0 Tri \202 uoperazine 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 1 Adapted from Fenton WS (2000) Review: most antipsychotic drugs are associated with weight gain. Evidence Based Ment Hlth 3: 58. Box 23.2 Weight changes with antidepressants \200 SSRIs: loss; sertraline: limited weight gain; citalopram: no change. TCAs: MAOIs/RIMAs: wei ght gain (phenelzine > moclobemide). Others: no change; venlafaxine: weight loss. \202 uoxetine, weight loss; paroxetine, \202 uvoxamine: slight weight \200 weight gain (amitriptyline > imipramine > clomipramine). weight loss (tranylcypromine) \200\224rarely weight gain; mianserin, mirtazepine; weight gain; reboxetine, trazodone: 23_Semple_Chap23.indd 931 12/7/2012 5:12:49 PM CHAPTER 23 Therapeutic issues 932 Lithium2 Proposed mechanisms Increased intake of high calorie drinks, hypothy- roidism, inc reased insulin secretion. Management Counseling and advice about diet and exercise, use of low- calorie drinks, avoid ance of salty foods (or adding salt to foods). Other mood stabilizers 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). Lamotrigine Not associated with weight gain \200\224making it the \200\230drug of choice \200\231 for those who have experienced marked weight gain with other mood stabilizers. 23_Semple_Chap23.indd 932 12/7/2012 5:12:49 PM WEIGHT GAIN WITH PSYCHIATRIC MEDICATION 933 1 Baptista T (1999) Body weight gain induced by antipsychotic drugs: mechanisms and managem ent. Acta Psych Scand 101: 3 \200\22316. 2 Baptista T (1995) Lithium and body weight gain. Pharmacopsychiat 28: 35 \200\22344. 23_Semple_Chap23.indd 933 12/7/2012 5:12:49 PM CHAPTER 23 Therapeutic issues 934 Antipsychotics and diabetes There have been recent concerns about the potential of SGAs to cause abnormalities in insulin sensitivity and diabetes (type II), yet the evidence that th ey are associated with increased risk for diabetes compared with FGAs is tentative. It is w orth noting: \200 The etiology of diabetes in a patient receiving antipsychotics may not be wholly attributab le to the drug \200\224many risk factors are shared with metabolic syndrome (see Box 23.3). For as yet unknown reasons, schizophrenic patients have a 2 \200\2233-fold higher risk of developing diabetes than the general population even when drug use is controlled. Psychiatr ists ought not to initiate treatment of diabetes themselves without consulting the patient \200\231s primary care physician and/or considering referral to a diabetes specialist. Youn ger patients treated with antipsychotics may be at higher risk of developing diabetes than older adults. Pathophysiology Not fully understood. Proposed mechanisms are: increased visceral adi- posi ty through histaminergic H1 antagonism, leptin resistance, \206\221 TNF- levels; inhibit ion of insulin secretion in pancreatic -cells through antago- nism of muscarinic M3 recep tors; \206\223 glucose sensitivity through antagonism of serotonergic 5-HT1A receptors; \206\221 insulin release through antagonism of adrenergic 2 receptors; inhibition of GLUT glucose transporter. Management \200 determine baseline measures, Prior to initiating antipsychotic treatment ideally oral gluco se tolerance test (OGTT) or fasting plasma glucose (FPG); otherwise random plasma glucose ( RPG) or urine glucose (UG) will suf \201 ce. When a patient gains 5% or more of their init ial weight at any time during therapy, consideration should be given to switching to an ant ipsychotic with less weight gain liability (see b p. 930). A general rank ordering of the S GAs risk of metabolic effects is: clozapine > olanzapine > quetiapine > risperidone > aripi prazole. Note: weight gain can occur with all of these drugs and considerable variability e xists among patients receiving the same drug regarding the risk of metabolic effects. For p atients at risk of diabetes changing to an antipsychotic less likely to cause metabolic eff ects should be balanced against the risks and bene \201 ts from continuing treatment with the same drug. Adjunctive treatments include: oral hypoglycaemics (e.g. metformin) or insul in; rosiglitazone and orlistat have been used with olanzapine and clozapine respectively; s ibutramine, amantadine, and topiramate have little supportive evidence and a high risk of a dverse side-effects. Lifestyle modi \201 cations highly motivated subjects and may be comp lementary to medication (i.e. calorie-controlled diet/regular physical exercise). that have the greatest to the least have been used successfully for weight control in 23_Semple_Chap23.indd 934 12/7/2012 5:12:49 PM ANTIPSYCHOTICS AND DIABETES 935 Box 23.3 Metabolic syndrome1 (Syndrome X, insulin resistance syndrome, Reaven \200\231s syn drome or CHAOS [Australia]) Essence Characterized by insulin resistance and abnormal adipose deposition and function. A ssociated with increased risk of developing atherosclerotic disease (HD and stroke), type 2 diabetes, fatty liver, and cancer. Affects a large number of people (up to 25% in some stu dies), and prevalence increases with age. Current guidelines allow diagnosis when at least 3 out of the following 5 criteria are present: \200 \211 100mg/dL (or receiving drug treatment for Fasting glucose hyperglycaemia). Blood pressure: hypertension). Triglycerides (TG): hypertr iglyceridaemia). High-density lipoprotein cholesterol (HDL-C) <40mg/dL in men or <50mg/dL i n women (or receiving drugs for reduced HDL-C). Waist circumference ethnic group, \211 90c m in men or \211 80cm in women. \211 130/85mmHg (or receiving drug treatment for \211 150mg/dL (or receiving drug treatment for \211 102cm in men or \211 88cm in women. If Asian Etiology The cause of the metabolic syndrome is unknown. Debate surrounds whether obesity o r insulin resistance is the cause of the metabolic syn- drome or if they are consequences o f a more far-reaching metabolic derangement. A number of markers of systemic in \202 ammat ion are often increased, e.g. CRP, \201 brinogen, IL-6, TNFA. Proposed pathophysiology De velopment of visceral fat \206\222 increased plasma levels of TNFA (as well as adiponectin , resistin, PAI-1) \206\222 production of in \202 ammatory cytokines and/or altered cell signaling leading to insulin resistance. Prevention Various strategies have been proposed. Usually include increased physical activity (e.g. walking 30min every day) and a healthy, r educed calorie diet. Treatment \200 The \201 rst-line treatment is change of lifestyle (i.e. calorie restriction and physical activity). If drug treatment is required, the individual disorders that comprise the metab olic syndrome are treated separately: diuretics and ACE inhibitors for hypertension; choles terol-lowering drugs to lower LDL cholesterol and triglyceride levels and to raise HDL leve ls; use of drugs that decrease insulin resistance, e.g. metformin and thiazolidinediones, i s controversial and local guidelines will apply. 1 The term \200\230metabolic syndrome \200\231 dates back to at least the late 1950s but came into common usage in the late 1970s to describe various associations of risk factors with diabetes that had been noted as earl y as the 1920s. Confusion arose because the term was used by different authors to describe different, albeit related, syndromes \200\224e.g. Haller (1997) Singer (1977), Phillips (19 77, 1978). It was the eponymous Gerald M. Reaven who coined the term \200\230Syndrome X \200\231 in his 1988 Banting lecture. He proposed insulin resistance as the underlying fact or and did not include abdominal obesity as part of the condition. Reaven GM (1988) Diabete s 37: 1595 \200\223607. 23_Semple_Chap23.indd 935 12/7/2012 5:12:49 PM CHAPTER 23 Therapeutic issues 936 Hyperprolactinaemia with antipsychotics Essence (see Box 23.4) Secretion of prolactin (PRL) by the pituitary is under inhibitory control via dopamine from the hypothalamus. Blockade of dopamine D2 receptors on the pituitary lactotroph cells by antipsychotics can raise prol actin levels within minutes to hours of starting treatment. It occurs frequently with FGAs and some SGAs (risperidone, amisulpiride) but is rare with other SGAs (olanzapine > quetiap ine, clozapine, ziprasidone, aripiprazole). Clinical features Include gynaecomastia, galactorrhoea, erectile dysfunction, loss of libid o, and hypogonadism in men and oligo/amenorrhoea, galactorrhoea, infertil- ity, loss of lib ido, acne, hirsutism, increased risk of osteoporosis, and pos- sibly of breast cancer in wo men. Epidemiology Prevalence of hyperprolactinaemia with \200\230prolactin-raising \200\231 ant ipsychotics is estimated to be about 34 \200\22342% in men and 59 \200\22375% in women. Risk factors Female sex (women of reproductive age are more at risk than postmeno- pausal w omen), postnatal period, children and adolescents. Differential diagnosis Diseases of the pituitary (e.g. prolactin-secreting pituitary adenom as) or hypothalamus, severe primary hypothyroidism, liver cirrhosis, end-stage renal diseas e, acromegaly, stress, pregnancy, post-partum period, chronic cocaine/marijuana use, opiate . Investigations \200 Measure PRL serum level: \200 When PRL-raising antipsychotics are used it is helpful to obtain a pretreatment PRL level. Secretion of PRL is pulsatile and may be raised in response to stress, meals, or post-ictal ly; hence, blood sample must be taken 1hr after eating or waking. Antipsychotics usually pr oduce PRL elevation of up to six times the upper limit of the reference range. Mild to mode rate elevations should be checked with a second sample to exclude physiological surges. Look out for signs of chest wall irritation (which can promote galactorrhoea and raise prol actin) and signs of a sellar mass (e.g. headache, visual \201 eld defects). Check TFTs (e xclude hypothyroidism), creatinine/U&Es (exclude renal failure), insulin-like growth factor -1 (exclude acromegaly). If history of chronic alcohol misuse, check LFTs and perform abdom inal examination to rule out hepatic cirrhosis. 23_Semple_Chap23.indd 936 12/7/2012 5:12:49 PM HYPERPROLACTINAEMIA WITH ANTIPSYCHOTICS 937 If clinically suspected, do a pregnancy test unless patient is postmenopausal or has had a hysterectomy. If patient is on oral antipsychotics and etiology remains uncertain, consider diagnostic short-term cessation of medication (72hrs usually suf \201 ces for serum PRL t o fall to near normal levels). Consider CT/MRI and/or a referral to endocrinology. Management \200 \200 Exclude other possible aetiologies. Consider a change of medication to a prolactin-sparing antipsychotic (e.g. clozapine, olanzapine, quetiapine, aripiprazole) or reduction in dose i f the patient \200\231s mental state is stable (monitor closely). Another option is augment ation with aripiprazole. If problems persist or medication changes are precluded (or not to lerated), refer to endocrinology for consideration of other treatments: combined oral contr aceptive (females only), dopamine agonists (amantadine, cabergoline, bromocriptine). \211 1yr, request bone mineral If patient has been amenorrhoeic for density (BMD) measurement i n order to screen for osteoporosis. 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. \200 Note: asymptomatic hyperprolactinaemia does not warrant (in itself) changes to medication. Box 23.4 Other drugs reported to cause hyperprolactinaemia \200 Antidepressants: e.g. SSRIs, MAOIs, and some TCAs. Dopamine-depleting agents, Other agents verapamil, oestrogens, antiandrogens. modest elevation with serotonergic antidepressants, \200 e.g. reserpine, tetrabenazine, methyldopa. , e.g. metoclopramide, cimetidine, cyproheptadine, 23_Semple_Chap23.indd 937 12/7/2012 5:12:49 PM CHAPTER 23 Therapeutic issues 938 Sexual dysfunction and psychiatric medication Degree of sexual dysfunction experienced by p atients taking psychiatric medication may be a major source of distress and a signi \201 c ant reason for non-adherence. Clinicians are notoriously poor at enquiring about these prob lems, despite reports that patients regard sexual side-effects as the most troublesome of a ll medication-related problems. Pathophysiology Not fully understood, but the proposed pharmacological mechanisms of psycho tropic-induced sexual dysfunctions are as follows: Libido Inhibited by dopamine blockade, histamine blockade, prolactin elevation, testosteron e decrease. Arousal (erection or vaginal lubrication) Inhibited by cholinergic blockade, A 1-adrenergic blockade, nitric oxide (NO) decrease, possibly dopamine blockade. Orgasm Inhibited by dopamine blockade, possibly prolactin elevation. Ejaculation Inhibited by prolactin elevation, A sibly dopamine blockade. 1-adrenergic blockade, pos- General points \200 Educate patients about possible sexual side-effects and routinely screen for any impairment of sexual performance. Be able to distinguish between psychotropic-induced sexual dysfunct ions and those related to underlying psychiatric or medical conditions, other concurrent dr ugs, alcohol/substance misuse, enviromental factors, relationship dif \201 culties. Optima l treatment for sexual dysfunctions requires the combination of pharmacological and psychol ogical interventions. Complaints of sexual dysfunction may suggest inadequate treatment of underlying mental illness. Antidepressants Sexual dysfunction is a possible adverse effect of all antidepressants and all dimensions of sexual functioning can be affected. Clomipramine, SSRIs (paroxetine, sert raline, citalopram, \202 uoxetine), and venlafaxine appear to be most likely to cause sex ual problems (30 \200\22360%). Other TCAs show intermediate risk of dysfunction (10 \200 \22330%). Bupropion, moclobemide, and mirtazepine seem to have the lowest rates of sexual s ide-effects. \200 Spontaneous remission occurs in 10% of patients and partial remission in 11% of cases. Dysf unction may be related to increased serotonergic transmission, peripheral A of NO, adrenerg ic/cholinergic imbalance. Sexual side-effects are likely to be dose related. Paroxetine is more likely to cause disorders of arousal and ejaculatory delay than other SSRIs. 1-adrenergic blockade, histaminergic antagonism, inhibition \200 23_Semple_Chap23.indd 938 12/7/2012 5:12:49 PM SEXUAL DYSFUNCTION AND PSYCHIATRIC MEDICATION 939 Serotonergic antidepressants are also employed in the treatment of premature ejaculation an d paraphilias. Management \200 \200 \200 \200 \200 Watchful waiting to see if symptoms subside (less likely with SSRIs). Reduce antidepressant to minimal effective dose. Delay drug intake until after sexual activity. \200\230Drug ho lidays \200\231 or scheduled interruptions in therapy (e.g. weekends). Switch to another ag ent known to have fewer adverse sexual effects (e.g. mirtazepine, bupropion, nefazodone, mo clobemide). Adjunctive therapy (e.g. mirtazepine, buspirone, bupropion, sildena \201 l, cy proheptadine, amantadine). Antipsychotics The prevalence of sexual dysfunction associated with antipsychotics ranges f rom 40 to 71%, with reports of problems in all groups of antipsychotic medication (usually reduced libido, impaired sexual arousal, orgasm dif- \201 culties, ejaculation problems). \200 Dysfunction may be related to dopamine blockade, histaminergic antagonism, anticholinergic effects, hyperprolactinaemia (and s decrease in estrogen and testosterone levels). Sexual s ide effects appear to be dose-dependent. 5-HT behavior. FGAs (esp. thioridazine) and risper idone can affect all phases of sexual response. Clozapine, quetiapine, and aripiprazole see m to have the lowest risk of sexual side-effects. \200 2A-blocking property of some of SGAs may facilitate sexual Management \200 \200 \200 Spontaneous remission may occasionally occur. Dose reduction where possible. Consider switc hing to a compound with less ejaculatory/erectile disturbances or to a less anticholinergic drug for disorders of arousal. Switching to a prolactin-sparing antipsychotic (e.g. quetia pine, clozapine, aripiprazole) may improve several sexual side-effects. Adjunctive treatmen t with dopamine agonists (e.g. amantadine, bromocriptine) may be tried, but evidence base i s poor. Consider use of phosphodiesterase inhibitor (e.g. sildena \201 l) for erectile dys function. A 1-blocking properties for Mood stabilizers 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 activity. Although the occurrence of sexual dys- function is estimated as 10 \200\22330%, i t is usually mild, not a source of distress, and does not lead to non-compliance. 23_Semple_Chap23.indd 939 12/7/2012 5:12:49 PM CHAPTER 23 Therapeutic issues 940 Carbamazepine and phenytoin both increase prolactin and decrease dehydroepiandrosterone and other adrenal androgen levels, making sex- ual dysfunction likely. Valproate and lamotrigine do not cause these changes, and are associated with a low likelih ood of sexual dysfunction. 23_Semple_Chap23.indd 940 12/7/2012 5:12:49 PM This page intentionally left blank CHAPTER 23 Therapeutic issues 942 Priapism Priapism1 is de \201 ned as a sustained, painful, involuntary erection that canno t be relieved by sexual intercourse or masturbation, and that is unrelated to sexual desire . Without intervention, it usually subsides within a few days, but 50 \200\22380% of affect ed men become permanently impotent. Stasis of blood for more than several hours leads to in creased blood viscosity, deoxygenation, and, ultimately, irreversible \201 brosis of corp oreal smooth muscle and cavernosal artery thrombosis. Thus, priapism is a urologic emergenc y requiring immediate intervention.2 (Clitoral priapism has also been reported and may be a ssociated with either pain and discomfort or increased libido and orgasmic response.)3 Pathophysiology Not completely understood. One proposed mechanism is penile vascu- lar dysr egulation caused by A 1-adrenergic blockade (this, in fact, blocks sympathetic stimuli resp onsible for penile detumescence), especially if in unbalance with cholinergic transmission (e.g. anticholinergic activity). Drug- induced priapism is the \200\230low \202 ow \200 \231, ischaemic form of priapism, whereby venous blood persists in the corpora cavernosa. I t is also believed to be an idiosyncratic reaction. Epidemiology Drug-induced priapism accounts for 15 \200\22341% of all cases of priapism. Risk factors History of prolonged erections, concurrent medications (see Box 23.5), chronic cocaine misuse, medical conditions (e.g. sickle cell disease, leukemia). Differential diagnosis Sickle cell disease, other medications (see Box 23.5), other rare ca uses: thalassaemia, leukemia, vasculitis, fat embolism, dialysis, prostate cancer, GU bladd er cancer, spinal cord stenosis, cauda equina compression. Investigations FBC, coagulation screen, penile blood gas analysis. Management \200 Always enquire about sexual side-effects and history of prolonged erections (50% of patient s presenting with priapism have a previous history of painless erections lasting for < 1hr) . Counsel patients about the possibility of developing priapism and educate them about the risks of leaving episodes of priapism untreated and the importance of seeking earlier treat ment (time to treatment is the single most important factor affecting outcome). Avoid psych otropics with high trazodone, sertraline, chlorpromazine, risperidone, ziprasidone) and pol ypharmacy with anticholinergic agents. Immediate intervention should involve conservative m easures such as pain control, vigorous hydration and cold compresses. 1-adrenergic antagonism (e.g. 23_Semple_Chap23.indd 942 12/7/2012 5:12:49 PM PRIAPISM 943 \200 Oral terbutaline can be tried as an early treatment. First-line therapy is intracavernosal injection of phenylephrine (the most selective and potent A penile detumescence in most pat ients if < 6hr after onset. Aspiration of blood from the penis followed by saline irrigatio n and, if necessary, injection of phenylephrine. If these interventions are unsuccessful, a diluted solution of phenylephrine may be used for irrigation. If medical interventions fai l, surgical care is warranted. Recurrent priapism can be managed with a trial of antiandrog ens (only in patients who are fully sexually mature), oral beta-agonists such as terbutalin e, a combination of prednisone and ketoconazole. 1-adrenergic agonist) that usually results in \200 Box 23.5 Drugs reported to cause priapism \200 Trazodone: 0.1% of patients taking the drug. It is typically seen within the \201 rst mon th of therapy, occurs in all age groups, and may occur even with low daily doses of 50 \200 \223100mg. Other psychotropics: quetiapine, ziprasidone, aripiprazole, chlorpromazine, thio ridazine, haloperidol, clozapine, zuclopenthixol), SSRIs (especially \202 uoxetine and se rtraline), bupropion, phenelzine, phenytoin. Other medications: calcium channel blockers), anticoagulants (heparin, warfarin), adrenergic A-blockers (prazosin, tamsulosin, terazosin) , hormones (testosterone, GnRH, tamoxifen), metoclopramide, omeprazole, intracavernosal inj ection of vasoactive drugs. trazodone-induced priapism is rare, occurring in less than antipsychotics (risperidone, olanzapine, sildena \201 l, antihypertensives (hydralazine, 1 Priapus, the son of Zeus and Aphrodite, was a god with an enormous penis who symbolized t he earth \200\231s fertility. 2 Banos JE, Bosch F, and Farre M (1989) Drug-induced priapism . Its etiology, incidence and treat- ment. Med Toxicol Adverse Drug Exp 4: 46 \200\22358. 3 Patel AG, Mukherji K, and Lee A (1996) Priapism associated with psychotropic drugs. Br J H osp Med 55: 315 \200\22319. 23_Semple_Chap23.indd 943 12/7/2012 5:12:49 PM CHAPTER 23 Therapeutic issues 944 Antipsychotic-induced Parkinsonism Essence A frequent adverse effect found in full form in at least 20% of patients treated wi th antipsychotic medication. Characterized by tremor, rigidity, and bradykinesia; the prese ntation is similar to that of idiopathic Parkinson \200\231s disease (b p. 168), although b radykinesia and resting tremor may be less prominent, micrographia, and festinant gait are less frequently observed, and symptoms are always bilateral. Is more common in elderly fema les and in those with pre-existing brain damage. Generally occurs within 4wks of treatment, is dose-dependent, and is a major cause of non-compliance. Assessment Routine inquiry and clinical examination is generally suf \201 cient to detect the onset of symptoms and should be carried out frequently in the \201 rst 3mths of treat ment. Monitoring may help establish the minimally effective dose of antipsychotic needed by individual patients, reducing discomfort and improving compliance. Pathophysiology D2 receptor blockade in the nigrostriatal pathway. Differential diagnosis Many drugs have been associated with Parkinsonism (see Box 23.5) and some may increase the likelihood of problems (e.g. prednisolone). Other differentials incl ude: idiopathic Parkinson \200\231s disease, dementia (e.g. DLB), negative symptoms of schi zophrenia, psychomotor retardation (e.g. in depression). Treatment Several strategies may be used, including: \200 \200 Dose reduction. Switching to another antipsychotic agent, e.g. clozapine/quetiapine < olanz apine/aripiprazole < risperidone (<8mg/day). Use of anticholinergic agents (e.g. procyclidi ne, orphenadrine, trihexyphenidyl) or amantadine (a dopamine agonist so beware of potential worsening of psychosis). Of note, symptoms are usually absent during sleep so night-time d ose may not be required. When treatment is by depot, there is some evidence that pipotiazin e palmitate, \202 upentixol, or zuclopenthixol decanoate may be better tolerated. Risperi done/paliperidone depot may be considered as another option. Note: anticholinergic agents are often used in younger patients. However, older patients ma y not be able to tolerate the side-effects of blurred vision, dry mouth, constipation, urin ary retention, and particularly cogni- tive impairment. This has led to the use of amantadi ne, which is better tolerated, or more frequent use of the newer antipsychotics, especially when patients already have early signs of Parkinson \200\231s disease. 23_Semple_Chap23.indd 944 12/7/2012 5:12:50 PM ANTIPSYCHOTIC-INDUCED PARKINSONISM 945 Follow-up If anticholinergics are prescribed, the need for their continued use ought to be kept under review. Their slow withdrawal should be attempted after the acute phase of treat ment, or following any lowering of antipsychotic dose, as drug-induced Parkinsonism tends t o resolve over time and addi- tional medication may no longer be ne eded. Box 23.5 Drugs reported to cause Parkinsonism \200 \200 \200 \200 \200 \200 Antidepressants (e.g. SSRIs, MAOIs, TCAs). Lithium. Anticonvulsants (e.g. carbamazepine, va lproate). Analgesics (e.g. NSAIDs, opiates). Drugs of abuse (e.g. cocaine, PCP). Cardiovasc ular drugs (e.g. amiodarone, diazoxide, diltiazem, methyldopa, metirosine, nifedipine, toca inide). GI drugs (e.g. cimetidine, domperidone, metoclopramide, prochlorperazine). Anti-inf ection drugs (e.g. aciclovir, chloroquine). Respiratory drugs (e.g. antihistamines, salbuta mol, terbutaline). Hormones (e.g. medroxyprogesterone). Cytotoxics (e.g. ciclosporin, inter ferons). Others (e.g. cyclizine, ondansetron, levodopa, tetrabenazine). \200 \200 \200 \200 23_Semple_Chap23.indd 945 12/7/2012 5:12:50 PM CHAPTER 23 Therapeutic issues 946 Akathisia Essence Akathisia derives from the Greek meaning \200\230not to sit still \200 \231 and describes an unpleasant, distressing side-effect of antipsychotic treatment. Chara cteristically manifests with a subjective component \200\224a feeling of inner restlessness (with the drive to engage in motor activity, esp. involv- ing lower limbs and trunk), and an objective component \200\224movements: such as pacing constantly; inability to stand, si t, or lie still; rocking; crossing/ uncrossing legs. Subjective distress may dominate in th e absence of any prominent motor phenomena. Clinical presentations \200 Acute akathisia antipsychotic or increasing its dose. Acute persistent akathisia Tardive ak athisia can persist or even get worse when antipsychotic medication is discontinued or redu ced. Can be associated with less intense subjective restlessness and dyskinetic movements. Is poorly responsive to anticholinergics. Pseudoakathisia with prominent negative symptoms and presents with overt motor restlessness without subjective distress. occurs within hours to weeks of commencing an \200 is the chronic form of primary akathisia. usually develops after \211 3mths of treatment and may occur in older, male, schizophrenic patients Pathophysiology Not yet fully understood. Theories include: dopaminergic/noradrenergic inte ractions (DA under-activity in the nucleus accumbens increases NE input from the locus coer uleus), imbalance of dopaminergic/serotoner- gic transmission (5-HT2A agonism inhibits DA r elease in the striatum), reduced GABAergic transmission in the globus pallidus due to dopam ine antagonism. Risk factors (see Box 23.6) Use of high-dose and/or high-potency antipsychotics, chronic us e of antipsychotics, rapid increase/sudden withdrawal of antipsychotics, use of intramuscul ar depot preparations, history of organic brain disease (e.g. dementia, alcoholism, HIV), h istory of previous akathisia, concomitant use of predisposing drugs (e.g. lithium, SSRIs). Differential diagnosis Anxiety/agitation (primary or secondary to other psychiatric disorde rs), drug withdrawal/discontinuation syndromes, acute confusional states, encephalitis/meni ngitis, Parkinsonism/dystonia/tardive dyskinesia, sero- tonergic syndrome (early symptoms), toxicity due to other drugs (e.g. recreational drugs \200\224amfetamine, MDMA, cocaine; an tidepressants; anti- histamines; sympathomimetics; salicylate), restless legs syndrome, iro n de \201 ciency anemia, endocrine disorders (e.g. thyrotoxicosis, hypo/hyper- glycaemia, phaeochromocytoma). 23_Semple_Chap23.indd 946 12/7/2012 5:12:50 PM AKATHISIA 947 Investigations FBC, LFTs, U&Es, glucose, TFTs, and urine drug screen. Management \200 Review history/medication to identify possible causative agent(s) and rule out any organic etiology. Beware of akathisia possibly leading to increase/worsening of suicidality, non-ad herence to treatment, violent behavior, substance misuse, long-term risk of tardive dyskine sia. If antipsychotic-related, treatment strategies are as follows: Change antipsychotic drug regimen \200 \200 \200 \200 Reduce dose of antipsychotic medication. Try a low-potency FGA (e.g. chlorpromazine). Switc h to SGA with low akathisia liability (e.g. quetiapine). Consider use of clozapine in cases of intractable akathisia. Add an anti-akathisia agent \200 Try beta-blocker (propanolol 40 \200\22380mg/day) or low-dose mirtazapine (5-HT2A receptor antagonist) 15mg/day as \201 rst-line. Alternative option is mianserine (15mg/day) or cyp roheptadine (8 \200\22316mg/day) (both 5-HT2A receptor antagonists). If patient has concurr ent Parkinsonism consider use of anticholinergic agents (e.g. benzatropine, orphenadrine, p rocyclidine, trihexyphenidyl). Consider benzodiazepines (e.g. clonazepam, diazepam, lorazep am) alone or with propanolol esp. in chronic akathisia. Amantadine (100mg/day) or clonidine (up to 0.15mg/day) may be tried if these treatments are ineffective. 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 dif \201 cult to treat, and it sho uld be borne in mind that therapeutic bene \201 t (e.g. of pro- pranolol) can take up to 3 mths. Follow-up \200 Once the akathisia has settled, any speci \201 c 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-t erm therapy may be necessary. Little data exists for agents other than propranolol (origina l optimism for long- term bene \201 t has not been borne out) or anticholinergics. The nee d for continued use of high-dose, high-potency antipsychotics should also be reviewed in th e light of any change in the clinical presentation of the primary psychiatric dis order. 23_Semple_Chap23.indd 947 12/7/2012 5:12:50 PM CHAPTER 23 Therapeutic issues 948 Box 23.6 Drugs reported to cause akathisia \200 Antipsychotics (usually high-potency) haloperidol, pipothiazine, prochlorperazine, promazin e, thioridazine (less likely), tri \202 uoperazine, zuclopenthixol, SGAs (risperidone/ zip rasidone/aripiprazole > olanzapine > quetiapine/clozapine). Citalopram, duloxetine, \202 uoxetine, \202 uvoxamine, Antidepressants imipramine (and other TCAs), mianserin, paroxet ine, sertraline, venlafaxine (withdrawal). Anxiolytics Others (withdrawal), metoclopramide, ondansetron, verapamil. Chlorpromazine (less likely), \200 Alprazolam, buspirone, lorazepam. Diltiazem, alpha-interferon, levodopa, lithium, melatonin 23_Semple_Chap23.indd 948 12/7/2012 5:12:50 PM This page intentionally left blank CHAPTER 23 Therapeutic issues 950