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 Tardive dyskinesia Essence Late onset (mean 7yrs), involuntary, repetitive, purposeless mov ements, occurring with long-term antipsychotic treatment (although also has been reported i n untreated schizophrenic patients). Importantly, patients are often unaware of the movemen ts, which are \201 rst detected by friends and family members. Operational diagnostic cri teria are \211 1 movement of mod- erate intensity or \211 2 movements of mild intensity a fter at least 3mths (1mth if > 60yrs) of antipsychotic treatment or within 4wks (8wks for d epot) of its discontinuation. Symptoms/signs Peri-oral movements are the most common (e.g. tongue, lips, jaw), hence the alternative terms: oral \200\223lingual, orofacial, oro \200\223bucco \200\223facial, or bu ccal \200\223 lingual \200\223masticatory dyskinesia. Other movements may include: axial \200\224 trunk twisting, torticollis, retrocollis, shoulder shrugging, pelvic thrusting; li mbs \200\224rapid movements of the \201 ngers or legs, hand clenching (and sometimes chor eoathetoid movements). Symptoms can be consciously suppressed, worsen with distraction, are exacerbated by stress and anti- Parkinsonian agents, and disappear during sleep. Periphera l TD is more frequently associated with comorbid acute movement disorders (akathisia, tremo r, Parkinsonism) than orofacial TD. Pathophysiology Not yet fully understood. Theories include: striatal dopaminergic/cholin- e rgic imbalance, up-regulation/supersensitivity of postsynaptic dopamine D2 receptors in the basal ganglia following chronic blockade, imbalance of D1 and D2 receptors leading to stri atal disinhibition of the thalamo- cortical pathway, striatal GABA hypofunction leading to enhanced DA transmission, Epidemiology Prevalence is 15 \200\22330% of chronically treated patients but may be as hig h as 70% in the \200\230high-risk \200\231 population. Approximately 50% of cases are reve rsible. Risk factors (see Box 23.7) Chronic use of antipsychotics (particularly in high dose), chan ge/cessa- tion of chronic treatment (especially intermittent treatment), concomitant antich olinergic treatment, elderly (over 60), female (5:4 = 1.7:1), history of organic brain dise ase (e.g. dementia, learning disability, epilepsy), previ- ous head injury, alcoholism, com orbid mood disorder, negative symptoms of schizophrenia, diabetes mellitus, history of prev ious drug-induced aka- thisia/Parkinsonism/dystonias, concomitant use of predisposing drugs (e.g. lithium, antidepressants, stimulants). Differential diagnosis Stereotypies, tic disorders, other causes of dyskinesia (e.g. Parkin son \200\231s disease or use of anti-Parkinsonian agents), hyperthyroidism (choreiform 23_Semple_Chap23.indd 950 12/7/2012 5:12:50 PM TARDIVE DYSKINESIA 951 movements of the limbs), other causes of chorea/athetoid movements (e.g. Sydenham \200\231s /Huntington \200\231s chorea, Wilson \200\231s disease), epilepsy. Investigations FBC, LFTs, U&Es, TFTs, Ca2+, serum copper, serum coeruloplasmin, ANA, ANCA. Management \200 \200 Review history/medication to identify possible causative agent(s). Reduce dose of potential causative agent, to achieve minimum effective dose that adequately controls psychotic symp toms. Anticholinergic agents will exacerbate the problem and should also be slowly reduced and stopped if possible. If residual symptoms are tolerable, it is best to \200\230wait an d see \200\231 before considering additional treatment, as TD tends to improve with time. I f residual symptoms are severe, interfere signi \201 cantly with functional abilities, or may be life-threatening, consider an alternative antipsychotic \200\224clozapine (reportedl y effective in up to 43% of refractory cases), then quetiapine > olanzapine > risperidone. Otherwise temporarily raising the dose of antipsychotic may give immediate relief, whilst a ddition of a speci \201 c treatment may be commenced (dose of antipsychotic should then be reduced again). Adjuvant agents \200 First line \200\224tetrabenazine (a monoamine-depleting agent) 25 \200\223200mg/ day, but b eware of its depressogenic effect. Dopamine agonists (e.g. low-dose bromocriptine 0.75 \200 \2237.5mg/day, levodopa [L-dopa], amantadine). Benzodiazepines (e.g. clonazepam if dystonia also present), but evidence base is poor. Calcium-channel blockers. Anticonvulsants (e.g. gabapentin, levetiracetam). Antioxidants (e.g. vitamin E, though ef \201 cacy disputed). O ther (e.g. botulinum toxin, donezepil, amino acids, ondansetron, melatonin, pyridoxine). Th ere is case report evidence for use of TMS (see \200 \200 \200 b p. 298). Course/prognosis \200 \210 30%/yr with 50% Symptoms typically wax and wane, remission rates clinically improved after 5yrs, even witho ut treatment. Response to treatment often requires the striking of a balance between reduct ion in dyskinesia vs. control of psychotic symptoms. Follow-up \200 \200 \200 Closely monitor residual symptoms. Regularly review the need for continued antipsychotic tr eatment. e notes. Clearly record TD symptoms and management plan in cas 23_Semple_Chap23.indd 951 12/7/2012 5:12:50 PM CHAPTER 23 Therapeutic issues 952 Box 23.7 Drugs reported to cause tardive dyskinesia \200 Antipsychotics SGAs (quetiapine, olanzapine, amisulpiride, risperidone). Non-antipsychotic medications: (phenelzine, sertraline, \202 uoxetine, trazodone, amitriptyline, amoxapine, imipramine), anti-emetics (metoclopramide, prochlorperazine), anti-epileptics (carbamazepi ne, phenytoin), antihistamines, lithium, amfetamines, methylphenidate, anti-Parkinson agent s (bromocriptine, L-dopa). : phenothiazines, haloperidol, loxapine, pimozide, rarely anticholinergics, antidepressants 23_Semple_Chap23.indd 952 12/7/2012 5:12:50 PM This page intentionally left blank CHAPTER 23 Therapeutic issues 954 Dystonic reactions Essence Syndrome of sustained, often painful muscular spasms, producing repeti- tive, twisting movements, or abnormal postures, that develop following exposure to antipsychotic medication. Etiology Remains unclear. Various mechanisms have been proposed such as altera- tion in dop aminergic \200\223cholinergic balance in basal ganglia or, paradoxically, increased nigrost riatal dopaminergic activity as a compensatory response to dopamine receptor blockade. Risk factors Previous/family history of dystonia, younger age group1 (rare in patients >45y rs), 4 > 5 (most likely due to use of higher doses of antipsychot- ics in men), liver failu re, clinically severe schizophrenia (esp. with marked negative symptoms), use of high-poten cy antipsychotics, hypocalcaemia, recent cocaine misuse. Acute dystonia Usually occurs within 1wk of commencing or rapidly increasing the dose of th e antipsychotic medication, or of reducing the anticholinergic medica- tion prescribed to t reat it. 50% of cases occur within 48hrs, rising to 90% within 5 days of exposure. Incidence 3 \200\22310% of patients exposed to all antipsychotics (up to 30% with high-pote ncy drugs). Symptoms/signs Muscles of head and neck are most commonly affected with torticollis, trismu s, jaw opening, forceful protrusion of the tongue, blepharospasm, grimacing, oculogyric spa sm, opisthotonus. Trunk and limbs are less commonly affected, and involvement of pharyngeal and laryngeal muscles can cause serious symptoms such as dysphagia and laryngospasm. Usual ly more generalized in younger patients (may be confused with \201 ts, esp. in children) and more localized (head and neck) in older patients. Course May \202 uctuate over hours, but most last minutes to hours without treatment. Tardive dystonia Develops days to months following exposure to dopamine receptor block- ing agents and does not improve rapidly with anticholinergic treatment. Incidence 1.5 \200\2234%. Symptoms/signs are similar to those seen in acute dystonia. It may present with a unique sy ndrome of retrocollis, opisthotonus, internal arm rotation, elbow extension with wrist \202 exion. Course tends to be chronic and symptoms can persist even when offending medication is remov ed. 23_Semple_Chap23.indd 954 12/7/2012 5:12:50 PM DYSTONIC REACTIONS 955 Differential diagnosis May resemble catatonia, tetany, temporal lobe epilepsy, malingering, con- version disorder. Management \200 \200 If severe, discontinue suspected agent. Emergency treatment with IM anticholinergic agents (e.g. procyclidine 5mg, benzatropine 2mg). Intravenous administration is necessary only if dystonic reaction is life threatening. Continue use of anticholinergic prophylactically for 5 to 7 days in addition to antipsychotic medication and taper it off over 2 \200\2233wks ( long-term treatment may predispose to TD). Consider switching to antipsychotic with low pro pensity to cause EPSEs (see Box 23.8). Alternative treatment includes use of amantadine (fe wer side-effects than other agents). Oculogyric crisis that is unresponsive to anticholiner gic drugs may bene \201 t from treatment with clonazepam. If treatment is unsuccessful che ck serum calcium concentrations in order to exclude hypocalcaemia. Routine prophylaxis shou ld be considered for patients with a history of previous drug-induced dystonic reaction. Ta rdive dystonia may respond to botulinum toxin, ECT, and deep brain stimulation (see b p. 29 9). Box 23.8 Agents reported to cause dystonias \200 Antipsychotics: \202 upentixol decanoate, haloperidol, olanzapine (rare), prochlorperazin e, quetiapine, sulpiride, risperidone (rare), alimemazine, zuclopethixol. Other psychotropi cs: benzatropine (rare), bupropion, buspirone, gabapentin, carbamazepine, cocaine (+ withdr awal), disul \201 ram (rare), mirtazapine, \202 uoxetine, midazolam, paroxetine, phenelz ine, sertraline, TCAs. Other (mostly rare/isolated cases): diphenhydramine, domperidone, er gotamine, indomethacin, metoclopramide, nifedipine, penicillamine, prochlorperazine, promet hazine, propranolol, sumatriptan. aripiprazole, clozapine (rare/abrupt withdrawal), amiodarone, azapropazone, 1 Note: in contrast with most medication side-effects, acute dystonias are more common in t he young than the elderly. This may be related to asymptomatic loss of dopaminergic neurons in later life. 23_Semple_Chap23.indd 955 12/7/2012 5:12:50 PM CHAPTER 23 Therapeutic issues 956 Neuroleptic malignant syndrome Essence A rare, life-threatening, idiosyncratic reaction to antipsychotic (and other) medication (see Box 23.9), characterized by: fever, muscular rigi dity, altered mental status, and autonomic dysfunction. Note: if diagnosed in a psychiatric setting, transfer patient to acute medi- cal services where intensive monitoring and treatment are available. Pathophysiology Theories: s to DA activity in the CNS \200\224i.e. striatum (rigidity), hyp otha- lamus (thermoregulation) \200\224by blockade of D2-receptors or d DA avail- ability; impaired Ca2+ mobilization in muscle cells leads to rigidity (like malignant hyperthermia1) ; sympathetic nervous system activation or dysfunction. Epidemiology Incidence 0.07 \200 \2230.2% (pooled data); 5:4 = 2:1. Mortality 5 \200\22320% \200\224death usually due to respiratory failure, cardiovascular co llapse, myoglobinuric renal failure, arrhythmias, or disseminated intravascular coagulation (DIC). Morbidity Rhabdomyolysis, aspiration pneumonia, renal failure, seizures, arrhythmias, DIC, respiratory failure, worsening of primary psychiatric disorder (due to withdrawal of antips ychotics). Symptoms/signs Hyperthermia (>38*C), muscular rigidity, confusion/agitation/altered level o f consciousness, tachycardia, tachypnoea, hyper/hypotension, diaphore- sis/sialorrhoea, tre mor, incontinence/retention/obstruction, creatinine kinase (CK)/urinary myoglobin, leukocyt osis, metabolic acidosis. Risk factors i Ambient temperature; dehydration; patient agitation or catatonia; rapid anti psychotic initiation/dose escalation; withdrawal of anti-Parkinsonian medication; use of hi gh-potency agents/depot IM preparations; history of organic brain disease (e.g. dementia, a lcoholism), affective disorder, previ- ous NMS; predisposing drugs (e.g. lithium, anticholi nergic agents). Differential diagnosis Catatonia (see Table 23.3); malignant hyperthermia1; encephalitis/me n- ingitis; heat exhaustion; Parkinsonism/acute dystonia; serotonergic syn- drome; toxicity due to other drugs (e.g. amfetamine, MDMA, cocaine, antidepressants, antihistamines, sympa thomimetics, salicylates); delirium tremens (DTs); rhabdomyolysis; septic shock; haemorrhag ic stroke; teta- nus; phaeochromocytoma; strychnine poisoning. Investigations FBC, blood cultures, LFTs, U&Es, calcium and phosphate levels, serum CK, uri ne myoglobin, ABGs, coagulation studies, serum/urine toxicology, CXR (if aspiration suspect ed), ECG; consider head CT (intracranial cause), LP (to exclude meningitis). 23_Semple_Chap23.indd 956 12/7/2012 5:12:51 PM NEUROLEPTIC MALIGNANT SYNDROME 957 Management \200 b p. 988) (Note: use of BDZs for acute behavioral disturbance ( restraint and IM injection may complicate the inter pretation of serum CK.) Stop any agents thought to be causative (esp. antipsychotics), or r estart anti-Parkinsonian agents. Supportive measures: oxygen, correct volume depletion/hypo tension with IV \202 uids, reduce the temperature (e.g. cooling blankets, antipyretics, c ooled IV \202 uids, ice packs, evaporative cooling, ice-water enema). Rhabdomyolysis \200 \224vigorous hydration and alkalinization of the urine using IV sodium bicarbonate to preve nt renal failure. Pharmacotherapy to reduce rigidity \200\224dantrolene (IV 0.8 \200\2232.5 mg/kg qds; PO 50 \200\223100mg bd), lorazepam (up to 5mg); 2nd line: bromocriptine (PO 2.5 \200\22310mg tds, increase to max 60mg/day), amantidine (PO 100 \200\223200mg bd); 3rd line : nifedipine; consider ECT (Note: i risk of fatal arrhythmias). Course May last 7 \200\22310 days after stopping oral antipsychotics and up to 21 days afte r depot antipsychotics (e.g. \202 uphenazine). Prognosis In the absence of rhabdomyolysis, renal failure, or aspiration pneumonia, and wit h 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). Co nsider prophylaxis (bromocriptine). Inform patient about risk of recurrence if given antips ychotic medication. Ensure this is recorded prominently in their medical notes. 23_Semple_Chap23.indd 957 12/7/2012 5:12:51 PM CHAPTER 23 Therapeutic issues 958 Box 23.9 Drugs reported to cause symptoms characteristic of NMS \200 Antipsychotics: \202 upentixol, \202 uphenazine, haloperidol, olanzapine, promazine, qu etiapine (rarely), risperidone, thioridazine. amantadine (+ withdrawal), Anti-Parkinsonian agents: anticholinergics (withdrawal), levodopa (+ withdrawal). Antidepressants: trimiprami ne, venlafaxine. Other: lithium, methylphenidate, metoclopramide, oral contraceptives. aripiprazole, chlorpromazine, clozapine (rarely), amoxapine, clomipramine, desipramine, phenelzine, carbamazepine (+ withdrawal), ganciclovir, ferrous sulfate, Table 23.3 Differentiating NMS from catatonia Feature NMS Catatonia Patient taking antipsychotics Usually Not usually 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 Catatonia symptoms. 23_Semple_Chap23.indd 958 12/7/2012 5:12:51 PM NEUROLEPTIC MALIGNANT SYNDROME 959 1 A rare disorder associated with exposure to inhaled esthetics and succinylcholine. Geneti c link- age found to chromosome 19. Possibly due to a muscle membrane defect, leading to d intracellular Ca2+ and intense muscle contractions. Temperature rises rapidly (up t o 1 C/ 5min). 23_Semple_Chap23.indd 959 12/7/2012 5:12:51 PM CHAPTER 23 Therapeutic issues 960 Serotonin syndrome (SS) Essence A rare, but potentially fatal syndrome occurring in the con text of initia- tion or dose increase of a serotonergic agent, characterized by altered men tal state, agitation, tremor, shivering, diarrhea, hyperre \202 exia, myo- clonus, ataxia, and hyperthermia. Although SSRIs are commonly linked to SS, many other drugs (e.g. amfetam ines, MAOIs, TCAs, lithium) have the potential of causing hyperserotonergic symptoms. SS ca n 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 o f serotonin: i production of serotonin due to i availability of precursors (L-tryptophan-co ntaining substances); d metabolism of serotonin (MAOIs, selegiline); i release of stored se rotonin (amfetamine, cocaine, fen \202 u- ramine, MDMA, meperidine); reuptake inhibition ( SSRIs, TCAs, SNRIs, NaSSAs, MDMA, dextromethorphan, meperidine, St John \200\231s wort); di rect stimulation of serotonin receptors (buspirone, LSD); unknown mecha- nisms (lithium). Epidemiology Incidence 71% for SSRIs (moderate/major symptoms; mild symptoms may be common, but tend to go unreported); mortality <1 in 1000 cases. Symptoms/signs (see Box 23.10) \200 \200 Psychiatric/neurological: Neuromuscular: hyperre \202 exia (usually lower rather than uppe r limbs), ataxia. hyperthermia (may be s to prolonged seizure activity, Autonomic: rigidity , or muscular hyperactivity), GI upset (nausea, diarrhea), mydriasis, tachycardia, hyper/hy potension. confusion, agitation, coma. myoclonus, rigidity, tremors (including shivering), Differential diagnosis NMS (see Table 23.4), malignant hyperthermia, infections (encephalit is/ meningitis, sepsis), metabolic disturbances, substance abuse (cocaine)/ withdrawal/over dose (LSD, PCP). Investigations FBC, U&Es, LFTs, glucose, pH, biochemistry (including calcium, magne- sium, phosphate, anion gap), CK, drug toxicology screen, CXR (if evidence of respiratory distress /possible aspiration), ECG monitoring (arrhythmia/ conduction problems \200\224prolonged QR S or QTc interval). Treatment \200 If severe, requires immediate transfer to emergency department for supportive treatment and active management. If overdose, consider gastric lavage and/or activated charcoal. IV acce ss \200\224to allow volume correction (dehydration: insensible \202 uid loss due to hyper thermia) and reduce risk of rhabdomyolysis. \200 23_Semple_Chap23.indd 960 12/7/2012 5:12:51 PM SEROTONIN SYNDROME 961 Rhabdomyolysis: Should be dealed with quickly, with emphasis on maintaining a high urine output combined with alkalinization using sodium bicarbonate (targ et urine pH of 6). If necessary, reduce the temperature (e.g. cooling blankets, antipyretic s, cooled IV \202 uids, ice packs, evaporative cooling, ice-water enema). Pharmacotherapy: Agitation, seizures, and muscular rigidity/ myoclonus best managed using a BDZ (e.g. lorazepam IV [slow] 1 \200\2232mg every 30min; clo nazepam). Serotonin receptor antagonists may be considered in selected cases (e.g. cyprohep tadine PO 4 \200\2238mg every 2 \200\2234hr [max 0.5mg/kg/day], chlorpromazine [risk of red uced seizure threshold], mirtazepine, methysergide, propranolol [mild 5-HT antagonist]). An tihypertensives are usually unnecessary unless the hypertension is persistent and clinicall y signi \201 cant (e.g. glyceryl trinitrate 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 \200\22336hrs with adequate supportive measures. Following an SSRI overdose, a patient who remains asymptomatic for sev- eral hours is unlikely to need further medical management . Box 23.10 Sternbach \200\231s diagnostic criteria1 \200 Other potential causes excluded (e.g. infection, metabolic, substance abuse, withdrawal). N o concurrent antipsychotic dose changes prior to symptom onset. At least three of the follo wing: \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Agitation/restlessness. Sweating. Diarrhea. Fever. Hyperre \202 exia. Ataxia. Mental state changes (confusion, hypomania). Myoclonus. Shivering. Tremor. 1 Sternbach H (1991) The serotonin syndrome. Am J Psychiat 148: 705 \200\22313. 23_Semple_Chap23.indd 961 12/7/2012 5:12:51 PM CHAPTER 23 Therapeutic issues 962 Table 23.4 Distinguishing SS from NMS Although the clinical presentation of these two syndromes is very simi- lar (i.e. autonomic dysfunction, alteration of mental status, rigidity, and hyperthermia), differentiation is very important as speci \201 c management may differ (e.g. use of chlorpromazine in SS, wh ich may worsen NMS) NMS SS Associated Rx Antipsychotics (idiosyncratic/normal dose) Serotonergic agents (OD/drug combination) Onset Slow (days to weeks) Rapid Progression Slow (24 \200\22372hrs) Rapid Muscle rigidity Severe ( \200\230lead pipe \200\231) Less severe Activity Bradykinesia Hyperkinesia 23_Semple_Chap23.indd 962 12/7/2012 5:12:51 PM This page intentionally left blank CHAPTER 23 Therapeutic issues 964 Antidepressant discontinuation1 syndrome Discontinuation symptoms can occur with all antide pressants and differ between antidepressant classes. However, they usually share three com- mon features: abrupt onset within days of stopping the antidepressant, a short duration wh en untreated, and quick resolution when the original antidepressant is reintroduced. It is estimated at least a third of patients experience discontinuation symptoms. They are usuall y mild and self-limit- ing but in a minority of cases they can be severe and prolonged. Clinical features2 SSRIs and related discontinuation syndrome \200 Sensory symptoms: sensations and numbness. Disequilibrium symptoms: headedness. General som atic complaints: fatigue, headache, sweating, and tremor. GI symptoms: Affective symptoms: tearfulness. Sleep disturbance: paraesthesia, visual disturbance, shock-like most common: dizziness, vertigo, and light- \202 u-like symptoms (myalgias and chills), \200 diarrhea, vomiting, and nausea/emesis. irritability, anxiety/agitation, low mood, and nightmares, vivid dreams, and insomnia. TCAs discontinuation syndrome Similar to SSRIs, but sensory and disequi- librium symptoms a re less common with TCAs. MAOIs discontinuation syndrome More severe than with other antidepressants and includes wor sening of depressive symptoms, acute confusion, hallucinations, paranoid delusions, and anx iety symptoms with depersonalization. Uncommon clinical presentations Rare syndromes such as mania/ hypomania (see b p. 308) and Parkinsonian symptoms (see b p. 945) may occur with all antidepressants. Course and duration Usually develops after 1mth of treatment, within 2 \200\2235 days after antide- pressant discontinuation or dose reduction. Onset of symptoms is unusual after mor e than 1wk. If untreated, duration is variable (1 day to 3wks). Resolution of symptoms usua lly occurs within 24hrs if antidepressant is reinstated. Etiology Not completely understood. Various underlying mechanisms have been postulated, suc h as acute decrease in synaptic serotonin in the face of down-regulated or desensitized ser otonin receptors, loss of inhibitory 5-HT tone on NE neurons, and cholinergic rebound. 23_Semple_Chap23.indd 964 12/7/2012 5:12:51 PM ANTIDEPRESSANT DISCONTINUATION SYNDROME 965 Risk factors Short half-life drugs (e.g. venlafaxine paroxetine), duration of treatment \211 8wks (plateau in incidence afterwards), high dose stopped, anxiety symp- toms at the s tart of treatment, previous history of discontinuation symp- toms, young age. Differential diagnosis Discontinuation symptoms can be misdiagnosed for: \200 \200 \200 Recurrence of depressive/anxiety symptoms. Treatment ineffectiveness due to covert non-adhe rence. Adverse reaction to new drug when switching across antidepressant classes. Other possibilities to be excluded are: \200 \200 \200 Underlying physical disorder. Withdrawal from drugs of abuse/alcohol. Mania/hypomania (timi ng of onset and symptoms such as dizziness and paraesthesia strongly suggest \200\230disco ntinuation mania \200\231). Management \200 Tapering antidepressant is recommended to reduce the risk of developing discontinuation syn drome (use of liquid preparations may be helpful in allowing greater \202 exibility). How ever, guidelines on the optimum rates of dose reduction are at best empirical (see b p. 268 ) and a cautious approach is advised (over a 4-wk period if duration of treatment \211 8wk s). If mild \200\223moderate and short-lived, symptoms can generally be tolerated by the pa tient, allowing for successful discontinuation of antidepressant. If severe, reintroduction of the original antidepressant rapidly resolves the symptoms. However, the syndrome may re cur in up to 75% of patients when the same antidepressant is later discontinued. Awareness of risk factors and symptoms of discontinuation syndrome, and education of patients prior t o stopping or tapering an antidepressant, should prevent unnecessary and expensive medical investigations. Some symptoms of moderate severity can be treated symptomatically (e.g. hyp notic for insomnia, anti-muscarinic agents for cholinergic rebound following TCA discontinu ation). For SSRI and SNRI discontinuation symptoms another option is to switch to \202 uo xetine (due to its long elimination half-life). If previous history of severe discontinuati on symptoms and poor adherence to treatment, choice of antidepressant with low propensity t o cause discontinuation symptoms (e.g. \202 uoxetine) should be considered. 1 The term \200\230discontinuation \200\231 is usually preferred to \200\230withdrawal \200\231 since the latter implies depend- ence and there is no evidence antidepressants hav e a signi \201 cant dependence liability according to internationally accepted criteria. 2 Haddad PM and Anderson IM (2007) Recognizing and managing antidepressant discontinuation s ymptoms. Adv Psychiat Treat 13: 447 \200\22357. 23_Semple_Chap23.indd 965 12/7/2012 5:12:51 PM CHAPTER 23 Therapeutic issues 966 Hyponatraemia and antidepressants Essence Low serum sodium (Na+<135mmol/L) is a rare, idiosyncratic side-effect of all antide pressants which may have serious consequences if undiagnosed. It is probably not dose-relat ed and its onset usually occurs within the \201 rst month of treatment. Etiology Incompletely understood, but probably due to the syndrome of inap- propriate secre tion of anti-diuretic hormone (SIADH) with resultant euvolaemic hypotonic hyponatraemia. It has been postulated serotonin may be involved in the regulation of ADH release. Risk factors Previous SIADH, history of hyponatraemia; low BMI, female gender, age >80yrs; physical co-morbidity: diabetes mellitus, hypertension, head injury, hypothyroidism, impair ed renal function, COAD; other medications (e.g. thiazides > loop diuretics, chemotherapy, NSAIDs, carbamazepine). Antidepressants \200 Highest risk (>1% incidence) sertraline. Medium risk (0.5 \200\2231% incidence) dosulepine, doxepine, imipramine, lofepramine, moclobemide, paroxetine, venlafaxine. Lowest risk trany lcypromine, mirtazepine, reboxetine. : citalopram, escitalopram, \202 uoxetine, : amitriptyline, clomipramine, (<0.5% incidence): nortriptyline, trazodone, phenelzine, Clinical features Depend upon the severity, duration, and rate of change in serum sodium. M ay be asymptomatic, or display symptoms and signs ranging from nausea, muscle cramps/weakne ss, malaise to hypertension, lethargy, confusion, and, if severe, seizures and coma. Investigations Check renal, hepatic, cardiac, thyroid, adrenal function; volume status; ser um lipids and protein (to exclude pseudohyponatraemia); serum glu- cose (raised in hyperton ic hyponatraemia); urine osmolality (>100mOsm/L indicates impaired free water excretion); s erum osmolality; urinary sodium concentration (usually >20 \200\22340mmol/L with SIADH). Differential diagnosis \200 Psychogenic polydipsia \200 Severe malnutrition. \200 Ant ipsychotic-induced hyperlipidaemia/hyperglycaemia). ; alcoholism. Cirrhosis Nephrotic syndr ome Malignancy, . (water intoxication, SIADH, severe \200 \200 , heart failure. e.g. lung small-cell, pancreas, prostate, lymphoma. 23_Semple_Chap23.indd 966 12/7/2012 5:12:51 PM HYPONATRAEMIA AND ANTIDEPRESSANTS 967 CNS disorders, subdural hemorrhage, head injury, Guillain \200\223Barr , vasculitis. Respi ratory disorders, Endocrine/metabolic hypoadrenalism, pituitary insuf \201 ciency, porphyr ia. Drugs, carbamazepine, NSAIDs, MDMA. e.g. meningoencephalitis, abscess, stroke, subarachnoid/ \200 e.g. TB, pneumonia, abscess, aspergillosis. disease, e.g. severe hypothyroidism, e.g. opiates, chlorpropramide, cytotoxic agents, diuretics, Management Prevention Baseline U&Es prior to commencing antidepressant, with moni- toring f or those at high risk (at 2 and 4wks, then every 3mths). Treatment \200 + is <125mmol/L: refer to specialist medical care and If serum Na withdraw offending agent immediately. If serum Na >135mmol/L. Consider a lower risk antidepressant (mirtazepine appears to have the lowest risk) or, if treatment urgent, ECT may be an option. Consider \202 uid restriction and/or careful use of demeclocycline under specialist advice. If necessary, rechallenge may be possible without recurrence (low dose, gradual increase, close monitoring). + is >125mmol/L: continue to monitor U&Es daily until 23_Semple_Chap23.indd 967 12/7/2012 5:12:51 PM CHAPTER 23 Therapeutic issues 968 Prescribing in pregnancy Data is limited (and often con \202 icting) regarding the safety of psychotropic drugs in pregnancy. There have been reports that psychotropics may be assoc iated with an increased risk of birth defects or neonatal adverse events. However, also unt reated mental illness during pregnancy is an independent risk factor for major congenital m alformations (MCMs) and obstetric complications (see Box 23.11 for guidance). Antipsychotics \200 Based on the available evidence no de \201 nitive association has been found between in ut ero antipsychotic exposure and an increased rate of MCMs and abnormal postnatal development . FGAs are usually considered to have minimal teratogenic potential. For SGAs, most evidenc e is with olanzapine and clozapine (increased rate of gestational diabetes, but no increase d risk of MCMs). Depot formulations and anticholinergic drugs should be avoided. \200 Antidepressants \200 Untreated affective illness in pregnant women may be associated with an increased risk of p re-term delivery, low birth weight, and poorer long-term developmental outcomes. TCAs and S SRIs do not seem to be major teratogens but can cause neonatal withdrawals (agitation, irri tability) if used in 3rd trimester. Among TCAs, nortriptyline is recommended since it is le ss anticholinergic and hypotensive than amitriptyline and imipramine. SSRIs (most experienc e is with \202 uoxetine; less safe is paroxetine) may be associated with low birth weight , spontaneous abortion and, if used in 3rd trimester, neonatal pulmonary hypertension. MAOI s and other antidepressants should be avoided. Anxiolytics \200 Neonatal respiratory depression, hypothermia, hypotonia ( \200\230 \202 oppy baby syndrome \200\231) and withdrawal syndromes may occur when benzodiazepines (BDZs) are used close to delivery. High doses and use in the 1st trimester increase the teratogenic risk. There may be an association between 1st trimester exposure to BDZs (esp. diazepam) and an increased risk of facial clefts. Short-term use and minimum effective dose are recommended if BDZs ar e necessary. Promethazine is often preferred. NICE advises the use of low-dose chlorpromazi ne and amitriptyline. \200 Mood stabilizers \200 