Adverse Effects during Therapeutic Use
The Extrapyramidal Syndromes
The EPS (Table 69–4) are a heterogeneous group of disorders that share the common feature of abnormal muscular activity. Among the typical antipsychotics, the incidence of EPS appears to be highest with the more potent drugs, such as haloperidol and flupentixol, and lower with less potent drugs, such as chlorpromazine and thioridazine. Atypical antipsychotics are associated with an even lower incidence of EPS. Although the physiologic mechanisms for this observation are not fully understood, several hypotheses have been put forth. In addition to the aforementioned antagonism of 5-HT2A receptors, some atypical drugs dissociate more rapidly from the D2 receptor and incite a lower degree of nigrostriatal dopaminergic hypersensitivity during chronic use.53,54,65 However, it is important to note that EPS may occur during treatment with any of the antipsychotics, typical or atypical, regardless of potency.
Table 69–4. The Extrapyramidal Syndromes |Favorite Table|Download (.pdf)
Table 69–4. The Extrapyramidal Syndromes
|Disorder||Time of Maximal Risk||Features||Postulated Mechanism||Possible Treatments|
|Acute dystonia||Hours to a few days||Sustained, involuntary muscle contraction; torticollis, lingual protrusion, blepharospasm, oculogyric crisis||Imbalance of dopaminergic/cholinergic transmission ||Anticholinergics, benzodiazepines|
|Akathisia||Hours to days||Restlessness and unease, inability to sit still||Mesocortical D2 antagonism||Dose reduction, trial of alternate drug, propranolol, benzodiazepines, anticholinergics|
|Parkinsonism||Weeks||Bradykinesia, rigidity, shuffling gait, masklike facies, resting tremor||Postsynaptic striatal D2 antagonism||Dose reduction, anticholinergics, dopamine agonists|
|Neuroleptic malignant syndrome||2–10 days||Altered mental status, motor symptoms, hyperthermia, autonomic instability (see Table 69-5)||D2 antagonism in striatum, hypothalamus, and mesocortex||Cooling, benzodiazepines, supportive care, consider dantrolene, bromocriptine, or other direct-acting dopamine agonists|
|Tardive dyskinesia||3 months—years||Late-onset involuntary choreiform movements, orobuccal, lingual, masticatory stereotypic movements||Excess dopaminergic activity||Recognize early and stop offending drug; addition of other antipsychotics; cholinergics|
Acute dystonia is a movement disorder characterized by sustained involuntary muscle contractions, often involving the muscles of the head and neck, including the extraocular muscles and the tongue but occasionally involving the extremities. These contractions are sometimes referred to as limited reactions, reflecting their transient nature rather than their severity. All of the currently available antipsychotics are associated with the development of acute dystonic reactions.107 Spasmodic torticollis, facial grimacing, protrusion of the tongue, and oculogyric crisis are among the more common manifestations. Laryngeal dystonia is a rare but potentially life-threatening variant that is easily misdiagnosed because it may present with throat pain, dyspnea, stridor, and dysphonia rather than the more characteristic features of dystonia.37
Acute dystonia typically develops within a few hours of starting treatment but may be delayed for several days. Left untreated, dystonia resolves slowly over several days after the offending xenobiotic is withdrawn. Risk factors for acute dystonia include male gender, young age (children are particularly susceptible), a previous episode of acute dystonia, and recent cocaine use.108,119 Although the reaction may appear dramatic and sometimes is mistaken for seizure activity, it is rarely life threatening. Of note, xenobiotics other than antipsychotics, particularly metoclopramide, the antidepressants, some antimalarials, histamine H2 receptor antagonists, anticonvulsants, and cocaine, may sometimes cause acute dystonia.108
Treatment of Acute Dystonia
Acute dystonia is generally more distressing than serious, but in rare cases, it may compromise respiration, necessitating supplemental oxygen and, occasionally, assisted ventilation.37,108 The response to parenteral anticholinergics often is rapid and dramatic, and every effort should be made to administer benztropine as the first-line agent (2 mg intravenously [IV] or intramuscularly [IM] in adults; 0.05 mg/kg up to 2.0 mg in children). Often, diphenhydramine is more readily available and can be used instead (50 mg IV or IM in adults; 1 mg/kg up to 50 mg in children). Parenteral benzodiazepines such as lorazepam (0.05–0.10 mg/kg IV or IM) or diazepam (0.1 mg/kg IV) should be considered if patients do not respond to anticholinergics, but it may also be used effectively as initial therapy. It is important to recognize that because the elimination half-lives of most anticholinergics are shorter than those of most antipsychotics, dystonia may recur, and administering additional doses of anticholinergics may be necessary over the subsequent 48 to 72 hours.27 Patients in whom acute dystonia jeopardizes respiration should be observed for at least 12 to 24 hours after initial resolution.
Akathisia (from the Greek phrase "not to sit") is characterized by a feeling of inner restlessness, anxiety, or sense of unease, often in conjunction with the objective finding of an inability to sit still. Patients with akathisia frequently appear uncomfortable or fidgety. They may rock back and forth while standing or may repeatedly cross and uncross their legs while seated. Akathisia can be difficult to diagnose and is easily misinterpreted as a manifestation of the underlying psychiatric disorder rather than an adverse effect of therapy.
Akathisia is common and may be an important determinant of a failure to adhere to therapy. Similar to acute dystonia, akathisia tends to occur relatively early in the course of treatment and coincides with peak serum antipsychotic concentrations.119 The incidence appears highest with typical, high-potency antipsychotics and lowest with atypical antipsychotics. Although most cases develop within days to weeks after initiation of treatment or an increase in dose, a delayed-onset (tardive) variant is also recognized.
The pathophysiology of akathisia is incompletely understood but appears to involve antagonism of postsynaptic D2 receptors in the mesocortical pathways.65,107 Interestingly, a similar phenomenon has been described in patients after the initiation of treatment with antidepressants, particularly the selective serotonin reuptake inhibitors.8,62
Akathisia may be difficult to treat. A reduction in the antipsychotic dose is sometimes helpful, as is substitution of another (generally atypical) antipsychotic. Treatment with lipophilic β-adrenergic antagonists such as propranolol may reduce the symptoms of akathisia, but there is little evidence supporting their use.60,77 Benzodiazepines produce short-term relief, and anticholinergics such as benztropine or procyclidine may reduce symptoms of akathisia, but they are more likely to be effective for akathisia induced by antipsychotics with little or no intrinsic anticholinergic activity.20,61
Parkinsonism is thought to result from antagonism of postsynaptic D2 receptors in the striatum107 and is characterized by rigidity, akinesia or bradykinesia, and postural instability. It is similar to idiopathic Parkinson's disease, although the classic "pill-rolling" tremor is often less pronounced.77 The syndrome typically develops during the first few months of therapy, particularly with high-potency antipsychotics. It is more common among older women, and in some patients, it may represent iatrogenic unmasking of latent Parkinson's disease.
Treatment of Xenobiotic-Induced Parkinsonism
The risk of xenobiotic-induced parkinsonism may be minimized by using the lowest effective dose of an antipsychotic. The addition of an anticholinergic often attenuates symptoms at the expense of additional side effects. This strategy often is effective in younger patients, although the routine use of prophylactic anticholinergics is not recommended. Addition of a dopamine agonist, such as amantadine, is sometimes used, particularly in older patients who may be less tolerant of anticholinergics, but this may aggravate the underlying psychiatric disturbance.63
The term tardive dyskinesia was coined in 1952 to describe the delayed onset of persistent orobuccal masticatory movements occurring in three women after several months of antipsychotic therapy.107 The adjective tardive, or late, was used to distinguish these movement disorders from the parkinsonian movements described above. The incidence of tardive dyskinesia in younger patients is approximately 3% to 5% per year but increases considerably with age. A prospective study of older patients treated with high-potency typical antipsychotics identified a 60% cumulative incidence of tardive dyskinesia after 3 years of treatment.50 Potential risk factors for tardive dyskinesia include alcohol use, affective disorder, prior electroconvulsive therapy (ECT), diabetes mellitus, and various genetic factors.107
Several distinct tardive syndromes are recognized, including the classic orobuccal lingual masticatory stereotypy, chorea, dystonia, myoclonus, blepharospasm, and tics. The atypical antipsychotics are generally believed to be responsible for a lower incidence of tardive dyskinesia and other drug-related movement disorders. However, whether this is true of all atypical antipsychotics is unclear. Among the atypical antipsychotics, clozapine is associated with the lowest incidence of tardive dyskinesia and risperidone with the highest incidence (when higher doses are used), but the reasons for this observation are uncertain.104,105,107
Treatment of Tardive Dyskinesia
Tardivedyskinesia is highly resistant to the usual pharmacologic treatments for movement disorders. Anticholinergics do not alleviate tardive dyskinesia and may worsen it. Calcium channel blockers, β-adrenergic antagonists, benzodiazepines, and vitamin E have all been used with only limited supporting evidence.35 Clozapine appears to temporarily suppress tardive dyskinesia. Although discontinuation of the causative drug may not produce total relief of symptoms, when possible, the antipsychotic should be discontinued as soon as signs or symptoms begin.
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS) is a potentially life-threatening drug-induced emergency. First described in 1960 in patients treated with haloperidol, this syndrome has been associated with virtually every antipsychotic 31 because the reported incidence of NMS ranges from 0.2% to 1.4% of patients receiving antipsychotics,2,23,103 but less severe episodes may go undiagnosed or unreported. As a result, much of the epidemiology and treatment of NMS is speculative and based only on case reports and case series.
The pathophysiology of NMS is incompletely understood but appears to involve abrupt reductions in central dopaminergic neurotransmission in the striatum and hypothalamus, altering the core temperature "set point"41 and leading to impaired thermoregulation and other manifestations of autonomic dysfunction. Blockade of striatal D2 receptors contributes to muscle rigidity and tremor.13,25,109 In some cases, a direct effect on skeletal muscle may play a role in the pathogenesis of hyperthermia.41 Altered mental status is multifactorial and may reflect hypothalamic and spinal dopamine receptor antagonism, a genetic predisposition, or the direct effects of hyperthermia and other drugs.42 Serotonin also appears to play a role in the pathogenesis of NMS because antipsychotics that antagonize 5-HT2A receptors seem to be associated with a lower incidence of NMS.4
Although NMS most often occurs during treatment with a D2 receptor antagonist, withdrawal of dopamine agonists may produce an indistinguishable syndrome. The latter typically occurs in patients with long-standing Parkinson's disease who abruptly change or discontinue treatment with dopamine agonists such as levodopa/carbidopa, amantadine, or bromocriptine.13 The resulting disorder is sometimes referred to as the parkinsonian-hyperpyrexia syndrome, and mortality rates of up to 4% are reported.71 Hospitalization for aspiration pneumonia, a common occurrence in older patients with Parkinson's disease, is a particularly high-risk setting for this complication and is particularly dangerous because the cardinal manifestations of NMS are easily misattributed to the combined effects of pneumonia and the underlying movement disorder.
The vast majority of NMS cases occur in the context of therapeutic use of antipsychotics rather than after overdose. Postulated risk factors for the development of NMS include young age, male gender, extracellular fluid volume contraction, use of high-potency antipsychotics, use of depot preparations, cotreatment with lithium, use of multiple drugs in combination, and rapid dose escalation.2,24,58
The manifestations of NMS include the tetrad of altered mental status, muscular rigidity or "lead pipe" rigidity, hyperthermia, and autonomic dysfunction. These symptoms may appear in any sequence, although in a review of 340 NMS cases, mental status changes and rigidity usually preceded the development hyperthermia and autonomic instability.110 Signs typically evolve over a period of several days, with the majority occurring within 2 weeks of starting treatment. However, it is important to recognize that NMS may occur even after prolonged use of an antipsychotic, particularly after a dose increase, the addition of another xenobiotic, or the development of intercurrent illness. It is also worth noting that the clinical course of NMS may fluctuate with remarkable rapidity, sometimes waxing and waning dramatically over a few hours.
There are no universally accepted criteria for the diagnosis of NMS, and at least four different sets of criteria have been proposed.3,23,33,58 The operating characteristics of these criteria have not been formally evaluated partly because of the absence of a gold standard. The criteria set forth by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) are perhaps the most widely cited, but their principal limitation is that they make no provision for a causal relationship with xenobiotics other than antipsychotics.33 Because NMS is an uncommon and potentially life-threatening disorder with highly variable clinical manifestations, an algorithmic approach to diagnosis in inadvisable. Rather, clinicians should be aware of its many possible clinical and laboratory features (Table 69–5) and entertain the possibility of NMS in any unwell patient receiving an antipsychotic, particularly when altered mentation, unexplained fever, or muscle rigidity is present, particularly in the setting of recent modifications to the antipsychotic regimen.
Table 69–5. Clinical and Laboratory Features of the Neuroleptic Malignant Syndrome2,24,58,110 |Favorite Table|Download (.pdf)
Table 69–5. Clinical and Laboratory Features of the Neuroleptic Malignant Syndrome2,24,58,110
|Altered mental status||Delirium, lethargy, confusion, stupor, catatonia, coma|
|Motor symptoms||"Lead pipe" rigidity, cogwheeling, dysarthria or mutism, parkinsonian syndrome, akinesia, tremor, dystonic posture, dysphagia, dysphonia, choreiform movements|
|Hyperthermia||Temperature >100.4°F (38°C)|
|Autonomic instability||Tachycardia, diaphoresis, sialorrhea, incontinence, respiratory irregularities, cardiac dysrhythmias, hypertension or hypotension|
|Laboratory findings||Increased muscle enzymes (creatine phosphokinase, lactate dehydrogenase, aldolase), leukocytosis, renal insufficiency (reflecting volume contraction and pigment nephropathy), acidemia, myoglobinuria, aminotransferase elevation, hypoxia, hyponatremia, increased prothrombin time/partial thromboplastin time|
It may be difficult to distinguish NMS from other toxin-induced hyperthermia syndromes, such as the anticholinergic (antimuscarinic) syndrome (see Chap. 50) and the serotonin syndrome (see Chap. 72), all of which share the common features of elevated temperature, altered mental status, and neuromuscular abnormalities. The most important differentiating feature is the medication history, with dopamine antagonists, antimuscarinics, and direct or indirect serotonin agonists (often in combination) as the most likely causes, respectively. Other helpful distinguishing features include the time course (NMS typically develops more gradually than serotonin syndrome and the antimuscarinic syndrome, both of which are characterized by a rapid onset) and the nature of neuromuscular abnormalities. Specifically, serotonin syndrome is characterized by myoclonus (spontaneous or inducible), shivering, and hyperreflexia, which occur rarely in patients with NMS. Because skeletal muscle contraction is governed by nicotinic rather than muscarinic acetylcholine receptors, patients with the antimuscarinic syndrome have few muscular abnormalities. However, patients with prominent CNS features may be highly resistant to physical restraint, giving the appearance of increased muscle tone.
Treatment of Neuroleptic Malignant Syndrome: General Measures
Treatment recommendations are largely based on general physiologic principles, case reports, and case series. Therapy should be individualized according to the severity and duration of illness and the modifying influences of comorbidity.13,84,111
Good supportive care is the cornerstone of treatment of NMS. It is essential to recognize the condition as an emergency and to withdraw the offending xenobiotic immediately. When NMS ensues after abrupt discontinuation of a dopamine agonist such as levodopa, the drug should be reinstituted promptly. All patients with NMS should be admitted to an intensive care unit. Supplemental oxygen should be administered, and assisted ventilation may be necessary in cases of respiratory failure, which may result from central hypoventilation, loss of protective airway reflexes, or rigidity of the chest wall muscles.
The hyperthermia associated with NMS is multifactorial in origin and, when present, should be treated aggressively. For patients with severe hyperthermia, it is difficult to overstate the importance of normalizing body temperature. Submersion in an ice-water bath is the most rapidly efficient technique, although this may be impractical in some settings (see Chap. 15). Other strategies include the use of active cooling blankets; the placement of ice packs in the groin and axillae; or evaporative cooling, which can be accomplished by removing the patient's clothing and exposing the patient to cooled water or towels immersed in ice water while maintaining constant air circulation with the use of fans.115
Hypotension should be treated initially with volume resuscitation with 0.9% sodium chloride solution followed by vasopressors if necessary. Alkalinization of the urine with sodium bicarbonate may reduce the incidence of myoglobinuric renal failure in patients with high creatine phosphokinase concentrations, but maintenance of intravascular volume and adequate renal perfusion are of far greater importance. Tachycardia does not require specific treatment, but bradycardia may necessitate the use of transcutaneous or transvenous electrical pacing. Venous thromboembolism is a major cause of morbidity and mortality in patients with NMS, and prophylactic doses of low-molecular-weight heparin should be considered in patients who likely will be immobilized for more than 12 to 24 hours.
Pharmacologic Treatment of Neuroleptic Malignant Syndrome
Benzodiazepines are the most widely used pharmacologic adjuncts for treatment of NMS and are considered first line-therapy. Despite the length of time that they have been available and recommended by many, dantrolene and bromocriptine are not well studied, and their incremental benefit over good supportive care is debated.84,89 However, these drugs are associated with relatively little toxicity, and the absence of definitive evidence should not preclude their use, particularly in patients with moderate or severe NMS.
Benzodiazepines are frequently used in the management of patients with NMS because of their rapid onset of action, which is particularly important when patients are agitated or restless. Benzodiazepine actions are nonspecific in nature, but they presumably attenuate the sympathetic hyperactivity that characterizes NMS by facilitating GABA-mediated chloride transport and producing neuronal hyperpolarization in a fashion analogous to their beneficial effects in cocaine toxicity.42 The primary disadvantage of benzodiazepines is that they may cloud the assessment of mental status.
Dantrolene reduces skeletal muscle activity by inhibiting ryanodine receptor calcium release channels, thereby interfering with calcium release from the sarcoplasmic reticulum. In theory, this process should reduce body temperature and total oxygen consumption and lessen the risk of myoglobinuric renal failure. Dantrolene may be particularly useful when muscular rigidity is a prominent feature of NMS.13 It may be given by mouth (50–100 mg/d) or by IV infusion (2–3 mg/kg/d or ≥10 mg/kg/d in severe cases), although the latter requires laborious reconstitution. A recent review of 271 published cases of NMS that included information regarding drug treatment found that combination therapy including dantrolene was associated with a prolonged clinical recovery but also found that dantrolene monotherapy was associated with higher mortality rate than other treatment modalities including supportive care.84 However, it is extremely difficult to draw meaningful conclusions regarding the effectiveness of dantrolene from this study in light of its design. Dantrolene is a relatively nontoxic drug suggested by some to be a reasonable therapeutic agent in patients with NMS, particularly those with prominent rigidity, although there is inadequate supportive evidence (see Antidote in Depth A22: Dantrolene Sodium).
Bromocriptine is a centrally acting dopamine agonist that is given orally or by nasogastric tube at doses of 2.5 to 10 mg three to four times a day. The rationale for its use rests in the belief that reversal of antipsychotic-related striatal D2 antagonism will ameliorate the manifestations of NMS. Other dopamine agonists anecdotally associated with success include levodopa74,99 and amantadine.40,49,103 An important consideration with dopaminergic agents, however, is that their use may be associated with exacerbation of the underlying psychiatric illness. There is no current evidence to support their use at this time.
ECT has been reported to dramatically improve the manifestations of NMS, presumably by enhancing central dopaminergic transmission. In one report, five patients received an average of 10 ECT treatments, and resolution generally occurred after the third or fourth session.73 Whether this result represents a true effect of ECT or simply the natural course of NMS with good supportive care alone is not clear. As with drug therapies for NMS, the efficacy of ECT remains unclear and its indications speculative, but its use seems reasonable in patients with severe, persistent, or treatment-resistant NMS and for those with residual catatonia or psychosis after resolution of other manifestations.13,74
Adverse Effects on Other Organ Systems
Sedation, dry mouth, and urinary retention occur commonly with the antipsychotics, particularly during the initial period of therapy. These symptoms occur most commonly with drugs that have potent antihistaminic and antimuscarinic activity. All antipsychotics can lower the seizure threshold, but seizures rarely complicate therapeutic use in patients without additional risk factors. Because hypothalamic dopamine normally inhibits prolactin release by the pituitary gland, hyperprolactinemia and galactorrhea may occur, although these are more common with atypical antipsychotic drugs.
All antipsychotics are associated with weight gain, dyslipidemia, steatohepatitis, and rare but dramatic instances of glucose intolerance, including fatal cases of diabetic ketoacidosis.6,44,80,106 The mechanisms of the lipid and carbohydrate effects are incompletely understood and not adequately explained solely by the weight gain associated with antipsychotic therapy because glucose disturbances often develop shortly after therapy is instituted. Other idiosyncratic reactions reported with use of antipsychotics include photosensitivity, skin pigmentation and cholestatic hepatitis (which occur with the phenothiazines), myocarditis, and agranulocytosis (which occurs with several drugs but most notably clozapine, ie, between 0.38% and 2% of patients).68 Most of these conditions result from an immunologically based hypersensitivity reaction and develop during the first month of therapy.
Antipsychotic overdose may produce a spectrum of manifestations affecting multiple organ systems, but most serious toxicity involves the CNS and cardiovascular system. Some of these manifestations are present to a minor degree during therapeutic use. They tend to be most pronounced during the early period of therapy but dissipate with continued use.
Impaired consciousness is a common and dose-dependent feature of antipsychotic overdose, ranging from somnolence to coma. It may be associated with impaired airway reflexes, but significant respiratory depression is uncommon. Many antipsychotics, including several of the atypical drugs, are potent muscarinic antagonists and may produce dramatic anticholinergic manifestations in overdose.11,21,26 Peripheral manifestations include tachycardia, decreased production of sweat and saliva, flushed skin, urinary retention, diminished bowel sounds, and mydriasis, although miosis also occurs. These findings may be present in isolation or coexist with central manifestations, which may be highly variable and may be mistakenly attributed to the underlying psychiatric illness. These manifestations include agitation, delirium, psychosis, hallucinations, and coma.
Mild elevations in body temperature are common and reflect impaired heat dissipation because of impaired sweating and increased heat production in agitated patients. Elevations in body temperature should always prompt a search for other manifestations of NMS. Tachycardia is a common finding in patients with antipsychotic overdose and reflects peripheral anticholinergic effects as well as a compensatory response to hypotension. Bradycardia is distinctly uncommon. Although it may be a preterminal event, its presence should prompt a search for alternate causes, including β-adrenergic antagonists, calcium channel blockers, cardioactive steroids, opioids, and myocardial ischemia. Hypotension is a common feature of antipsychotic overdose. Peripheral α1-adrenergic blockade reduces vasomotor tone. Central maintenance of vasomotor tone may be impaired, albeit by an unknown mechanism.
The electrocardiographic (ECG) manifestations of antipsychotic overdose are similar to those of CA toxicity (see Chaps. 22 and 73) and include prolongation of the QRS complex and a rightward deflection of the terminal 40 msec of the QRS complex (T40msec, a tall, broad terminal component of the QRS complex in lead aVR). These changes reflect blockade of the inward sodium current (INa). Prolongation of the QT interval results from blockade of the delayed rectifier potassium current (IKr), creating a substrate for development of torsades de pointes.70 This situation is sometimes evident during maintenance therapy and may underlie the apparent increase in sudden cardiac death among users of antipsychotics.81,83 A published meta-analysis of the operating characteristics of the ECG in patients with cyclic antidepressant toxicity found the ECG was a relatively poor predictor of seizures, dysrhythmia, and death.7 However, the ECG is a dynamic instrument, particularly in the initial hours after overdose, and few studies have evaluated longitudinal changes in the ECG.59