Side Effects - Psychopharmacology

Side Effects

Extrapyramidal Side Effects. Extrapyramidal symptoms (EPS), serious neurologic symptoms, are the major side effects of antipsychotic drugs. They include acute dysto-nia, pseudoparkinsonism, and akathisia. Although often collectively referred to as EPS, each of these reactions has distinct features. One client can experience all the reactions in the same course of therapy, which makes distinguishing among them difficult. Blockade of D2 receptors in the midbrain region of the brain stem is responsible for the development of EPS. Conventional antipsychotic drugs cause a greater incidence of EPS than do atypical antipsychotic drugs, with ziprasidone (Geodon) rarely causing EPS (Daniel, Copeland, & Tamminga, 2006).

Therapies for acute dystonia, pseudoparkinsonism, and akathisia are similar and include lowering the dosage of the antipsychotic, changing to a different antipsychotic, or administering anticholinergic medication (discussion to follow). Whereas anticholinergic drugs also produce side effects, atypical antipsychotic medications are often pre-scribed because the incidence of EPS side effects associ-ated with them is decreased.

Acute dystonia includes acute muscular rigidity and cramping, a stiff or thick tongue with difficulty swallow-ing, and, in severe cases, laryngospasm and respiratory dif-ficulties. Dystonia is most likely to occur in the first week of treatment, in clients younger than 40 years, in males, and in those receiving high-potency drugs such as halo-peridol and thiothixene. Spasms or stiffness in muscle groups can produce torticollis (twisted head and neck), opisthotonus (tightness in the entire body with the head back and an arched neck), or oculogyric crisis (eyes rolled back in a locked position). Acute dystonic reactions can be painful and frightening for the client. Immediate treatment with anticholinergic drugs, such as intramuscular benztro-pine mesylate (Cogentin) or intramuscular or intravenous diphenhydramine (Benadryl), usually brings rapid relief.

Table 2.4 lists the drugs, and their routes and dosages, used to treat EPS. The addition of a regularly scheduled oral anticholinergic such as benztropine may allow the client to continue taking the antipsychotic drug with no further dystonia. Recurrent dystonic reactions would necessitate a lower dosage or a change in the antipsychoticdrug.

 Drug-induced parkinsonism, or pseudoparkinsonism, is often referred to by the generic label of EPS. Symptoms resemble those of Parkinson’s disease and include a stiff, stooped posture; mask-like facies; decreased arm swing; a shuffling, festinating gait (with small steps); cogwheel rigid-ity (ratchet-like movements of joints); drooling; tremor; bradycardia; and coarse pill-rolling movements of the thumb and fingers while at rest. Parkinsonism is treated by changing to an antipsychotic medication that has a lower incidence of EPS or by adding an oral anticholinergic agent or amantadine, which is a dopamine agonist that increases transmission of dopamine blocked by the antipsychotic drug.

Akathisia is reported by the client as an intense need to move about. The client appears restless or anxious and agitated, often with a rigid posture or gait and a lack of spontaneous gestures. This feeling of internal restlessness and the inability to sit still or rest often leads clients to discontinue their antipsychotic medication. Akathisia can be treated by a change in antipsychotic medication or by the addition of an oral agent such as a beta-blocker, anti-cholinergic, or benzodiazepine.

Neuroleptic Malignant Syndrome. Neuroleptic malignant syndrome (NMS) is a potentially fatal idiosyncratic reac-tion to an antipsychotic (or neuroleptic) drug. Although the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (American Psychiatric Associa-tion, 2000) notes that the death rate from this syndrome has been reported at 10% to 20%, those figures may have resulted from biased reporting; the reported rates are now decreasing. The major symptoms of NMS are rigidity; high fever; autonomic instability such as unstable blood pres-sure, diaphoresis, and pallor; delirium; and elevated levels of enzymes, particularly creatine phosphokinase. Clients with NMS usually are confused and often mute; they may fluctuate from agitation to stupor. All antipsychotics seem to have the potential to cause NMS, but high dosages ofhigh-potency drugs increase the risk. NMS most often occurs in the first 2 weeks of therapy or after an increase in dosage, but it can occur at any time.

Dehydration, poor nutrition, and concurrent medical illness all increase the risk for NMS. Treatment includes immediate discontinuance of all antipsychotic medica-tions and the institution of supportive medical care to treat dehydration and hyperthermia until the client’s physical condition stabilizes. After NMS, the decision to treat the client with other antipsychotic drugs requires full discussion between the client and the physician to weigh the relative risks against the potential benefits of therapy.

Tardive Dyskinesia. Tardive dyskinesia (TD), a syndro me of permanent involuntary movements, is most commonly caused by the long-term use of conventional antipsychotic drugs. About 20% to 30% of patients on long-term treatment develop symptoms of TD (Sadock & Sadock, 2008). The pathophysiology is still unclear, and no effective treatment has been approved for general use. However, Woods, Saksa, Baker, Cohen, and Tek (2008) report success in treating TD with levetiracetam in clinical trials. The symptoms of TD include involuntary movements of the tongue, facial and neck muscles, upper and lower extremities, andtruncal musculature. Tongue thrusting and protruding, lip smacking, blinking, grimacing, and other excessive unnec-essary facial movements are characteristic. After it has devel-oped, TD is irreversible, although decreasing or discontinuing antipsychotic medications can arrest its progression. Unfor-tunately, antipsychotic medications can mask the beginning symptoms of TD; that is, increased dosages of the antipsy-chotic medication cause the initial symptoms to disappear temporarily. As the symptoms of TD worsen, however, they “break through” the effect of the antipsychotic drug.

Preventing TD is one goal when administering antipsy-chotics. This can be done by keeping maintenance dosages as low as possible, changing medications, and monitoring the client periodically for initial signs of TD using a stan-dardized assessment tool such as the Abnormal Involun-tary Movement Scale . Clients who have already developed signs of TD but still need to take an antipsychotic medication often are given one of the atypi-cal antipsychotic drugs that have not yet been found to cause or, therefore, worsen TD.

Anticholinergic side effects

Often occur with the use of antipsychotics and include orthostatic hypotension, dry mouth, constipation, urinary hesitance or retention, blurred near vision, dry eyes, pho-tophobia, nasal congestion, and decreased memory. These side effects usually decrease within 3 to 4 weeks but do not entirely remit. The client taking anticholinergic agents for EPS may have increased problems with anticholinergic side effects. Using calorie-free beverages or hard candy may alleviate dry mouth; stool softeners, adequate fluid intake, and the inclusion of grains and fruit in the diet may prevent constipation.

Other Side Effects. Antipsychotic drugs also increase blood prolactin levels. Elevated prolactin may cause breast enlargement and tenderness in men and women; dimin-ished libido, erectile and orgasmic dysfunction, and men-strual irregularities; and increased risk for breast cancer, and may contribute to weight gain.

Weight gain can accompany most antipsychotic medi-cations, but it is most likely with the atypical antipsy-chotic drugs, with ziprasidone (Geodon) being the exception. Weight increases are most significant with clozapine (Clozaril) and olanzapine (Zyprexa). Since 2004, the FDA has made it mandatory for drug manufac-turers that atypical antipsychotics carry a warning of the increased risk for hyperglycemia and diabetes. Though the exact mechanism of this weight gain is unknown, it is associated with increased appetite, binge eating, carbo-hydrate craving, food preference changes, and decreased satiety in some clients. In addition, clients with a genetic predisposition for weight gain are at greater risk (MullerKennedy, 2006). Prolactin elevation may stimulate feeding centers, histamine antagonism stimulates appe-tite, and there may be an as yet undetermined interplay of multiple neurotransmitter and receptor interactions with resultant changes in appetite, energy intake, and feeding behavior. Obesity is common in clients with schizophre-nia, further increasing the risk for type 2 diabetes melli-tus and cardiovascular disease (Newcomer & Haupt, 2006). In addition, clients with schizophrenia are less likely to exercise or eat low-fat nutritionally balanced diets; this pattern decreases the likelihood that they can minimize potential weight gain or lose excess weight. It is recommended that clients taking antipsychotics be involved in an educational program to control weight and decrease body mass index.

Most antipsychotic drugs cause relatively minor cardio-vascular adverse effects such as postural hypotension, palpi-tations, and tachycardia. Certain antipsychotic drugs, such as thioridazine (Mellaril), droperidol (Inapsine), and mesoridazine (Serentil), also can cause a lengthening of the QT interval. A QT interval longer than 500 ms is considered dangerous and is associated with life-threatening dysrhyth-mias and sudden death. Though rare, the lengthened QT interval can cause torsade de pointes, a rapid heart rhythm of 150 to 250 beats per minute, resulting in a “twisted” appear-ance on the electrocardiogram; hence the name torsade de pointes (Glassman, 2005). Thioridazine and mesoridazine are used to treat psychosis; droperidol is most often used as an adjunct to anesthesia or to produce sedation. Sertindole (Serlect) was never approved in the United States to treat psychosis, but was used in Europe and was subsequently withdrawn from the market because of the number of cardiac dysrhythmias and deaths that it caused.

Clozapine produces fewer traditional side effects than do most antipsychotic drugs, but it has the potentially fatal side effect of agranulocytosis. This develops suddenly and is characterized by fever, malaise, ulcerative sore throat, and leukopenia. This side effect may not be manifested immediately and can occur up to 24 weeks after the initia-tion of therapy. Initially, clients needed to have a weekly white blood cell count (WBC) above 3,500 per mm³ to obtain the next week’s supply of clozapine. Currently, all clients must have weekly WBCs drawn for the first 6 months. If the WBC is 3,500 per mm³ and the absolute neutrophil count (ANC) is 2,000 per mm³, the client may have these labs monitored every 2 weeks for 6 months, and then every 4 weeks. This decreased monitoring is dependent on continuous therapy with clozapine. Any interruption in therapy requires a return to more frequent monitoring for a specified period of time. After clozapine has been discontinued, weekly monitoring of the WBC and ANC is required for 4 weeks.