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key drug. Key drug selected because it was the first and is still in use.
Antipsychotics, also known as major tranquilizers or neuroleptics, are used commonly in the treatment of a variety of psychotic disorders. Their use in schizophrenia and in the management of behavioral and psychologic symptoms is discussed in this chapter. Primary care providers offer general or acute care for patients who may be taking these antipsychotic drugs. This chapter provides some very general information for them. These drugs are specialty drugs, and providers who prescribe these drugs routinely will require prescribing information with much greater detail. Providers who see geriatric patients, especially in the hospital or a nursing care facility, should be prepared to use this category of drugs; they too may need more detailed information.
There is growing documentation of prescribing off-label antipsychotic drugs, particular in nursing homes to calm patients with dementia. Medicare has threatened to institute penalties for this use of antipsychotic drugs. Research suggests antipsychotic medications are overprescribed in the older demented patient population. The use of these medication off-label, particularly quetiapine for treating insomnia in patients with no psychotic disorders, is also under current criticism from the medical community as being not standard practice.
The first antipsychotic on the market, chlorpromazine, was introduced in the early 1950s. This is the key drug among the phenothiazine first-generation antipsychotic agents. Currently, antipsychotics are divided into two generations. The first generation includes the older, “typical” drugs that treat the positive but not the negative symptoms associated with a psychotic state. Second-generation drugs have far fewer extrapyramidal symptoms (EPS) and tardive dyskinesia (TD), and they are used to treat both positive and negative symptoms of schizophrenia. With the exception of risperidone, they are prolactin sparing.
Extrapyramidal Symptoms
Although antipsychotic drugs often are effective, almost all are associated with adverse effects. The most important adverse effects associated with antipsychotic drugs include EPS, some of which may be irreversible. EPS include parkinsonian syndrome, akathisia, dystonia, neuroleptic malignant syndrome, and TD.
TD (abnormal involuntary movements) may be progressive and irreversible, even after the drug is discontinued. It is characterized by rhythmic involuntary movement of the tongue, face, mouth, or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). These may be accompanied by involuntary movements of the extremities. TD has been the major limitation of first-generation antipsychotics because symptoms of TD can be disabling, preventing the patient from returning to society, even after the schizophrenia is controlled.
Neuroleptic malignant syndrome (NMS): Symptoms usually occur weeks after initiation of treatment with antipsychotics. NMS is an idiosyncratic reaction to an antipsychotic or neuroleptic drug; symptoms typically develop over a period of hours to days, and the condition is life threatening. Major symptoms include fever, catatonic stupor, muscle rigidity, autonomic instability, tachycardia, delirium, and myoglobinemia.
Parkinsonian symptoms typically occur more commonly in the elderly and with higher-potency antipsychotics, except risperidone. Symptoms include masked facies, tremor, bradykinesia, rigidity, cogwheeling, drooling, and festination.
Akathisia may be difficult to differentiate from anxiety because the two appear to be so similar. Symptoms include an intensely unpleasant need to move, restlessness, and agitation. Because of the discomfort that is felt, akathisia is often a big factor in noncompliance regarding medications.
Acute dystonia: Symptoms include muscular rigidity, usually of the tongue, neck, face, or trunk. It is most likely to occur within the first week of antipsychotic drug treatment. Acute dystonia can be frightening, extremely uncomfortable, and life threatening if laryngeal dystonia occurs.
Therapeutic Overview
It is important to understand that psychosis is not a disease. Psychosis is the term that is used to describe a general symptom complex in which gross impairment of reality is demonstrated. It has many causes—both organic and psychiatric. Box 49-1 lists symptoms that are commonly associated with the presentation of a clinical psychosis. Table 49-1 shows the most common medical disorders that may present with psychiatric symptoms, but not all of these represent psychotic symptoms. A large number of diverse and even common medications can cause psychotic symptoms (Table 49-2). Table 49-3 lists different psychiatric disorders that may present with psychosis. Therefore, it is difficult to talk about treating the general symptoms of psychosis; it is more productive to talk about specific psychotic disorders such as schizophrenia.
TABLE 49-1
Medical Conditions Associated with Psychiatric Symptoms
| Causes | Example |
| Metabolic and endocrine | Addison’s disease |
| Calcium imbalance | |
| Carcinoid syndrome | |
| Cushing’s syndrome | |
| Electrolyte abnormalities | |
| Hepatic failure | |
| Hyperparathyroidism | |
| Hyperthyroidism | |
| Hypoglycemia | |
| Hypothyroidism | |
| Hypoxia | |
| Magnesium imbalance | |
| Pheochromocytoma | |
| Porphyria | |
| Renal failure | |
| Serotonin syndrome | |
| Wilson’s disease | |
| Electrical | Complex partial seizures |
| Peri-ictal states (depression, hallucinations) | Postictal states (depression, dissociation, or disinhibition) |
| Temporal lobe status epilepticus | |
| Neoplastic | Carcinoid syndrome |
| Carcinoma of the pancreas | |
| Metastatic brain tumors | Primary brain tumor |
| Remote effects of carcinoma | |
| Arterial | Arteriovenous malformations |
| Hypertensive lacunar state | |
| Inflammation (cranial arteritis, lupus) | |
| Migraine | |
| Multi-infarct states | Subarachnoid bleeds |
| Subclavian steal syndrome | |
| Thromboembolic phenomena | |
| Transient ischemic attacks | |
| Mechanical | Concussion |
| Normal pressure hydrocephalus | |
| Subdural or epidural hematoma | |
| Trauma | |
| Infectious | Abscesses |
| AIDS | |
| Hepatitis | |
| Meningoencephalitis (including tuberculosis, fungal, herpes) | |
| Multifocal leukoencephalopathy | |
| Subacute sclerosingpanencephalitis | |
| Syphilis | |
| Nutritional | Vitamin B12 deficiency |
| Folate deficiency | |
| Niacin deficiency | |
| Pyridoxine (vitamin B6) deficiency | |
| Thiamine deficiency | |
| Degenerative and neurologic | Aging |
| Alzheimer’s disease | |
| Heavy metal toxicity | |
| Huntington’s disease | |
| Jakob-Creutzfeldt disease | |
| Multiple sclerosis | |
| Parkinson’s disease | |
| Pick’s disease |
Modified from Gabbard GO: Gabbard’s treatment of psychiatric disorders,ed 4, New York, 2007, American Psychiatric Publishing.
TABLE 49-2
Medications That Can Cause Psychotic Symptoms
Acyclovir
Amantadine
Amphetamine-like drugs
Anabolic steroids
Anticholinergics and atropine
Anticonvulsants
Antidepressants, all
Baclofen
Barbiturates
Benzodiazepines
α-Adrenergic blockers
Calcium channel blockers
Cephalosporins
Corticosteroids
Dopamine receptor agonists
fluoroquinolone antibiotics
Histamine H1-receptor blockers
Histamine H2-receptor blockers
HMG-CoA reductase inhibitors (statins)
NSAIDs
Opioids
Procaine derivatives
Salicylates
Sulfonamides
Data from The Medical Letter: Some drugs that cause psychiatric symptoms, Med Lett 44:1134, 2002, and Gabbard GO: Gabbard’s treatment of psychiatric disorders, ed 4, New York, 2007, American Psychiatric Publishing.
TABLE 49-3
Psychiatric Disorders That May Present with Psychosis
| Type of Psychiatric Disorder | Examples |
| Chronic psychosis (severe) | Schizophrenia |
| Schizoaffective disorder, bipolar type (with prominent episodes of mania) | |
| Schizoaffective disorder, depressed type (with prominent depressive episodes) | |
| Schizophreniform (<6 months’ duration) | |
| Chronic psychosis (less severe or bizarre) | Delusional disorder |
| Shared psychotic disorder | |
| Episodic psychosis | Depression with psychotic features |
| Bipolar disorder (manic or depressed) | |
| Brief psychotic disorder | |
| PTSD; borderline personality disorder |
Modified from Stern TA et al: Massachusetts General Hospital handbook of general hospital psychiatry,ed 5, St Louis, 2004, Mosby.
Many elderly patients are particularly vulnerable to the development of psychotic symptoms. The confluence of medical disorders, psychiatric disorders, and medications may easily provoke psychotic symptoms, particularly when patients move from an unfamiliar environment to a strange setting, or when a change disturbs the tenuous balance they are maintaining while coping with medical and psychiatric problems. Geriatric patients with dementia may exhibit behavioral and psychologic symptoms, which may or may not represent psychosis. These symptoms commonly include agitation, physical aggression, delusions, and hallucinations. Other behaviors, such as refusing personal care, being unable to communicate or perform daily activities, wandering, being restless, and participating in self-destructive acts, may require the use of some of these medications, sometimes for brief intervals. Research has demonstrated that the risk of developing metabolic syndrome in children and adolescents increases sharply after 3 to 12 months of antipsychotic treatment.
Schizophrenia
One of the diseases that may present with psychotic symptoms is schizophrenia. Schizophrenia is a disease that is heterogeneous and complex. The pathophysiology of schizophrenia is poorly understood. Early theories involved the dopaminergic system. Recently, serotonergic pathways have been implicated. Newer theories focus on the interplay between dopaminergic and serotonergic systems, along with the involvement of muscarinic, α-adrenergic, and histaminergic systems and the presence of genetic Y chromosome disease.
Assessment
Schizophrenia is diagnosed by history after the patient is assessed in three areas:
Antipsychotic drugs should not be used unless the practitioner has performed a thorough physical and psychiatric assessment, the diagnosis has been ascertained, and other therapy has been ruled out. Key diagnostic questions that should be asked include the following:
Before antipsychotic drugs are initiated, take baseline vital signs. Baseline laboratory tests that should be completed include liver function tests, CBC, ECG, and UA. These tests should be repeated periodically, as dictated by the drug that is taken and the comorbidities of the patient. History of previous responses to medications, especially antipsychotics, should be noted.
Mechanism of Action
The exact mechanism of antipsychotic drug action is unknown. These drugs are thought to work by blocking postsynaptic dopamine receptors in the hypothalamus, basal ganglia, limbic system, brainstem, and medulla, and to some extent serotonin receptors. Much work has been done to elucidate which receptors each drug affects. How this receptor blocking causes specific changes in behavior and cognition is not known. See Table 49-4 for specific neurotransmitter-receptor blocking actions of individual medications. Each neurotransmitter is associated with specific side effects. However, the correlation between the two is not completely understood. A very complicated and overlapping set of mechanisms interact to produce a wide variety of effects. Another complication is that these drugs produce different effects from patient to patient. Most cause sedation in some people and agitation in others (Box 49-2). Some antipsychotic drugs cause metabolic side effects such as obesity and diabetes by activating the SMAD3 protein, which plays a role in the transforming growth factor beta pathway—a cellular mechanism responsible for inflammation and insulin signaling, among other processes.
BOX 49-2 Neurotransmitter and Adverse Effects
