An old woman dressed too warmly for the weather mutters on a street corner. A line of bag-bearing individuals trudge into a homeless shelter, apparently oblivious to others. A city establishes a jail-diversion program to route mentally ill people from incarceration to appropriate treatment. A tormented young man responds to voices in his head and kills his family. This is the world of untreated schizophrenia.
Approximately 2.5 million Ameri-cans suffer from chronic schizophrenia, a disorder that brands them with stigma. Visible schizophrenics?the homeless, the hopeless, and the headliners?persuade the general populace to fear them as harmful. In fact, most schizophrenics are more likely to harm themselves than others.1 The positive symptoms (delusions and hallucinations) make their lives unproductive: fewer than 10% of schizophrenia patients are ever steadily or fully employed or live independently. The negative symptoms and cognitive deficits (flattened emotions and disordered thinking) erode their ability to make deep or lasting relationships. Once these patients detach from society, reintegration is rare.2
Furthermore, substance abuse and alcoholism are common among people with schizophrenia, and they smoke more than any other group of patients. Schizophrenia patients account for 20% of all hospital bed-days and occupy more than 50% of all psychiatric beds in the United States. Approximately 40% of patients with schizophrenia attempt suicide, and approximately 10% meet this tragic end.3
The cause of schizophrenia is unknown, but a strong genetic component is obvious, because children of people with schizophrenia are 10 times more likely to develop it than others. Researchers have identified some neural irregularities in the fetus, but the disease becomes apparent only when patients reach their late teens and early 20s or thereafter. Several large studies are under way to determine what differences and similarities patients and their relatives possess.4
From these studies, scientists aspire to fathom the cognitive disruptions that affect short-term memory, attention, and executive functions; lacking these, schizophrenics have trouble with planning and problem solving. Certain areas receiving considerable attention are olfaction and memory. Patients with schizophrenia often have impaired odor detection and identification. These deficits appear to be independent of either symptom severity or other cognitive impairment.5,6
Memory deficits, which almost all people with schizophrenia experience, can be examined using psychiatric screening tools (such as a word list recall), as well as magnetic resonance imaging and positron emission tomography. Early results have classified patients as "cortical" or "subcortical." Cortical patients tend to be male, to develop illness early, and to have reduced temporal lobe gray matter and hypometabolism. Subcortical patients have ventricular enlargement and more negative symptoms. In the near future, psychiatrists may categorize patients by type of memory deficit.7
Today?s drugs have successfully controlled positive symptoms, but the obstinate cognitive problems escape ideal resolution. Current antipsychotic drugs reduce dopamine levels where the neu-rotransmitter is overexpressed. The disease, however, reduces the amount of dopamine released in other parts of the cortex, such as the striatum.2,3
Available drugs are classified in 3 groups. Each group affects different target symptoms, with each generation broadening the scope of their efficacy with unique dopamine, serotonin, and acetylcholine receptor binding profiles.3
The first-generation, or traditional, agents (eg, chlorpromazine and halo-peridol) have been used for several decades, and they address positive symptoms. With these agents, patients have fewer delusions and hallucinations but often remain withdrawn and unengaged. Extrapyramidal symptoms (EPS)?especially movement disorders, tardive dyskinesia (TD), and elevated prolactin levels?represent barriers to both care and compliance. Often, an antiparkinsonian agent is necessary to treat side effects. The traditional agents are no longer considered first-line treatment, but because of the relatively low cost they are still used by many patients. Medication and treatment compliance is hampered, possibly by side effects and probably by the nature of the disorder.
The second-generation agents (eg, risperidone and ziprasidone) target positive and negative symptoms and cause some, but fewer, EPS, less TD, and less prolactin elevation.3
The third-generation agents (eg, clozapine, olanzapine, and quetia-pine) have demonstrated efficacy in positive, negative, mood, and cognitive symptoms. With these agents, EPS, TD, and elevated prolactin levels are rare. These drugs, however, have been associated with what some authors call "metabolic syndrome": weight gain, elevated serum triglyc-erides, and glucose dysregulation.8,9 Schizophrenia is associated with a higher prevalence of diabetes (approximately 2 times that of the general populace) independent of treatment.
Although psychiatrists anticipated that the second- and third-generation agents would ameliorate the compliance problems often associated with the first generation?s adverse events, compliance remains a problem.10
In the last year, however, 2 important developments occurred. First, the FDA approved the addition of "treatment of recurrent suicidal behavior in patients with schizophrenia or schizo-affective disorder who are at chronic risk" to Clozaril?s indications; generic clozapine does not carry this indication. Clozaril may reduce suicidality via direct antidepressant action, improved cognitive function and insight, diminished negative symptoms, reduced substance abuse, and improved compliance.11
Next, aripiprazole (Abilify) a new atypical antipsychotic, was approved. It has a unique receptor binding profile that combines partial agonist activity at D2 and 5-HT1A receptors with potent antagonism at 5-HT2A receptors. Given once daily, aripiprazole 15-30 mg is as effective as haloperidol 10 mg/day and risperidone 6 mg/day in short-term treatment of schizophrenia and more effective than haloperidol 7-10 mg/day in maintenance of response in chronic schizophrenia. Aripiprazole appears to be well tolerated, with most studies suggesting a frequency of adverse effects similar to placebo. Aripiprazole seems not to cause significant EPS, hyperprolactinemia, excessive weight gain, or cardiac rhythm disturbance. Limited data suggest that aripiprazole is not associated with impaired glucose tolerance.12
In the search for potential drug targets, scientists are scrutinizing other receptors, and the nicotinic receptors offer promise, based on the hypothesis that schizophrenia-riddled brains cannot focus on a stimulus because they cannot inhibit, or "gate," irrelevant material. In normal individuals, a novel stimulus will elicit an electric signal, P50, but repress the response by 80% if the sound is repeated. Most schizophrenia patients, however, respond to every tone identically. The problem is a defect in a nicotinic receptor gene linked to attention. Nicotine intake transiently normalizes the P50 gating response, leading some researchers to suspect that the high incidence of smoking in schizophrenia patients is the result of unconscious efforts to self-medicate.13
Glutamate, the brain's main excitatory neurotransmitter, is also a potential drug target, because its decrease in concentration has been linked to both psychotic symptoms and cognitive impairments.
Also in the near future, clinicians await a second- or third-generation agent in a decanoate dosage form. Currently limited to haloperidol or fluphenazine forms, decanoates are given intramuscularly every 2 to 4 weeks and ensure compliance. They have been proven to decrease hospitalization and recurrence of psychotic episodes. Their side-effect profile, however, is troublesome. Risperdal Consta, a saline-based solution, is currently in late-stage regulatory review in the United States and has been approved in Europe. It is associated with less pain than the injectable formulations of older, conventional antipsychotics, whose solutions are oil-based.14,15
Implications for Pharmacists
Nancy Lee Head, founding president of the District of Columbia?s Mental Health Consumer League, has said, "Few people realize schizophrenia?s enduring burden. Once labeled as schizophrenic, patients disappear behind the label." She has related the story of a man who was an accomplished pianist who developed schizophrenia. His prognosis was poor, until he responded well to a newer agent. A significant turning point in his recovery occurred when people began once again to refer to him as a pianist, rather than a schizophrenic.
Excellent studies document improved compliance and prognosis when people with schizophrenia have good provider relationships.16 Pharmacists can best serve these patients by recognizing that each patient has a unique clinical picture and will need individualized treatment. Pharmacists will need to be patient and empathet-ic, and willing to explain more than once if necessary. They should arm patients with information and warn them about potential side effects. In particular, pharmacists can encourage patients to prepare for increased appetite, control their eating, and exercise more.
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