Schizophrenia and Other Psychotic Disorders, Exercises of Psychiatry

Download Schizophrenia and Other Psychotic Disorders and more Exercises Psychiatry in PDF only on Docsity! a dimensional approach to the disorder, in which positive, negative, cognitive, and affective symp- toms, which are present to varying degrees in every patient with schizophrenia, are characterized as sep- arate components of the illness. The subtypes of the disorder represent a categorical approach to symp- tom description, each defined by the presence or absence of specific symptoms. These two approaches to symptom description serve different, complemen- DEFINITIONS Schizophrenia is a heterogeneous disorder defined by sustained periods of psychosis and functional deterioration in the major arenas of life, such as interpersonal relations, education, employment, and self-care (1). The boundaries of the disorder have been a source of debate since its earliest delineation by Kraepelin (2) and Bleuler (3) a century ago. Formerly, especially in American psychiatry, all chronic and recurrent psychotic symptoms were grouped together under the category of schizophre- nia. Since the advent of DSM-III in 1980, however, it has been recognized that episodic psychosis in the context of severe mood symptoms and psychosis attributable to identifiable medical causes are sepa- rate entities that must be ruled out before a diagno- sis of schizophrenia can be made. The presentation of schizophrenia varies enor- mously. The current definition of schizophrenia includes distinct symptom domains, each of which may vary independently, as well as diagnostic sub- types. The concept of symptom domains represents Schizophrenia and Other Psychotic Disorders Winter 2004, Vol. II, No. 1 17F O C U S R E V I E W Michael D. Jibson, M.D., Ph.D. Ira D. Glick, M.D. Rajiv Tandon, M.D. Schizophrenia is a chronic, debilitating psychotic disorder that affects 1% of adults. Symptoms of the illness are highly variable from person to person but typically include “positive” symptoms (delusions, hallucina- tions, thought disorganization), “negative” symptoms (blunted affect, social dysfunction, lack of motiva- tion), cognitive impairments, and mood disturbance. Recurrence of active psychosis, progression of symptoms, and deterioration in all areas of life function are the rule. Given the combination of onset in early adulthood and persistent dysfunction, schizophrenia incurs enormous financial and personal costs. The biological basis of the disorder is not clear but is known to include genetic, environmental, and devel- opmental factors. Recent research findings underscore the importance of dopamine systems and matura- tional changes in the brain. Treatment includes psychosocial interventions to address social deficits, family issues, and functional impairments and medication treatment to control symptoms. Atypical antipsychotic medications are used as first-line pharmacotherapy; clozapine is used for patients with treatment-refractory illness, and depot conventional antipsychotics are used for responsive but noncompliant patients. Optimal treatment is provided in community-based centers with expertise in the disorder. Ensuring adequate sup- port for such treatment, however, is a continuing challenge. From the University of Michigan Health System and Stanford University School of Medicine. Send reprint requests to Dr. Jibson, University of Michigan Health System, 1500 E. Medical Center Drive, Ann Arbor, MI 49109-0118; e-mail, mdjibson@umich.edu. CME Disclosure Statement Michael D. Jibson, M.D., Ph.D., Clinical Associate Professor of Psychiatry, University of Michigan Health System Speakers Bureau: AstraZeneca, Pfizer, Janssen Ira D. Glick, M.D., Professor of Psychiatry and Behavioral Science, Stanford University School of Medicine Advisory, Research Support, Speakers Bureau: Janssen, Pfizer, Lilly, AstraZeneca, Bristol-Myers Squibb Rajiv Tandon, M.D., Professor of Psychiatry, University of Michigan Health System Speakership honoraria, Consultant: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Hallucinations are false perceptions occurring in any sensory modality. Auditory hallucinations, especially voices, are the most common in patients with schizophrenia (7). Hallucinatory voices may vary in frequency, intensity, number of speakers, and content. Command hallu- cinations, voices instructing the patient to do some- thing, may place the patient at risk of acting on the commands. Visual hallucinations, although some- times associated with substance intoxication or with- drawal, are also common in schizophrenia (7). Similarly, tactile, olfactory, and gustatory hallucina- tions may occur in schizophrenia and are not uniquely attributable, as some older texts suggested, to seizures, substance abuse, or other medically iden- tifiable causes. Thought disorganization is most often noted as bizarre behavior or a disruption of the logical associ- ations of speech. Disorganization is especially dis- ruptive to the routine tasks of life and creates severe problems in social, occupational, and self-care func- tions. Catatonia is an altered state of motor activity and attention. Lack of movement is common and may be accompanied by either catalepsy (waxy flexibil- ity), in which the person maintains a posture into which he or she has been passively moved by the examiner, or negativism, in which the patient actively resists such attempts by the examiner. Echopraxia refers to the patient’s inappropriately mirroring movements of the examiner. Spontaneous movements may be stereotypic and bizarre, or patients may exhibit excessive motor activity that appears without direction or purpose. Speech may be absent (mutism) or may repeat the examiner’s speech in a rigid and stereotypic way (echolalia). The patient may appear stuporous or may be internally preoccupied with other psychotic symptoms. Positive symptoms may occur episodically or con- tinuously. Even in episodic cases, however, it is rare for positive symptoms to remit completely. Most patients experience some degree of active psychosis whether or not they receive treatment. However, treatment has a significant impact on symptom severity and on the long-term course of illness. Negative symptoms of schizophrenia are charac- terized by the absence of certain functions (see Table 1) (8). Blunted affect refers to the loss of an individ- ual’s ability to communicate via facial expression, tone of voice, eye contact, posture, gestures, respira- tory pattern, and so forth. Normal communication tary functions and aid the clinician in conceptual understanding, prognostication, and treatment selection. SYMPTOM DOMAINS Positive symptoms are synonymous with active psychosis; they are referred to as “positive” in the sense that they are added onto normal experience. They include delusions, hallucinations, and thought disorganization (Table 1). Delusions are the most common psychotic symptom in schizophrenia, occurring in 65% of patients (4, 5). Hallucinations and thought disorganization are each described in about 50% of patients. Most patients experience multiple symptoms (4). Positive symptoms are highly correlated with hospitalization but only min- imally with other measures of dysfunction. Delusions are false beliefs based on internally gen- erated concepts of reality or on incorrect inferences about actual events. By definition they are not amenable to correction by contrary evidence or per- suasive argument. Although they may occur within the context of specific cultural customs or belief sys- tems, they are not shared by others who have a sim- ilar background, and they are readily acknowledged by peers to be aberrant. They occur in a wide range of categories, such as persecutory, religious, somatic, grandiose, and so forth. Ideas of reference, the belief that neutral events are uniquely directed to the indi- vidual, are of special note because of their frequency. Among such delusions are the belief that messages from the television or radio are directed specifically at the person, that newspaper articles secretly refer to the person, or that conversations among strangers are about the person. Also common is the belief that one’s thoughts are being read or controlled by oth- ers, a symptom so striking that it was once thought to be pathognomonic for schizophrenia (6). In fact, none of these symptoms are unique to schizophre- nia, nor do they carry special significance for treat- ment or prognosis (5), but their diversity is mentioned here to alert the clinician to the range of possibilities that must be considered in the assess- ment of possible psychotic symptoms. 18 Winter 2004, Vol. II, No. 1 F O C U S T H E J O U R NA L O F L I F E LO N G L E A R N I N G I N P S YC H I AT RY JIBSON ET AL. Table 1. Symptom Domains in Schizophrenia Positive Symptoms Negative Symptoms Cognitive Impairment Mood Disturbance Delusions Blunted affect Inattention Blunted affect Hallucinations Alogia Memory impairment Bizarre or inappropriate affect Thought disorganization Anhedonia Impaired executive function Dysphoric mood Catatonia Social isolation Language disturbance Lack of motivation Winter 2004, Vol. II, No. 1 receptors. The D1 family consists of the D1 and D5 receptor subtypes. These subtypes are widespread in the human CNS, are found only postsynaptically, and have not been directly implicated in the patho- genesis or treatment of psychotic symptoms. It has been noted, however, that they may play a modula- tory role in pathways involving the D2 receptor. The D2 family comprises dopamine D2, D3, and D4 receptors, each of which has a unique anatomic distribution and binding affinity for antipsychotic drugs. D2 and D3 receptors are found both postsyn- aptically and as presynaptic autoreceptors; D4 recep- tors are only found postsynaptically and are localized to mesolimbic and mesocortical structures. Attention was drawn to the D4 receptor when researchers noted that clozapine, an antipsychotic with unique efficacy and no association with extrapyramidal side effects, has a higher affinity for D4 receptors than for other subtypes (66). Subsequent studies involving the therapeutic effi- cacy of selective dopamine D4 antagonists and a neuropathologic role for D4 receptors in the schizo- phrenia brain have been more equivocal (67). The precise role of the D4 receptor subtype in the patho- genesis and treatment of schizophrenia thus remains unclear. Aberrations in dopaminergic pathways also differ by location. In the prefrontal cortex, hypoactivity of dopaminergic systems appears to be correlated with cognitive and negative symptoms of illness (61). In contrast, active psychosis appears to be related to an excess of dopaminergic activity in mesocortical and mesolimbic pathways. Motor symptoms may arise in response to dopamine blockade of the nigrostri- atal pathway. Finally, elevation of prolactin levels with antipsychotic medication treatment is the result of dopamine blockade of the tuberoinfundibular pathway (65). The therapeutic need to increase dopamine in some brain regions, to decrease dopaminergic transmission in others, and to avoid alteration of this activity in still others poses unique problems in the pharmacotherapy of schizophrenia. The atypical antipsychotics introduced in the 1990s began to address some of these problems. The appellation “atypical” refers to the lower propensity of these medications to cause parkin- sonism, or extrapyramidal side effects, as well as long-term choreoathetotic movement disorders such as tardive dyskinesia. Compared with the conventional agents, atypical antipsychotics cause significantly fewer parkinsonian symptoms at stan- dard doses. In addition, in contrast to the 5%–7% cumulative annual risk of tardive dyskinesia with conventional agents, atypical antipsychotics are associated with these symptoms in only about 0.5% of cases per year of medication exposure (68, annually in lost productivity (54). This translates to $7,000–$8,000 per year per patient, irrespective of treatment setting, and additional costs to the family of $11,000–$12,000 per year (55). Both short-term and long-term institutionalization are common. A high percentage of hospital beds are used for this population, and treatment of the dis- order accounts for an estimated 2.5% of all health care expenditures (56). BIOPSYCHOSOCIAL UNDERPINNINGS Schizophrenia very likely represents the final pathway of a complex interaction of a variety of genetic, developmental, and environmental factors (57). The absence of a conclusive biological model for the development of schizophrenia may be attrib- uted in part to the wide range of findings that must be accounted for in such a model. Genetic factors are clearly prominent, as indicated by the 50% con- currence rate for the illness among identical twins (58). Second-trimester viral infection has been asso- ciated with an elevated risk of illness (59). Perinatal anoxia, birth trauma, and toxic exposures have also been shown to predispose affected individuals to the development of the disorder (60). A number of bio- logical and psychological correlates of illness early in life have also been identified and must be accounted for in any neuropathologic model of the illness (61). These considerations led to the development of the “two-hit” hypothesis, which suggests that both genetic predisposition and environmental or devel- opmental factors must be present for the develop- ment of the disorder (62). Despite the challenge of integrating these broad-ranging factors, an early delineation of a model linking them to the sympto- matic manifestations of the disorder has been sketched. DOPAMINE HYPOTHESIS The involvement of dopaminergic pathways in the pathogenesis of psychosis was originally sug- gested by the correlation of the efficacy of antipsy- chotic medications with dopamine D2 receptor blockade (63). This correlation, is as strong with the atypical antipsychotics (64) as with the conventional neuroleptics, where it was originally observed. There is also an increasing recognition of the importance of the unique anatomical distributions of the five dopamine receptor subtypes and of the preferential effects of atypical agents at these receptor subtypes (65). The dopamine receptor subtypes are grouped into two families on the basis of their similarity in struc- ture and function to either dopamine D1 or D2 21F O C U S JIBSON ET AL. R E V I E W schizophrenia treatment remains to be determined. Another intriguing development in the dopamine hypothesis of schizophrenia involves catechol O- methyltransferase (COMT), an enzyme in the cata- bolic pathway of dopamine to its major metabolite, homovanillic acid. In animal models, greater COMT activity is correlated with more rapid metabolism of dopamine and a corresponding decrease in memory functions that are dependent on dopaminergic neurons. In humans, polymorphism of the COMT gene is associated with significant changes in prefrontal dopaminergic activity and pre- dicts performance on some cognitive tests. Interestingly, the more active form of COMT, which has valine at position 158 of the membrane-bound enzyme (position 108 of the solubilized enzyme), in contrast to the less active variant with serine at that position, is correlated—although weakly—with schizophrenia in some family-based studies (61, 76). This finding represents the first time a family link- age study has been correlated with a specific genetic defect that is plausibly connected to the pathogene- sis of schizophrenia. STRUCTURAL HYPOTHESIS The most consistently demonstrated biological finding in schizophrenia is enlargement of the lateral ventricles, often accompanied by dilatation of the cortex, but localization of a specific structural lesion has proved elusive. Neuroimaging and postmortem studies suggest that this reduction of structural material is due to widespread diminution of neuritic processes rather than the loss of cell bodies from a specific brain structure (77). This finding provides support for a neurodevelopmental model for the ill- ness, in which genetic and environmental factors interact to adversely affect the normal developmen- tal processes of synaptic pruning, programmed cell death, experience-modulated neuronal proliferation, and axonal myelination (47) that typically occur during adolescence and young adulthood. This model corresponds well with the development of active psychotic symptoms in early adulthood, but less well with studies of the progression of anatomic abnormalities. Although some studies have shown evidence of progression of ventricular enlargement with continued or recurrent illness, other studies suggest more static lesions (47). This issue remains under active investigation. ASSESSMENT AND DIFFERENTIAL DIAGNOSIS There are no pathognomonic features or specific diagnostic tests for schizophrenia. The diagnosis is 69). In addition to the dramatic reduction in the risk of some side effects, modest reductions in the severity of negative and cognitive symptoms have been noted with atypical agents (70, 71). The atyp- ical antipsychotics are all effective antagonists of the dopamine D2 receptor, and at clinically relevant doses their blockade of this receptor is comparable to that of conventional agents, but with the advan- tage of a greater degree of separation between clin- ically effective doses and doses required to produce extrapyramidal side effects (71). Two major hypotheses have been proposed to account for the favorable side effect profile—the “atypicality”—of the novel agents. The first is based on the observation that these agents all have greater activity at serotonin 5-HT2 receptors than at dopamine D2 sites. It has been proposed that block- ade of the serotonin system has a modulatory effect on motor pathways (72). A second, more recent, observation is that the atypical agents occupy the dopamine D2 receptor only briefly, in contrast with the longer occupancy observed for conventional agents (73). It has been suggested that this looser binding precludes these drugs from causing motor side effects. A comparison of these qualities among various conventional and atypical antipsychotics provides some support for this model (64). A second approach to the problem of simultane- ous pharmacology of multiple dopaminergic systems is the use of partial dopamine agonists (74). Unlike antagonists, which bind to receptors and prevent their activation by neurotransmitters, partial ago- nists bind and activate target receptors but elicit a lower level of receptor activation than the intrinsic neurotransmitter. The consequences of this partial activation depend on the condition of the receptor before initiation of treatment. When the receptor is hyperstimulated, competitive partial activation has the effect of reducing activity. When the untreated receptor is at a low level of stimulation, partial acti- vation has the effect of increasing its activity. The potential benefits of partial agonists in the treatment of schizophrenia are twofold (75). First, by avoiding high levels of dopamine blockade in motor systems, the extrapyramidal side effects and tardive dyskinesia associated with conventional antipsychotic agents may be avoided. Second, partial agonists have the potential to simultaneously address the hypodopaminergic activity of the prefrontal cor- tex and the excessive dopamine of the mesolimbic and mesocortical pathways, thus treating both posi- tive and negative symptoms. A number of clinical trials have been conducted with partial agonists (74), and one agent, aripiprazole, has been found effective and approved for clinical use in the United States. However, the optimal role of partial agonists in 22 Winter 2004, Vol. II, No. 1 F O C U S T H E J O U R NA L O F L I F E LO N G L E A R N I N G I N P S YC H I AT RY JIBSON ET AL. Winter 2004, Vol. II, No. 1 element in distinguishing among the primary psy- chiatric disorders. Significant periods of intense and sustained mood disturbance, with or without psy- chotic symptoms, alert the clinician to the possibil- ity of bipolar disorder or depression with psychotic features. Family history, although not conclusive, may also yield clues as to the presence or absence of a mood disorder. In contrast, a history of poor school and work performance, aberrant social func- tion, and other operational impairments suggests a likely diagnosis of schizophrenia. The diagnosis of schizoaffective disorder has been somewhat problematic over the years, given the lack of clarity as to diagnostic and prognostic features. The disorder is currently defined by periods of psy- chosis with clear mood features, interspersed with psychosis independent of affective symptoms. The prevalence, response to treatment, and expected out- come of the disorder remain ambiguous. TREATMENT AND OUTCOMES The two basic treatment domains, psychosocial and pharmacological, are essential elements of the treatment of schizophrenia. In general, patients are more likely to benefit from participation in commu- nity-based programs specializing in the treatment of chronically and severely mentally ill persons than from treatment with individual practitioners. Because of the severe global and wide-ranging psy- chopathology of the disorder, only specialty pro- grams are likely to have the resources and expertise to address the range of treatment issues pertinent to this population. Elements of such programs include social support, vocational rehabilitation, social skills training, case management, family education and support, and intensive medication management. PSYCHOSOCIAL TREATMENTS A variety of psychosocial interventions for schizo- phrenia have been shown to be effective in decreas- ing relapse rates and improving function and quality of life. These treatments are based on the recognition of the critical role that social interactions and sup- port play in most areas of function and in quality of life. Psychosocial treatments also assist the patient in maintaining essential services, including housing, income, and personal support. Perhaps most impor- tant, psychosocial interventions encourage and sup- port compliance with medication treatment and maintenance of an ongoing relationship with a psy- chiatrist. Social skills training focuses on the interpersonal deficits that patients with schizophrenia have. It addresses specifically the problems in communica- based on the presence of psychotic symptoms in the context of functional deterioration, after mood dis- orders and medical causes have been excluded. Hence, the diagnosis may be characterized by signif- icant uncertainty early in the course of illness. Another obstacle to early diagnosis is resistance on the part of physicians, even when symptoms are obviously consistent with the disorder, possibly because of the stigma associated with schizophrenia. Acute psychotic episodes arising in the context of schizophrenia, bipolar disorder, substance abuse, medical illness, and other disorders are remarkably similar, and they cannot be reliably distinguished from one another on the basis of their immediate presentation. The presence or absence of grandiose or persecutory delusions, visual hallucinations, agita- tion, or cognitive impairments is not uniquely related to any one cause of illness and should not be taken as evidence of a specific diagnosis. Assessment of a patient begins with an appraisal of the presenting symptoms to determine whether they represent psychosis or some form of nonpsychotic reality distortion. Examples of nonpsychotic symp- toms that might be mistaken for psychosis include dissociative episodes, flashbacks to traumatic events, extreme social phobia, body image distortions asso- ciated with eating disorders, obsessive ruminations, and cognitive disorganization associated with stress or anxiety. Projective psychological testing may sometimes aid the clinician in making these distinc- tions. Medical causes of psychosis are sought through a medical history, a review of systems, a standard screening physical examination, and selected labora- tory tests. Although no clear consensus exists on which tests are essential, a reasonable start includes a complete blood count, serum chemistry studies (electrolytes, liver enzymes, blood urea nitrogen, cre- atinine, calcium, etc.), a urine toxicology screen for substances of abuse, and urinalysis. Brain imaging may be useful for patients experiencing initial episodes of psychotic symptoms, but it rarely shows pathology in the absence of other neurological symptoms. Similarly, tests for rare but treatable con- ditions such as Wilson’s disease, porphyria, encephalitis, neurosyphilis, and so forth are best reserved for situations in which suggestive symptoms are present. Substance-induced psychosis, related either to intoxication or to withdrawal from alcohol or depressant drugs, is commonly seen in emergency services settings. The diagnosis is made by history, toxicology screen results, and findings from the physical examination, with particular attention to vital signs and level of consciousness. The chronological history of symptoms is a key 23F O C U S JIBSON ET AL. R E V I E W continued treatment (91). Other side effects include mild akathisia, mild dry mouth, and mild weight gain. The primary advantage of this drug is its low risk of extrapyramidal side effects. The cost for treat- ment is in the intermediate range at $3,400 per year for 400 mg/day (45). Ziprasidone is most effectively used at doses of 120–160 mg/day (92). The drug’s 7-hour elimina- tion half-time is consistent with its recommended twice-daily dosing. Absorption of the medication is strongly affected by food, and oral doses should be administered with meals. Ziprasidone is available in tablets as well as in sterile solution for intramuscular injection (93)—the only atypical agent available by this route. The use of injectable doses of 10–20 mg, up to a total of 40 mg/day, has been approved for the treatment of acute psychotic agitation. Blood levels of ziprasidone are modestly lower when carba- mazepine is administered concurrently. Common side effects include mild sedation early in treatment, mild nausea, weakness, nasal congestion, and mild QTc prolongation; some patients find the medica- tion mildly stimulating. Some anecdotal evidence suggests that side effects may be greater during tran- sitions from this medication to others; it may be advantageous to stay with treatment rather than switch prematurely. Ziprasidone appears to cause only minimal weight gain, in contrast with other agents. The clinical risk associated with the QTc pro- longation appears to be low. Clinical trials have shown no evidence of an increased risk of arrhyth- mias or sudden death (94), and the FDA has required only an intermediate level of warning on the package insert. The drug should be used with caution, how- ever, in the presence of other agents that prolong the QT interval. Ziprasidone is priced slightly lower than other atypical agents, at an average cost of $2,700 per year (45). The most recent development in antipsychotic therapy is the introduction of the dopamine partial agonist aripiprazole. The medication was studied at doses up to 30 mg/day (75, 95) and is recommended for use at 10–15 mg in once-daily doses for most patients. The manufacturer estimates that 80% of patients who respond to the medication will do so in the middle dose range. The drug’s elimination half- time is 75 hours, which provides good stability between doses but makes dose adjustments rather slow. Aripiprazole is metabolized through the cytochrome P450 system, and serum levels of the drug are affected by inducers and inhibitors of those pathways. Common side effects include headache, nausea and vomiting, insomnia, and, in a few patients, weight gain in excess of 7% of base weight, although the drug is weight neutral in most patients. At higher doses, some patients also experience som- vation of prolactin levels, and moderate weight gain. At doses above 6–8 mg/day, extrapyramidal side effects are more common than with other atypical antipsychotics. For this reason, higher doses of the medication should be avoided. Risperidone is rela- tively inexpensive compared with other atypical agents, costing about $2,800 per year at an average dose of 4 mg/day (45). Olanzapine (87, 88) was introduced in 1996, shortly after risperidone. Olanzapine is typically administered at doses of 15–20 mg/day but is rou- tinely and safely given at doses up to 40 mg/day, well above the FDA-approved maximum of 20 mg. Given the drug’s 30-hour elimination half-time, blood levels remain steady, and once-daily dosing can be pre- scribed. Although drug-drug interactions involving olanzapine are rare, smoking is known to decrease its blood levels by as much as 30%. This can be a signif- icant issue for patients who are stabilized on the med- ication in a smoke-free hospital environment and then resume smoking at home. The medication is available in coated tablets and a rapid-disintegrating formulation. The tablet coating protects the medica- tion from oxidation; if the tablet is cut, it must be taken immediately. The rapid-disintegrating formula- tion is easily administered but is absorbed with the same 5-hour time to peak concentration as the coated tablet. Weight gain is a frequent and significant side effect of olanzapine and has the associated risks of hyperglycemia and diabetes. Other common side effects of olanzapine are moderate sedation, mild akathisia, mild hypotension, dry mouth, and consti- pation. Extrapyramidal side effects have been reported at higher doses, although they are rare and tend to be mild. Olanzapine is relatively expensive, at an average cost of $5,500 a year for 15–20 mg/day (45). Quetiapine (89, 90), approved in 1997, is most effective at doses of 400–800 mg/day. The drug’s elimination half-time is relatively short at 6–7 hours, and its dopamine D2 receptor occupancy time is also brief. Accordingly, quetiapine is approved for twice- daily dosing, although anecdotal accounts of stable patients being successfully maintained on once-daily regimens abound. The significance of quetiapine’s brief D2 receptor occupancy is not clear, but it has been suggested as an explanation for the exception- ally low risk of extrapyramidal side effects with this medication (73), a quality it has in common with clozapine. Quetiapine is available in tablets. This agent is somewhat more susceptible to drug-drug interactions than other antipsychotics, particularly inducers and inhibitors of the cytochrome P450 sys- tem, such as carbamazepine and fluvoxamine. Sedation and hypotension in the early stages of treat- ment are the most troublesome side effects of quetia- pine. Both problems improve significantly with 26 Winter 2004, Vol. II, No. 1 F O C U S T H E J O U R NA L O F L I F E LO N G L E A R N I N G I N P S YC H I AT RY JIBSON ET AL. Winter 2004, Vol. II, No. 1 In some instances, however, adjunctive medications clearly have a place in schizophrenia treatment. Benzodiazepines are effective for short-term use for rapid control of psychotic agitation, especially when used in conjunction with antipsychotics (97). They are also well tolerated in long-term use for persistent agitation, anxiety, or akathisia, and they have modest benefits in some patients for control of psychosis (98). Antidepressants should be reserved for cases of severe depression and anhedonia that have not responded to antipsychotic monotherapy. Patients with persistent demoralization and patients with neg- ative symptoms such as avolition and social isolation, although presenting symptoms similar to the vegeta- tive signs of depression, do not respond to antide- pressant medications, and these symptoms are not appropriate targets of treatment. Mood stabilizers provide only transient benefit in the treatment of psychosis (99) and should be reserved for cases of persistent and troublesome mood instability in patients who have been treated for an adequate dura- tion with an appropriate dose of antipsychotics. The simultaneous use of more than one antipsy- chotic agent is common in clinical practice, despite a dearth of studies to demonstrate the efficacy or safety of such combinations and a consistent bias against them in expert consensus guidelines (100–102). There is also evidence that untested antipsychotic combinations are sometimes used in preference to clozapine with patients who have treatment-refrac- tory illness, even though clozapine is known to be effective in many such cases (103). The pharmaco- logical justification for the practice is weak, since antipsychotic medications all appear to work by the same mechanism—that is, blockade of the dopamine D2 receptor. Differences in activities at other recep- tors and in receptor occupancy times, however, could nolence. Aripiprazole shows no evidence of extrapyramidal side effects at any dose tested. As with ziprasidone, some side effects may be more promi- nent during transitions to other antipsychotic med- ications. Preliminary estimates suggest that the drug will cost $2,700–$3,000 a year, making it competi- tive with other atypical antipsychotics. The availability of several first-line atypical antipsychotics, including the partial agonist aripipra- zole, raises the issue of how best to select medication treatment, for both patients with new-onset illness and patients with recurring illness. Several general principles can serve as useful guidelines in this regard. First, the first-line atypical antipsychotic medications appear to be equally efficacious in the treatment of psychotic disorders (96). It is likely that aripiprazole has similar efficacy. Second, the first-line medications have been found in large controlled studies to be equally well tolerated. Third, although the number of patients who drop out of treatment because of side effects is the same for each medication (96), each one has a unique set of side effects (Table 3). Fourth, there is some evidence that these agents have differ- ential effects among patients. That is, although the same percentage of patients respond to each drug, an individual patient may respond preferentially to one rather than another. Finally, clozapine has clearly documented superior efficacy compared with either conventional or other atypical agents, and it should be considered for any patient who has not responded to other medications. The use of adjunctive medications in the treatment of schizophrenia is common but not well studied in controlled clinical trials. The use of adjunctive med- ications is often justified on the basis of a patient’s experiencing some level of psychotic symptoms even with optimal doses of an antipsychotic medication. 27F O C U S JIBSON ET AL. R E V I E W Table 3. Side Effects of Atypical Antipsychotic Medications EPS at EPS at Anticholin- Prolactin Weight Average Higher ergic Hypo- QTc Pro- Sedation Elevation Gain Doses Doses Symptoms tension longation Risperidone + ++ + +/– ++ +/– + +/– Olanzapine + +/– ++ +/– + + +/– 0 Quetiapine ++ +/– + 0 0 + ++ +/– Ziprasidone +/– +/– +/– +/– + +/– +/– + Aripiprazole +/– 0 +/– 0 0 +/– +/– 0 Clozapine ++ 0 ++ 0 0 ++ ++ +/– Key: EPS, extrapyramidal symptoms; 0, does not occur; +/-, rare; +, occasional; ++, more frequent Source: Adapted from Jibson MD, Tandon R: New atypical antipsychotic medications. J Psychiatric Res 1998; 32:215–228 and therefore tend to be general in their recommen- dations for treatment. Thus, the APA Practice Guideline for the Treatment of Patients With Schizophrenia specifies only that a combination of pharmacological and psychosocial interventions should be used (108). TMAP, in contrast, freely incorporates expert consensus, but attempts to main- tain a high level of flexibility for the physician. For treatment of schizophrenia, TMAP recommends atypical antipsychotic monotherapy for at least 3 weeks at doses up to the manufacturers’ recom- mended maximums. For nonresponding patients, it encourages trials of at least three first-line atypical antipsychotics and one conventional antipsychotic, followed by a trial of clozapine (109). Additional algorithms for the handling of side effects and the use of adjunctive agents are also given. TMAP was designed not only as a treatment aid for clinicians but also to study the effectiveness of treatment algorithms in improving care and managing costs (110). Each of these approaches has certain strengths and limita- tions, but it is not clear that they have had the desired impact on quality of care and cost-effectiveness (111). FUTURE DIRECTIONS Despite more than a century of intensive research on the neurobiology of schizophrenia, many aspects of the disorder remain elusive. Nevertheless, the past few years have seen remarkable progress in this area, and it can reasonably be expected that progress will continue at a brisk pace. A number of other research questions are also currently under investigation, such as whether it is possible to predict and prevent the development of schizophrenia in predisposed indi- viduals, whether there are biological markers for response to specific medications, and whether addi- tional genetic family linkages can be identified. Laboratory studies provide ever more detailed maps of neurotransmitter and receptor localization. Further investigations into receptor subtypes may yet yield important insights into the function of antipsy- chotic medications. Meanwhile, treatment continues in the real world. The trend of deinstitutionalization and community care places increasing numbers of patients in com- munity mental health and similar settings. Such sys- tems are currently at the limits of their capacity, and it is not clear that they are equal to the task of pro- viding state-of-the-art care for each individual in their charge as the numbers of patients increase and funding becomes more scarce. The dilemma of advancing research and improved treatments offset by financially strained systems of care, the irony of American medicine, is particularly acute in psychia- serve as a rational basis for antipsychotic polyphar- macy. Clozapine is sometimes combined with another agent in nonresponsive patients. Depot and oral medications are occasionally combined (see below). At present the appropriate role of antipsy- chotic polypharmacy in the treatment of schizophre- nia is unresolved. Depot antipsychotic agents also have a role in the treatment of schizophrenia. Although the conven- tional antipsychotics haloperidol and fluphenazine decanoate are the only options currently available, they should not be overlooked for responsive but noncompliant patients who remain at risk of symp- tom relapse. Depot medications offer the advantages of guaranteed compliance and steady serum drug lev- els. The absence of daily peak serum levels with these medications may also be associated with lower total side effects than equivalent doses of the oral formula- tion (104). Depot antipsychotics may occasionally be used at low doses in combination with atypical agents to provide the patient with a measure of protection against relapse in the event of noncompliance with the oral medication. The major disadvantages of depot medications are poor patient acceptance and lengthy times for dose adjustments. Although atypi- cal agents are not available in depot formulations in the United States, a long-acting formulation of risperidone has been developed and is currently avail- able outside the United States. Depot risperidone has been shown to be effective and well tolerated in clin- ical trials (105), and it now awaits FDA review. COST-EFFECTIVENESS Given the costs associated with schizophrenia and its treatment, it is not surprising that numerous attempts have been made to study and improve the cost-effectiveness of therapy. Despite the purported greater acceptability to patients of atypical antipsy- chotics, their effect on the economics of schizophre- nia treatment has generally been found to be neutral because of their significantly higher acquisition cost (106). It is more difficult to quantify the relationship between costs and quality of life measures (107). One widely used approach to cost containment in the treatment of severe and persistent mental disor- ders is the use of treatment guidelines and algo- rithms. Based on a combination of empirical studies and expert consensus, the more general guidelines and more specific algorithms attempt to define a rational approach to treatment involving both clini- cal and economic issues. Among the best known of these are the American Psychiatric Association’s prac- tice guidelines and the Texas Medication Algorithm Project (TMAP). The APA practice guidelines focus on the most rigorously established empirical findings, 28 Winter 2004, Vol. II, No. 1 F O C U S T H E J O U R NA L O F L I F E LO N G L E A R N I N G I N P S YC H I AT RY JIBSON ET AL.