US Pharm. 2009;34(11):HS-2-HS-9.
Patients with mental illness constitute a population that can be challenging for any health care provider, but they offer great opportunities for a pharmacist to make a meaningful contribution. The pharmacist's role might involve assisting in the selection of medication regimens, managing adverse drug reactions, or facilitating adherence. These interventions can be particularly important for patients with schizophrenia.
DIAGNOSIS AND CLINICAL PRESENTATION
Schizophrenia is a chronic, debilitating mental illness that affects approximately 1% of the population.1 Owing to the 10% lifetime prevalence of suicide in patients with the disorder, early recognition and appropriate treatment are imperative.2 Schizophrenia typically presents in late adolescence and persists throughout the patient's life, and males typically experience symptoms 5 to 7 years earlier than females.1,3
Symptoms of schizophrenia may be classified as positive, negative, or cognitive. Positive symptoms include disorganized speech or behavior and psychotic characteristics such as delusions or hallucinations. Delusions, or fixed false beliefs, occur when a patient misinterprets an experience, leading to erroneous beliefs involving paranoia or persecution. Hallucinations involve more vivid sensory disruptions, with auditory hallucinations being the most common.1,3 Negative symptoms, including affective flattening, alogia, avolition, and reduced social drive (see TABLE 1), involve the diminution or absence of normal functions; they often are refractory to treatment.3,4 Cognitive symptoms are highly prevalent and may include difficulties with verbal fluency, attention, and working memory.3 Antipsychotic medications have little effect on cognitive symptoms; as a result, these symptoms affect a patient's ability to obtain employment, establish personal relationships, and function in many social settings.3
According to Diagnostic and Statistical Manual of Mental Disorders-IV-TR criteria, a patient can be diagnosed with schizophrenia if he or she presents with at least two of the following symptoms in addition to social dysfunction for a significant amount of time during a 1-month period, with some symptoms persisting for at least 6 months: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms.4 The diagnosis can also be made solely on the basis of bizarre delusions or hallucinations involving voices.4
Although the neurochemistry behind schizophrenia is not fully understood, the disorder is thought to be caused by increased dopaminergic transmission.1 This increase in dopamine effect causes the brain to be hypersensitive to stimuli, making it difficult for the patient to distinguish between reality and his or her delusions or hallucinations.1 Researchers continue to explore the roles that neurotransmitters other than dopamine, such a serotonin and acetylcholine, might play in schizophrenia.1
Owing to the complex nature of schizophrenia, treatment typically involves both pharmacologic and nonpharmacologic therapies.
Although nonpharmacologic interventions may be perceived as treatment modalities that cannot change the biochemistry of schizophrenia, they can help patients learn how to cope with their illness. Fostering healthy relationships, maintaining employment, learning from others who struggle with mental illness, and participating in cognitive behavioral therapy can all be effective components of a patient's treatment.5
A 2-year randomized study compared the effect of integrated treatment versus standard treatment in 547 newly diagnosed schizophrenia patients. Standard-treatment patients were offered access to a community mental-health center and received minimal home visits; integrated-treatment patients received home visits from an assigned assertive community-treatment team member and were offered family treatment sessions and social-skills training. Both arms were offered antipsychotic medications. Patients in the integrated-treatment arm showed clinically significant improvement in positive and negative symptoms and substance abuse, but no improvement in depression or suicidal behavior. The integrated-treatment group had a statistically significant decrease in hospital stays during the first year, but the difference was not significant at 2 years. Finally, the mean antipsychotic dose for patients in the integrated-treatment arm was significantly lower.6 This trial illustrates that psychiatric care has a positive impact on a patient's life when pharmacotherapy is augmented with lifestyle coaching and family involvement.
Most patients with schizophrenia require chronic treatment with medications to control symptoms and achieve remission. Once a patient attains a satisfactory clinical response, the regimen should continue indefinitely. First-line medication options include first- and second-generation antipsychotics.1
First-Generation Antipsychotics (FGAs): FGAs, also known as conventional or typical antipsychotics, work via dopamine receptor antagonism.1 TABLE 2 includes a list of FGAs. This class of antipsychotics is associated with movement disorders, including extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Symptoms of EPS include akathisia, dystonia, and pseudoparkinsonism (see TABLE 1). Akathisia can be treated either by lowering the antipsychotic dosage or with benzodiazepines or centrally acting beta-blockers such as propranolol; dystonia and pseudoparkinsonism can be treated with anticholinergic agents such as benztropine or diphenhydramine.1 TD, which typically presents as abnormal orofacial movements, develops in 30% of patients on long-term FGAs. Unlike EPS, TD cannot be treated with medications, and it may be irreversible even after the offending antipsychotic is discontinued.1
Second-Generation Antipsychotics (SGAs): Whereas FGAs work primarily as dopamine-2 receptor antagonists, the mechanisms are much broader for SGAs (also known as atypical antipsychotics). In addition to having an antagonistic effect on dopamine, SGAs also antagonize norepinephrine and serotonin receptors (TABLE 2). Aripiprazole has a unique mechanism of action involving mixed dopaminergic agonism and antagonism in addition to antagonism of serotonergic receptors.1
Owing to serotonergic antagonism, SGAs are not associated with high rates of EPS, with the exception of aripiprazole, which causes akathisia in approximately 10% of patients.7 Although patients taking SGAs usually do not experience movement-disorder issues, SGAs come with new risks that may negatively affect patient adherence. Clozapine and olanzapine are associated with metabolic syndrome, specifically weight gain, diabetes, and dyslipidemia; other atypical antipsychotics, however, offer minimal to no risk of these metabolic effects.8 Clozapine also carries a risk of seizures, anticholinergic effects, hypersalivation, myocarditis, and agranulocytosis.9 The incidence of agranulocytosis in patients taking clozapine is 0.39%, and the incidence of death from agranulocytosis is 0.012%.10 The FDA requires all providers prescribing clozapine to be registered with the Clozaril National Registry. Absolute neutrophil counts must be monitored weekly for 6 months when therapy is initiated or adjusted, and continuously throughout the course of therapy.1 Risperidone and paliperidone are associated with hyperprolactinemia, leading to acute adverse events such as galactorrhea (spontaneous flow of milk from nipple), amenorrhea (absence of menses), and sexual dysfunction. Osteoporosis may be a long-term effect of hyperprolactinemia.9,11
Both conventional and atypical agents, particularly haloperidol, chlorpromazine, iloperidone, thioridazine, and ziprasidone, are associated with prolongation of the QTc interval, with the last two agents having the highest incidence.9,12,13 The incidence of QTc prolongation with these agents is approximately twice that of a healthy population not taking antipsychotics.14 Providers must always consider the side effects of antipsychotics and discuss them with their patients prior to prescribing.
There is very little literature supporting the idea that SGAs are more effective than FGAs. A number of meta-analyses have been published comparing the efficacy of the two classes, as have meta-analyses comparing various SGAs with one another, but no conclusions have been made about the comparative efficacy of the various agents.9,15,16 Both CUtLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) and CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) showed that atypical antipsychotics offer no benefit over conventional antipsychotics; however, CATIE 2 concluded that clozapine may have an advantage over other atypical antipsychotics in treatment-refractory patients.17-19 Clozapine's benefit may be a result of the increase in provider interaction due to monitoring for agranulocytosis.20
Improvements in sleep disturbance and agitation may be seen in the first 2 days of antipsychotic therapy; however, the full effect may not be seen for 6 to 8 weeks. If the patient reports no symptom relief in 2 to 4 weeks, either the antipsychotic dose should be increased or a new agent should be selected.1,21
Recommended doses of FGAs and SGAs are given in TABLE 2.22 These doses have been suggested by the manufacturers of the respective agents; however, practitioners often prescribe outside of the recommended range. While this often is unavoidable in treatment-resistant patients, the practice may result in adverse events and limited additional efficacy. Also, many patients probably will not require the higher end of the dosing range for FGAs. Specifically, patients experiencing their first psychotic break will likely respond to much lower doses of antipsychotics and be more sensitive to adverse events than a patient in a more advanced stage of schizophrenia.21 Additionally, it should be noted that the total daily dose of most antipsychotics can be administered once daily if tolerated, and this will improve adherence. Exceptions to this are clozapine, quetiapine, and ziprasidone, which probably will require multiple daily doses to control symptoms. Finally, treatment with multiple antipsychotics should be considered a last resort and avoided if at all possible, as it often provides no additional efficacy and increases the risk of intolerable side effects.
In general, FGAs are more affordable than SGAs, with perphenazine and fluphenazine costing more than other FGAs. Currently, the only generic SGAs are clozapine and risperidone. Cost should be a major consideration when choosing an antipsychotic, with a preference for FGAs if a patient can tolerate them.
Other Medications: Whereas antipsychotics remain the primary pharmacologic treatment for schizophrenia, a number of other medications may be used to augment them. One such class is the mood stabilizers, which often are used in patients experiencing increased agitation or aggression. Overall, patients with schizophrenia are not violent; however, episodes in which positive symptoms are exacerbated may lead to increased agitation.3 During such instances, mood stabilizers may be beneficial. In a meta-analysis of 11 studies comparing antipsychotic monotherapy with lithium augmentation, more patients receiving lithium had a clinically significant response, with a number needed to treat of 8.23 Two small studies have compared antipsychotic monotherapy with carbamazepine augmentation; in these studies, patients on carbamazepine showed clinically significant overall global improvement.24 Similarly, there is only limited evidence to support the use of augmentation therapy with valproate, including a single small study showing less agitation in the valproate augmentation group versus the antipsychotic monotherapy group.25 A meta-analysis of five studies evaluating the efficacy of antipsychotic augmentation with lamotrigine showed that 20% to 30% of clozapine-resistant patients with schizophrenia had a clinically significant improvement when lamotrigine was added.26 In a randomized, double-blind, placebo-controlled study of patients with schizophrenia, the addition of topiramate resulted in a reduction of both positive and negative symptoms compared with patients on antipsychotic monotherapy.27 Mood stabilizers have great potential for the treatment of schizophrenia, but more research is needed.
Benzodiazepines have been studied for their benefits in augmenting antipsychotics. Although the studies have been small, they have shown some advantage over antipsychotic monotherapy in treating agitation in schizophrenia. This effect is short-lived, however, with a return of symptoms within 1 hour of a benzodiazepine dose.28
One of the most straightforward algorithms for the treatment of schizophrenia was published by the Texas Department of State Health Services (FIGURE 1). This algorithm is based on evidence when available, and expert consensus where no evidence exists. If a patient fails trials of two stages of this algorithm with no appreciable improvement in symptoms, the diagnosis of schizophrenia should be re-evaluated, and the possibility of co-occurring substance abuse should be considered.29
A number of studies have been designed to measure patient adherence to antipsychotics compared with other medications, but the results are difficult to interpret. This is primarily because each study defines and measures nonadherence differently. A meta-analysis of adherence studies reported that patients take an average of 58% of their prescribed antipsychotic doses (range 24%-90%). The meta-analysis found that patients take medications for physical ailments an average of 76% of the time (range 60%-92%), implying that adherence to antipsychotics may be lower than adherence to other medications.30 Some barriers to care in patients with schizophrenia include stigma about mental illness, lack of access to care, and fragmentation of services.5 A pharmacist can help a patient overcome these barriers through education and identification of patient-assistance programs when financial issues arise. Additionally, the pharmacist may recommend the use of long-acting depot antipsychotic injections to improve adherence to medication therapy. Recommended doses of depot antipsychotics are given in TABLE 2.
Despite the fact that there is no cure for schizophrenia, providing patients with guideline-based treatments supported by primary literature will afford the best opportunity for controlling the symptoms of their illness. The process of choosing appropriate medications and monitoring for appropriate adverse reactions should be facilitated by a pharmacist whenever possible.
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20. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60:82-91.
21. APA Practice Guidelines. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia. 2nd ed.
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25. Schwarz C, Volz A, Li C, Leucht S. Valproate for schizophrenia. Cochrane Database Syst Rev. 2008;(3):CD004028.
26. Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2009;109:10-14.
27. Afshar H, Roohafza H, Mousavi G, et al. Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled clinical trial. J Psychopharmacol. 2009;23:157-162.
28. Volz A, Khorsand V, Gillies D, Leucht S. Benzodiazepines for schizophrenia. Cochrane Database Syst Rev. 2007;(1):CD006391.
29. Moore TA, Buchanan RW, Buckley PF, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry. 2007;68:1751-1762.
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