CLINICAL HANDBOOK OF SCHIZOPHRENIA - PART 4 pdf

of standard antipsychotic drug treatment and, (2) for reduction of the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk of reexperiencing suicidal behavior. One generally accepted norm to establish treatment resistance is failure in at least two trials of antipsychotic drugs for at least 6 weeks each at doses equal to 10–20 mg of haloperidol per day, or its equivalent. Treatment-resistant patients often have at least moderate positive, negative, or disorgani - zation (incoherence, loose association, inappropriate affect, and poverty of thought con - tent) symptoms and impaired social functioning despite at least two adequate trials of antipsychotic drugs chosen from two or more different classes of these agents. Off-label uses of clozapine sometimes seen in clinical settings include use for patients with unman - ageable extrapyramidal symptoms (EPS), tardive dyskinesia (TD), refractory bipolar dis - order, refractory obsessive–compulsive disorder (OCD), and Parkinson’s disease. CLOZAPINE THERAPY INITIATION AND ISSUES RELATED TO EARLY STAGES OF TREATMENT Medical Assessments The patient should have a thorough history and physical examination (Table 18.1). The history should include information regarding any history of blood dyscrasias, sei- zure disorder, cardiovascular disease, hepatic and renal disease, as well as any immuno- suppressive diseases such as HIV. Laboratory testing should include a complete baseline blood count with white blood cell (WBC) count and absolute neutrophil count (ANC), complete metabolic assay including serum electrolytes and renal function tests, and an electrocardiogram (ECG) with QTc interval. Clozapine dosing and titration may re- quire modification in individuals with any of the aforementioned preexisting condi- tions. Patient and Family Education Risks, benefits, and treatment alternatives should be discussed with the patient and fam - ily, and documented in the treatment record (Table 18.1). The hematological and cardio - vascular risks must be discussed in detail. The specific monitoring protocol regarding blood draws should be discussed with patients and families, and agreed upon in advance. In some treatment settings, home visits for blood drawing may be arranged to facilitate adherence with monitoring. Dosing and Titration The starting dose of clozapine is 12.5 mg once or twice daily (Table 18.1). The small starting dose helps to assess for early hypotensive reactions. Patient should be observed for sedation and changes in blood pressure and pulse. The dose can be increased by 25–50 mg daily up to a target dose of 300–450 mg/day by the end of 2 weeks for young, medically healthy individuals. Subsequent dosage increments may be made once or twice weekly in increments not to exceed 100 mg. Twice-daily dosage is recom - mended in view of the half-life of clozapine. The dose generally need not exceed 450– 600 mg/day in most adults < 60 years old in the initial phase of treatment. The maxi - mum recommended dose is 900 mg/day, if response is unsatisfactory at 600 mg/day. The dosage of clozapine in older adults is usually 100–300 mg/day. A quick-dissolving formulation of clozapine is now available for individuals who have difficulty swallow - 180 III. SOMATIC TREATMENT ing pills. Patients who respond to clozapine should be continued on the lowest dose re - quired to maintain remission. Management of Potential Early Side Effects Hematological Effects Agranulocytosis (granulocyte count < 500/mm 3 ) and granulocytopenia (granulocyte count < 1,500/mm 3 ) are rare (less than 1%), but serious potential side effects of clozapine therapy. Agranulocytosis and granulocytopenia, if they occur, usually develop in the first 2–6 months of therapy. The risk is higher in older adults, women, and in patients of Ash - kenazi Jewish descent with the human leukocyte antigen HLA-B38 phenotype. Mortality is higher in African American populations who develop agranulocytosis. Coadministra - 18. Clozapine 181 TABLE 18.1. Clinical tips for clozapine initiation and management Clinical point/adverse effect Management tips Medical assessment prior to clozapine initiation • History and physical. • Screen for blood dyscrasia, seizure disorder, cardiovascular disorder, immunosuppressive disease. • Labs: complete blood count with differential, metabolic assay. • ECG Patient and family education • Discussion of hematological and cardiovascular risk. • Agreed upon (in advance) monitoring schedule, arrange in- home blood draws if possible. Initial dosing and titration • Healthy adults: 12.5mg once or twice daily, increased as tolerated in increments of 25–50 mg/day to a target dose of 300–450 mg/day. May require doses of 600–900 mg/day for treatment of schizophrenia. • Median dose to reduce suicidal behavior on the order of 300 mg/day. Hematological effects • Weekly WBC/ANC for first 6 months. • Every-other-week WBC/ANC for Months 6–12 if no complications. • Monthly WBC/ANC after 12 months and beyond, if no complications. Sedation • Most pronounced in first month; minimize with slow titration and lowest effective dose. Seizure risk • Most pronounced with high overall dosage and fast titration. Minimize with slow titration. Use valproate if anticonvulsant is needed. Cardiovascular risks (hypotension, myocarditis, etc.) • Low starting dose, slow titration. • ECG follow-up, especially in those with past cardiac history. • Increase fluid intake, potential use of fludrocortisone for hypotension. Long-term weight gain • Follow ADA guidelines for monitoring parameters. • Education, diet control, and behavioral measures (involve family, case managers). • Potential benefit with sibutamine. Continued refractory symptoms • Add on high-potency conventional antipsychotic (haloperidol). • Add on risperidone. • Add on anticonvulsant (valproate or lamotrigine). tion of drugs such as carbamazepine, which have bone marrow–suppressing effects, can potentially increase the risk for agranulocytosis. It is necessary to monitor hematological status (white blood cell count [WBC] and absolute neutrophil count [ANC]) on a weekly basis for the first 6 months of clozapine therapy (Table 18.1). Patients should be in - structed to report onset of fever, sore throat, weakness, or other signs of infection promptly. If the total WBC falls below 3,000 or if the ANC falls below 1,500, medical or hematological consultation should be obtained. Agranulocytosis is a medical emergency and is managed by reverse isolation and prophylactic broad-spectrum antibiotics. Treat - ment with granulocyte colony-stimulating factor (G-CSF) and granulocyte–macrophage colony-stimulating factor (GM-CSF) have been reported to decrease morbidity and to shorten the duration of illness secondary to agranulocytosis. Other hematological side ef - fects associated with clozapine therapy include benign leukocytosis (0.6%), leukopenia (3%), eosinophilia (10%), and elevated erythrocyte sedimentation rate. Neurological/Mental Status Effects Sedation, occurring in 10–58% of clozapine-treated individuals, is perhaps the most com - mon and immediately troubling neurological side effect. Fortunately, some sedation is likely to resolve gradually after early phases of titration. Additionally, effects of daytime sedation can be minimized by giving most of the clozapine dose at night. Clozapine reduces seizure threshold and the occurrence of seizures is dose related— 0.7% per 100 mg dose. Valproate is preferred by many clinicians as the safest and best- tolerated anticonvulsant in clozapine-treated patients experiencing seizures. During the first few months of clozapine treatment some patients develop benign fe- vers (100–103°F). This is usually self-limiting, and can be managed with antipyretics. However, the more serious condition of neuroleptic malignant syndrome (NMS) also is more common in the first 14 days of clozapine treatment. Concurrent treatment with lithium is a risk factor for NMS. Management of NMS includes discontinuation of antipsychotic and supportive measures to reduce the body temperature, including use of a hypothermia blanket and hydration. Drugs such as amantadine, benzodiazepines, dantro- lene, and bromocriptine can be effective. Electroconvulsive therapy (ECT) also has been used in refractory cases. Finally, approximately 10% of clozapine-treated patients experience obsessive– compulsive symptoms such as repeated handwashing. Decreasing clozapine dose or addi - tion of a serotonin selective reuptake inhibitor (SSRI) may help to alleviate these symptoms. Cardiovascular and Other Side Effects Cardiovascular side effects that may be associated with clozapine therapy include tachy - cardia, orthostatic hypotension, prolongation of QTc interval, deep vein thrombosis, myocarditis, and cardiomyopathy. Clozapine should be discontinued in patients who de - velop myocarditis or cardiomyopathy. Tachycardia is due to vagal inhibition and can be treated with beta-adrenergic antagonists such as atenolol; however, this may also potenti - ate the hypotensive effects of clozapine. Low starting dose and gradual titration can re - duce the hypotensive side effects. Additional treatment measures include fluid intake of at least 2 liters/day, support stockings, increased sodium intake, and fludrocortisone treatment. Sialorrhea (hypersalivation) occurs in 31–54% of individuals on clozapine therapy. Sialorrhea may respond to clonidine patches (0.1 mg weekly). Anticholinergic agents may be helpful for some patients but should be approached cautiously because of additive ef - fects and the possibility of anticholinergic delirium. Clozapine itself has strong anticho - 182 III. SOMATIC TREATMENT linergic effects that can lead to urinary retention, constipation, and gastrointestinal (GI) obstruction. It has been postulated (McGurk et al., 2005), that anticholinergic effects may be responsible for worsening of spatial working memory in individuals with schizo - phrenia. Slow titration of clozapine and use of lowest effective dose minimize anticholin - ergic effects. Enuresis/urinary incontinence (0.23%) is a potential additional embarrassing side ef - fects of clozapine. Avoiding fluids in the evening, voiding before going to bed, scheduling middle-of-the-night awakening to empty the bladder, and using enuresis alarms can be of help. Ephedrine, intranasal desmopressin (DDAVP), and oxybutynin have been reported to be beneficial in the management of clozapine-induced enuresis. MAINTENANCE CLOZAPINE THERAPY IN CLINICAL SETTINGS Once clozapine has been initiated and a stable, maintenance dose achieved, tasks for the clinician include (1) ongoing hematological monitoring, (2) monitoring for long-term, ad - verse medication effects and physical health monitoring, and (3) ongoing symptom as - sessment and functional outcome evaluation (Table 18.1). Hematological Monitoring Fortunately, recommendations for regular serum monitoring with respect to hematologi- cal effects were modified in 2005. Current monitoring frequency suggests weekly WBC counts and ANC monitoring for the first 6 months of therapy, then every 2 weeks (if no complications) for months 6–12 of treatment, and after 12 months of therapy (if no complications) every 4 weeks ad infinitum. If therapy is discontinued, monitoring should continue for an additional 4 weeks from time of discontinuation. Long-Term Health Monitoring Monitoring for long-term adverse medication effects with clozapine is largely centered on evaluation of weight gain and development of metabolic abnormalities such as develop - ment of type 2 diabetes. Many studies overwhelmingly confirm that atypical antipsy - chotic medications produce substantially more weight gain compared to conventional antipsychotic agents, and clozapine is generally agreed to have significant weight gain po - tential. Additional related consequence of the atypical antipsychotics are their effect on serum lipids. Clozapine, which often produces substantial weight gain, may also be asso - ciated with increases in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, and with decreased high-density lipoprotein (HDL) cholesterol. The Ameri - can Diabetes Association (ADA) and the American Psychiatric Association (APA) have recommended that individuals maintained on atypical antipsychotic medications (includ - ing clozapine) should have baseline assessment of personal and family history of obesity– diabetes–cardiovascular risk factors, weight and height, waist circumference, blood pres - sure, and fasting plasma glucose and lipid profiles. Weight should be measured at weeks 4 and 8 of treatment, week 12 of treatment, and quarterly thereafter. Additional monitor - ing recommendations are personal history reassessment annually, waist circumference an - nually, blood pressure and fasting plasma glucose at 12 weeks, then annually thereafter, and fasting lipid profile at 12 weeks, then every 5 years thereafter. Hypertension may be associated with weight gain and lipid abnormalities in some clozapine-treated patients. Education, diet control, and behavioral measures may prevent excessive weight gain. In 18. Clozapine 183 those with weight gain, medication treatment can be attempted (e.g., sibutamine), with careful monitoring of side effects. Additional adverse effects that may be associated with long-term treatment include somnolence, sialorrhea, and urinary incontinence (all of which may be dose dependent to some degree). Myocarditis may occur with patients maintained on clozapine therapy. In rare cases, agranulocytosis may occur even after years of uncomplicated treatment, and isolated cases of apparent movement disorders or TD have been reported. It is known that schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy compared with that in the general population. A recent ex - pert consensus panel has recommended that mental health care providers perform appro - priate physical health monitoring that typically occurs in primary care settings for their patients with schizophrenia who do not receive such monitoring. Patients with severe, treatment-refractory illness are likely to belong to this group of disadvantaged individuals who often have difficulty accessing care in standard primary settings. Physical health consensus recommendations overlap somewhat with ADA–APA guidelines (body mass index, plasma glucose levels, lipid profiles). Additional parameters of physical health monitoring include monitoring for signs of myocarditis, sexual dysfunction, and EPS–TD in patients on clozapine (particularly individuals age 50 and older). Ongoing Symptom Evaluation and Functional Outcome Assessment Cognitive functioning and quality of life may improve in those who have good response to clozapine therapy. Additionally, potential reduction in suicidality maintains safety and allows patients to engage in recovery interventions. There is also fairly consistent evi- dence that clozapine therapy may reduce aggressive behavior and allow some individuals with previously extremely severe illness to transition to more independent, less restrictive residential settings. Maximization of clozapine dosage on the order of 600–900 mg/day should be attempted in patients who tolerate the drug but appear to be refractory (check- ing serum levels may be somewhat useful, although there are no clear, standardized target levels). The median dose to reduce risk of suicidal behavior in clinical trials was approxi - mately 300 mg/day (range: 12.5–900 mg/day). Treatment adherence should remain an ongoing concern, although, perhaps because of the need for ongoing serum monitoring, a number of reports suggest that treatment ad - herence is actually better for clozapine compared to other antipsychotic compounds. For individuals who are refractory with optimized clozapine dosing there have been reports that adjunctive treatment with other antipsychotics (high-potency conventional agents such as haloperidol, or atypical agents such as risperidone), or anticonvulsant com - pounds, such as lamotrigine, may be of benefit for some patients. KEY POINTS • Clozapine is the prototype drug from the antipsychotic class often referred to as atypical antipsychotics. • Clozapine use is generally reserved for the most severe forms of schizophrenia and is the treatment of choice for refractory patients. • In addition to its efficacy in severely ill/refractory patients with schizophrenia, clozapine has been demonstrated to reduce the risk of recurrent suicidal behavior. • Clozapine therapy may reduce aggressive behavior and allow some individuals with previ - ously severe illness to transition to more independent, less restrictive residential settings. 184 III. SOMATIC TREATMENT • Common side effects of clozapine therapy include sedation, tachycardia, orthostasis, sialorrhea, and weight gain/metabolic abnormalities (e.g., elevated serum glucose and de - velopment of diabetes). • Due to the potential for rare but serious hematological effects (agranulocytosis or granulo - cytopenia) it is necessary to monitor hematological status continuously for as long as indi - viduals are maintained on clozapine therapy. • Because risk of clozapine-related hematological effects are greatest in the first 6 months of therapy, the need for frequent serum monitoring decreases over time and is only necessary on a monthly basis after 12 months of therapy without complications. REFERENCES AND RECOMMENDED READINGS American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, & North American Association for the Study of Obesity. (2004). Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care, 27(2), 596–601. Kane, J., Honigfeld, G., Singer, J., Meltzer, H. Y., & the Clozapine Collaborative Study Group. (1988). Clozapine for the treatment-resistant schizophrenia: A double blind comparison with chlorpromazine. Archives of General Psychiatry, 45, 789–796. Marder, S. R., Essock, S. M., Miller, A. L., Buchanan, R. W., Casey, D. E., Davis, J. M., et al. (2004). Physical health monitoring of patients with schizophrenia. American Journal of Psychiatry, 161(8), 1334–1349. McGurk, S. R., Carter, C., Goldman, R., Green, M. F., Marder, S. R., Hie, H., et al. (2005). The effects of clozapine and risperidone on spatial working memory in schizophrenia. American Journal of Psychiatry, 162(5), 1013–1016. Meltzer, H. Y., Alphs, L., Green, A. I., Altamura, A. C., Anand, R., Bertoldi, A., et al. (2003). Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial. Ar- chives of General Psychiatry, 60(1), 82–91. Meltzer, H. Y., Burnett, S.,Bastani, B.,& Ramirez,L. F. (1990). Effectof sixmonths ofclozapine treat- ment on the quality of life of chronic schizophrenic patients. Hospital and Community Psychia- try, 41, 892–897. National Alliance on Mental Illness. Available online at www.nami.org. Physicians’ Desk Reference (59th ed.). (2005). Montvale, NJ: Thompson. Seshamani, M. (2002). Is clozapine cost-effective?: Unanswered issues. European Journal of Health Economics, 3(Suppl. 2), S104–S113. U.S. Food and Drug Administration. Available online at www.fda.gov. Wahlbeck, K., Cheine M.,& Essali,M. A.(2000). Clozapine versus typicalneuroleptic medication for schizophrenia. Cochrane Database of Systematic Reviews, 2, CD000059. 18. Clozapine 185 CHAPTER 19 OTHER MEDICATIONS BRITTON ASHLEY AREY STEPHEN R. MARDER Although antipsychotics are the first-line agents for the treatment of schizophrenia, large areas of need are still unmet. First, many patients with schizophrenia demonstrate only partial responses to antipsychotics. Second, as the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) revealed, a large proportion of patients discontinue their antipsychotic due to lack of efficacy or tolerability issues. Last, neither the first- nor second-generation antipsychotics adequately address symptom domains such as cognition and negative symptoms. Both of these domains have been shown to have significant im- pact on functional outcomes in schizophrenia. In this chapter, we discuss alternative and adjunctive medication strategies for the treatment of schizophrenia, including mood stabilizers, benzodiazepines, and antidepres - sants. Furthermore, we present the evidence supporting treatments for co-occurring dis - orders such as depression, mania, anxiety, and obsessive–compulsive disorder. Finally, we mention new medications and mechanisms in development for the treatment of schizo - phrenia. We do not discuss treatment strategies for the side effects of antipsychotics, such as extrapyramidal symptoms, tardive dyskinesia, weight gain, or metabolic issues (for a discussion of these side effects, see Dolder, Chapter 17, this volume). MOOD STABILIZERS Mood stabilizers or antiepileptic agents have been widely used in the treatment of schizo - phrenia. Citrome, Jaffe, Levine, and Allingham (2002) showed that the use of mood sta - bilizers in the New York State mental health system nearly doubled from 1994 to 2001, with 47.1% of inpatients diagnosed as having schizophrenia in 2001 receiving a mood stabilizer. We discuss the evidence for the use of mood stabilizers as monotherapy and as aug - mentation agents to address the core symptoms of schizophrenia. We also discuss data that support using these medications as adjunctive treatment for affective symptoms and 186 agitation in schizophrenia. Finally, we make recommendations for the use of mood stabi - lizers in schizophrenia based on the evidence presented. Lithium There is little evidence that lithium has any inherent antipsychotic properties; indeed, studies to date show that as a sole agent, lithium is ineffective in the treatment of schizo - phrenia. There is some support for increasing response rates in schizophrenia by augmenting antipsychotics with lithium. However, in a meta-analysis, Leucht, Kissling, and McGrath (2004) showed that the advantage of lithium augmentation was not significant when pa - tients with affective symptoms were excluded from the studies. Additionally, more pa - tients taking lithium discontinued the studies, suggesting a lower tolerability of lithium augmentation. Thus, despite some evidence in favor of lithium augmentation, the overall results are inconclusive and suggest that it may only be effective for patients with affec - tive symptoms. A limited body of evidence indicates that lithium, as augmentation to antipsychotics, helps atypical mania, schizoaffective disorder, or schizophreniform disorder, both as an acute treatment and to prevent recurrence. Indeed, some literature suggests that it may be useful to subtype schizoaffective disorders into primarily affective versus schizophrenia types, and to treat them accordingly. To this end, adding mood stabilizers such as lithium to the treatment of patients with predominant affective or manic symptoms appears to be effective. Further support for this strategy comes from a literature review by Keck, McElroy, Strakowski, and West (1994), which demonstrated that the combination of lith- ium and antipsychotics is superior to antipsychotics alone for schizoaffective, bipolar- type patients. Last, some literature suggests that concomitant administration of lithium alongside an antipsychotic may be useful in certain patients with aggression, agitation, or psychomotor excitement. At present, however, available data do not support the use of lithium montherapy or adjunctive therapy in the treatment of the core symptoms of schizophrenia. On the other hand, lithium does appear to be a useful comedication when added to an antipsychotic for patients with either concomitant affective symptoms or agitation and aggression. Valproate Valproate is currently one of the most frequently prescribed drugs in treatment of schizo - phrenia spectrum disorders. A study by Citrome et al. (2002) showed that in the New York State mental health system between 1994 and 2001, adjunctive use of valproate nearly tripled among patients with a diagnosis of schizophrenia, and was ultimately pre - scribed for 35% of patients with schizophrenia, making it the most commonly prescribed mood stabilizer for that population. A Cochrane Database review by Basan and Leucht (2004) showed that studies evalu - ating valproate as monotherapy to treat schizophrenia are extremely limited and show no benefit. Furthermore, this review concluded that the effectiveness of adjunctive valproate on overall outcomes in schizophrenia remains unclear. A more promising strategy involves the use of valproate to augment antipsychotics in the short-term treatment of patients who demonstrate agitation or excitement. In a study of 249 patients hospitalized with acute exacerbation of schizophrenia, with a moderate degree of uncooperativeness and hostility or excitement and tension, Citrome and col - leagues (2004) showed that adding valproate to either risperidone or olanzapine was well 19. Other Medications 187 tolerated, produced a faster onset of action in the combination group, and indicated re - duced hostility and core psychotic symptoms. This advantage for valproate augmentation was not sustained, however, beyond the first week of treatment. Based on the randomized trial–derived evidence currently available, therefore, no data support or refute the use of valproate as an adjunctive agent in the long-term treat - ment of schizophrenia. However, it may be reasonable to consider valproate for acutely ill inpatients with agitation in the first weeks of treatment and when more rapid improve - ment is important. We also support the use of valproate in patients with unstable moods when an antipsychotic alone fails to lead to mood stability. Carbamazepine A review of the available literature by Leucht et al. (2002) determined that carbamazepine monotherapy has not been shown to be effective in the treatment of schizophrenia when compared to placebo or antipsychotic. Some studies have shown a trend indicating a ben - efit from carbamazepine as an adjunct to antipsychotics in the treatment of schizophre - nia, but the trials have had small numbers of subjects, and a review of the available data has indicated inconsistent and inconclusive results. Some preliminary data show that carbamazepine may be useful in treating affective symptoms of schizophrenia, and may decrease violent behavior in psychotic patients. However, the studies are extremely limited, and further research is warranted on the use of carbamazepine in patients with excitement, aggression, mania with psychosis, and bi- polar-type schizoaffective disorder. Furthermore, it is important to note that because carbamazepine induces metabolic activity and can therefore lower the dose of certain antipsychotics (e.g., haloperidol, thiothixene) when administered adjunctively, when it is withdrawn, a corresponding in- crease of the antipsychotic may occur. Indeed, studies of patients on haloperidol demon- strated that the adjunctive use of carbamazepine was associated with a dramatic fall in haloperidol plasma levels and a worse clinical outcome compared to the monotherapy group. Thus, at present, neither carbamazepine monotherapy nor augmentation can be rec - ommended on the basis of the available evidence for routine use in the treatment of schizophrenia. Lamotrigine Several lines of evidence suggest that glutamate may be involved in schizophrenia pathophysiology. Postmortem studies have revealed a lower density of glutamatergic re - ceptors in patients with schizophrenia; and lower levels of cerebrospinal fluid (CSF) glu - tamate have been found in patients with schizophrenia compared to normal controls. The most compelling evidence is provided by the psychomimetic effects of the N-methyl-d- aspartic acid (NMDA) antagonists phencyclidine and ketamine. When administered to normal controls, both agents can induce positive, negative, and cognitive symptoms simi - lar to those observed in patients with schizophrenia. Hence, there has been much interest and speculation about the role of lamotrigine, which acts on the glumatate system, in the treatment of schizophrenia. Despite this, there are few studies in the literature about the effects of lamotrigine in the treatment of schizophrenia. There are no reported randomized, controlled clini - cal trials of lamotrigine monotherapy in schizophrenia, and few trials of adjunctive treatment. 188 III. SOMATIC TREATMENT Small, open-label trials of clozapine-treated patients with treatment-resistant schizo - phrenia have shown that the addition of lamotrigine to clozapine resulted in significant improvement in Brief Psychiatric Rating Scale (BPRS) total scores. These results are fur - ther supported by one randomized controlled trial of lamotrigine added to clozapine, in which both positive and general psychopathological symptoms improved with lamotri - gine augmentation. However, data for lamotrigine augmentation with other antipsychotics are less clear. Indeed, there have been mixed results when lamotrigine was used as an adjuvant to antipsychotics other than clozapine. Kremer and colleagues (2004), in a double- blind, placebo-controlled study of 38 patients with treatment-resistant schizophrenia, found that the addition of lamotrigine to either first- or second-generation antipsychotics resulted in improvement in positive symptoms and general psychopathology in patients who completed the study, regardless of whether they were on a typical or atypical antipsychotics. In contrast, in a small, naturalistic outcome study of 17 patients with treatment-resistant schizophrenia, Dursun and Deakin (2001) showed that only when lamotrigine was added to clozapine did patients experience a reduction in psychotic symptoms; there was no significant improvement when lamotrigine was added to risperidone, haloperidol, olanzapine, or fluphenthixol. Therefore, although the addition of lamotrigine may be useful for some patients with treatment-resistant schizophrenia who are currently being treated with clozapine, further use of lamotrigine in schizophrenia treatment is not supported by the available literature. Summary As monotherapy for schizophrenia, mood stabilizing drugs have no documented beneficial effect. However, when these drugs are used as adjunctive therapies to antipsychotics, some positive effects have been demonstrated. Lithium has demonstrated effects on affective symptoms associated with schizophrenia and schizophrenia-related illnesses. Evidence for antiaggressive effects exists for several of the mood stabilizers, but it is perhaps best vali- dated for the use of adjunctive valproate in acutely ill inpatients to hasten recovery and re- duce agitation in the first week of treatment, although there is no evidence supporting the long-term use of adjunctive valproate for the treatment of aggression in schizophrenia at this time. Finally, preliminary evidence suggests that the addition of lamotrigine to cloza - pine may be beneficial in treatment-resistant schizophrenia, but more studies are needed to substantiate this effect, and to validate the same findings with other antipsychotics. BENZODIAZEPINES Medications that affect gamma-aminobutyric acid (GABA), such as benzodiazepines, may have a potential role in the treatment of schizophrenia. This is supported by data in - dicating that schizophrenia may be associated with a down-regulation in cortical GABA- ergic function. Because GABA can reduce dopaminergic activity, increasing GABA func - tion with certain benzodiazepines could be effective in treating positive and negative symptoms of schizophrenia. To date, the literature contains no consistent evidence that benzodiazepines in monotherapy effectively treat the core symptoms of schizophrenia. A review of the data reveals that the majority of available studies indicate some positive benzodiazepine effects in reducing agitation, anxiety, or global impairment. However, only slightly more than half of the double-blind, controlled trials published on benzodiazepines as monotherapy 19. Other Medications 189 [...]... (2003) Clinical potential of omega-3 fatty acids in the treatment of schizophrenia CNS Drugs, 17(15), 1081–1091 Evins, A E., Cather, C., Deckersbach, T., Freudenreich, O., Culhane, M A., Olm-Shipman, C M., et al (2005) A double-blind placebo-controlled trial of bupropion sustained-release for smoking cessation in schizophrenia Journal of Clinical Psychopharmacology, 25(3), 218–225 Joy, C B., Mumby-Croft,... dosage, has a low-to-high efficacy rate and a mild-to-moderate cognitive side effect profile Predictors of a positive response to ECT in patients with schizophrenia include acute schizophrenia onset, short duration of schizophrenia episode, and presence of delusions, hallucinations, or catatonic features Predictors of a negative response to ECT in patients with schizophrenia include long length of schizophrenic... trial Archives of General Psychiatry, 46 , 922–928 Kremer, I., Vass, A., Gorelik, I., Bar, G., Blanaru, M., Javitt, D C., et al (20 04) Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia Biological Psychiatry, 56(6), 44 1 44 6 Lehman, A F., Kreyenbuhl, J., Buchanan, R W., Dickerson, F B., Dixon, L B., Goldberg, R., et al (20 04) .The Schizophrenia Patient... Leucht, S (20 04) Valproate for schizophrenia Cochrane Database of Systematic Reviews, 1, CD0 040 28 Braga, R J., Petrides, G., & Figueira, I (20 04) Anxiety disorders in schizophrenia Comprehensive Psychiatry, 45 , 46 0 46 8 19 Other Medications 195 Citrome, L., Casey, D E., Daniel, D G., Wozniak, P., Kochan, L D., & Tracy, K A (20 04) Adjunctive divalproex and hostility among patients with schizophrenia. .. to 25% of patients with schizophrenia do not adequately benefit from pharmacotherapy alone; thus, ECT is recommended as a treatment option Predictors of response and benefit of ECT in patients with schizophrenia include an acute onset of schizophrenia, short duration of schizophrenia episode and presence of mood symptoms, delusions or hallucinations, and catatonic features Negative indicators of response... Although the majority of the literature on the use of antidepressants in schizophrenia involves tricyclics and SSRIs, several studies reported on the use of bupropion in schizophrenia In a double-blind, randomized, placebo-controlled study (Evins et al., 2005) on the use of bupropion for smoking cessation in patients with schizophrenia, subjects in the bupropion group had no worsening of clinical symptoms... symptoms are found in 50% of patients with newly diagnosed schizophrenia, and 33% of people with chronic schizophrenia who have relapsed Depression is common in schizophrenia and is associated with disability, reduction of motivation to accomplish tasks and the activities of daily living, increased duration of illness, more frequent relapses, and increased risk of suicide Diagnosing schizophrenia with depression... effectiveness of antidepressants in persons with schizophrenia The Schizophrenia Patient Outcomes Research Team (PORT; Lehman et al., 20 04) study also acknowledged the existence of several single-blind, randomized controlled trials of antidepressants in patients with schizophrenia, and similarly concluded that the results were mixed The evidence regarding whether antidepressants worsen the course of schizophrenia. .. summarizing these results, there appears to be no evidence-based rationale for the use of benzodiazepine monotherapy in the treatment of schizophrenia The adjunctive use of benzodiazepines with antipsychotics is often helpful for the short-term treatment of agitation and anxiety during the acute phase of the illness Benzodiazepine augmentation may be particularly useful when patients are receiving antipsychotics... component of neuronal membranes, and that abnormalities of phospholipid metabolism may be present in patients with schizophrenia This has given rise to the theory that omega-3 polyunsaturated fatty 1 94 III SOMATIC TREATMENT acids, and eicosapentanoic acid (EPA) in particular, may have a role in treating this illness However, clinical data thus far in support of the role of fatty acids in treating schizophrenia . colleagues (20 04) , in a double- blind, placebo-controlled study of 38 patients with treatment-resistant schizophrenia, found that the addition of lamotrigine to either first- or second-generation. double-blind placebo-controlled trial of bupropion sustained-release for smoking cessation in schizophrenia. Journal of Clinical Psychopharmacology, 25(3), 218–225. Joy, C. B., Mumby-Croft, R.,. antipsychotics in schizophrenia. Biologi - cal Psychiatry, 56(6), 44 1 44 6. Lehman, A. F., Kreyenbuhl, J., Buchanan, R. W., Dickerson, F. B., Dixon, L. B., Goldberg, R., et al. (20 04) .The Schizophrenia