Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment.

OBJECTIVE: To report efficacy and safety of galcanezumab in adults with chronic cluster headache. BACKGROUND: Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptide and inhibits its biological activity. METHODS: This study comprised a prospective baseline period, a 12-week double-blind, placebo-controlled treatment period, and a 52-week open-label period. Up to six protocol-specified concomitant preventive medications were allowed if patients were on a stable dose for 2 months prior to the prospective baseline period. Patients were randomized 1:1 to monthly subcutaneous galcanezumab (300 mg) or placebo. The primary endpoint was overall mean change from baseline in weekly attack frequency with galcanezumab compared to placebo. Key secondary endpoints were ≥50% response rate and percentage of patients meeting sustained response. Results from the double-blind treatment period are reported. RESULTS: A total of 237 patients were randomized and treated (120 placebo; 117 galcanezumab). At baseline, the mean age was 45 years and 63% were using ≥1 preventive drug. The primary endpoint was not met; mean change in weekly attack frequency was -4.6 placebo versus -5.4 galcanezumab (p = 0.334). Key secondary endpoints also were not met. Injection site-related treatment-emergent adverse events were more common in the galcanezumab than the placebo group, with significantly more injection site erythema. CONCLUSION: Treatment with galcanezumab 300 mg did not achieve its primary and key secondary endpoints. This study underscores the potential distinct biology of cCH as well as the significant unmet need for safe, effective, and well-tolerated preventive treatment. The safety profile of galcanezumab in cCH is consistent with that observed in trials of episodic CH and migraine. TRIAL REGISTRATION: NCT02438826; https://www.clinicaltrials.gov/ct2/show/NCT02438826.

Trial of Galcanezumab in Prevention of Episodic Cluster Headache.

BACKGROUND: Episodic cluster headache is a disabling neurologic disorder that is characterized by daily headache attacks that occur over periods of weeks or months. Galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, may be a preventive treatment for cluster headache. METHODS: We enrolled patients who had at least one attack every other day, at least four total attacks, and no more than eight attacks per day during a baseline assessment, as well as a history of cluster headache periods lasting at least 6 weeks, and randomly assigned them to receive galcanezumab (at a dose of 300 mg) or placebo, administered subcutaneously at baseline and at 1 month. The primary end point was the mean change from baseline in the weekly frequency of cluster headache attacks across weeks 1 through 3 after receipt of the first dose. The key secondary end point was the percentage of patients who had a reduction from baseline of at least 50% in the weekly frequency of cluster headache attacks at week 3. Safety was also assessed. RESULTS: Recruitment was halted before the trial reached the planned sample size of 162 because too few volunteers met the eligibility criteria. Of 106 enrolled patients, 49 were randomly assigned to receive galcanezumab and 57 to receive placebo. The mean (±SD) number of cluster headache attacks per week in the baseline period was 17.8±10.1 in the galcanezumab group and 17.3±10.1 in the placebo group. The mean reduction in the weekly frequency of cluster headache attacks across weeks 1 through 3 was 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (difference, 3.5 attacks per week; 95% confidence interval, 0.2 to 6.7; P = 0.04). The percentage of patients who had a reduction of at least 50% in headache frequency at week 3 was 71% in the galcanezumab group and 53% in the placebo group. There were no substantial between-group differences in the incidence of adverse events, except that 8% of the patients in the galcanezumab group had injection-site pain. CONCLUSIONS: Galcanezumab administered subcutaneously at a dose of 300 mg once monthly reduced the weekly frequency of attacks of episodic cluster headache across weeks 1 through 3 after the initial injection, as compared with placebo. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT02397473.).

Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial.

Importance: Migraine is a disabling neurological disease characterized by severe headache attacks. Treatment options reduce migraine frequency for many patients, but adverse effects lead to discontinuation in many patients. Objective: To demonstrate that galcanezumab is superior to placebo in the prevention of episodic migraine with or without aura. Design, Setting, and Participants: The EVOLVE-1 (Evaluation of LY2951742 in the Prevention of Episodic Migraine 1) trial was a double-blind, randomized, placebo-controlled (January 11, 2016, to March 22, 2017) trial comparing galcanezumab (120 mg and 240 mg) vs placebo. Patients received treatments once monthly for 6 months (subcutaneous injection via prefilled syringe) and were followed up for 5 months after their last injection. It was a multicenter, clinic-based study involving 90 sites in North America. Participants in the study were adults (aged 18 to 65 years) with at least a 1-year history of migraine, 4 to 14 migraine headache days per month and a mean of at least 2 migraine attacks per month within the past 3 months, and were diagnosed prior to age 50 years. During the study, no other preventive medications were allowed. A total of 1671 patients were assessed; 809 did not meet study entry or baseline criteria, and 858 were included in the intent-to-treat population. Interventions: Patients were randomized (2:1:1) to monthly placebo, galcanezumab, 120 mg, and galcanezumab, 240 mg. Main Outcomes and Measures: The primary outcome was overall mean change from baseline in the number of monthly migraine headache days during the treatment period. Secondary measures included at least 50%, at least 75%, and 100% reduction in monthly migraine headache days, migraine headache days with acute medication use, and scores from the Migraine-Specific Quality of Life questionnaire, Patient Global Impression of Severity, and Migraine Disability Assessment. Treatment-emergent adverse events and serious adverse events were reported. Results: Of the 1671 patients assessed, 858 (mean age, 40.7 years; 718 women [83.7%]) met study entry criteria and received at least 1 dose of investigational product. The primary objective was met for both galcanezumab doses; treatment with galcanezumab significantly reduced monthly migraine headache days (both P < .001) by 4.7 days (120 mg) and 4.6 days (240 mg) compared with placebo (2.8 days). All key secondary objectives were also significant after multiplicity adjustment. There were no meaningful differences between 120-mg and 240-mg doses of galcanezumab on measures of efficacy. Completion rate during treatment was high (81.9%; n = 718), and the incidence of discontinuation owing to adverse events was less than 5% across all treatment groups. Conclusions and Relevance: Galcanezumab 120-mg and 240-mg monthly injections provided clinical benefits and improved functioning. The incidence rate of adverse events was low, demonstrating the favorable tolerability profile of galcanezumab. Trial Registration: ClinicalTrials.gov Identifier: NCT02614183.

Pharmacogenomic associations with weight gain in olanzapine treatment of patients without schizophrenia.

OBJECTIVE: Pharmacogenomic analyses of weight gain during treatment with second-generation antipsychotics have resulted in a number of associations with variants in ankyrin repeat and kinase domain containing 1 (ANKK1)/dopamine D2 receptor (DRD2) and serotonin 2C receptor (HTR2C) genes. These studies primarily assessed subjects with schizophrenia who had prior antipsychotic exposure that may have influenced the amount of weight gained from subsequent therapies. We assessed the relationships between single-nucleotide polymorphisms (SNPs) in these genes with weight gain during treatment with olanzapine in a predominantly antipsychotic-naive population. METHOD: The association between 5 ANKK1, 54 DRD2, and 11 HTR2C SNPs and weight change during 8 weeks of olanzapine treatment was assessed in 4 pooled studies of 205 white patients with diagnoses other than schizophrenia who were generally likely to have had limited previous antipsychotic exposure. RESULTS: The A allele of DRD2 rs2440390(A/G) was associated with greater weight gain in the entire study sample (P = .0473). Three HTR2C SNPs in strong linkage disequilibrium, rs6318, rs2497538, and rs1414334, were associated with greater weight gain in women but not in men (P = .0032, .0012, and .0031, respectively). A significant association with weight gain for 2 HTR2C SNPs previously reported associated with weight gain, -759C/T (rs3813929) and -697G/C (rs518147), was not found. CONCLUSIONS: Associations between weight gain and HTR2C and DRD2 variants in whites newly exposed to olanzapine may present opportunities for the individualization of medication selection and development based on differences in adverse events observed across genotype groups.

Antipsychotic monotherapy among outpatients with schizophrenia treated with olanzapine or risperidone in Japan: a health care database analysis.

PURPOSE: Antipsychotic monotherapy is often recommended over antipsychotic polypharmacy because of fewer adverse events, reduced treatment complexity, and lower medication cost. This study compared the rate and the duration of antipsychotic monotherapy following initiation of olanzapine or risperidone in the treatment of outpatients with schizophrenia in Japan. METHODS: Outpatients diagnosed with schizophrenia in the Japan Medical Data Center database were identified using International Statistical Classification of Diseases and Related Health Problems, 10th Revision, diagnosis codes. Patients were between 20 and 65 years old, initiated on olanzapine or risperidone therapy between August 2003 and July 2008, and continuously enrolled during the 6 months prior to and the 12 months following the initiation date. Antipsychotic polypharmacy was defined as concurrent use of two or more antipsychotics. The probability of monotherapy during the 12-month follow-up period was assessed using a propensity score-adjusted generalized estimating equation model. Duration of monotherapy was contrasted using a propensity score-adjusted bootstrapping model. RESULTS: After applying all inclusion and exclusion criteria, the final analytic sample consisted of 332 olanzapine- and 496 risperidone-treated outpatients. At treatment initiation, 61.5% of the olanzapine-treated patients and 45.6% of the risperidone-treated patients received antipsychotic monotherapy (P < 0.001). After correcting for background differences, monotherapy was more common among olanzapine-treated patients (P = 0.001). In addition, olanzapine was used as monotherapy for a longer duration (P = 0.006). CONCLUSION: Consistent with prior global research, this retrospective naturalistic study of schizophrenia outpatients in Japan found that olanzapine is more likely to be used as monotherapy and to be used as monotherapy for a longer duration than risperidone.

Dopamine pathology in schizophrenia: analysis of total and phosphorylated tyrosine hydroxylase in the substantia nigra.

INTRODUCTION: Despite the importance of dopamine neurotransmission in schizophrenia, very few studies have addressed anomalies in the mesencephalic dopaminergic neurons of the substantia nigra/ventral tegmental area (SN/VTA). Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the production of dopamine, and a possible contributor to the anomalies in the dopaminergic neurotransmission observed in schizophrenia. OBJECTIVES: In this study, we had three objectives: (1) Compare TH expression (mRNA and protein) in the SN/VTA of schizophrenia and control postmortem samples. (2) Assess the effect of antipsychotic medications on the expression of TH in the SN/VTA. (3) Examine possible regional differences in TH expression anomalies within the SN/VTA. METHODS: To achieve these objectives three independent studies were conducted: (1) A pilot study to compare TH mRNA and TH protein levels in the SN/VTA of postmortem samples from schizophrenia and controls. (2) A chronic treatment study was performed in rodents to assess the effect of antipsychotic medications in TH protein levels in the SN/VTA. (3) A second postmortem study was performed to assess TH and phosphorylated TH protein levels in two types of samples: schizophrenia and control samples containing the entire rostro-caudal extent of the SN/VTA, and schizophrenia and control samples containing only mid-caudal regions of the SN/VTA. RESULTS AND CONCLUSION: Our studies showed impairment in the dopaminergic system in schizophrenia that could be mainly (or exclusively) located in the rostral region of the SN/VTA. Our studies also showed that TH protein levels were significantly abnormal in schizophrenia, while mRNA expression levels were not affected, indicating that TH pathology in this region may occur posttranscriptionally. Lastly, our antipsychotic animal treatment study showed that TH protein levels were not significantly affected by antipsychotic treatment, indicating that these anomalies are an intrinsic pathology rather than a treatment effect.

Cost-effectiveness of several atypical antipsychotics in orally disintegrating tablets compared with standard oral tablets in the treatment of schizophrenia in the United States.

OBJECTIVE: Although the use of innovative drug delivery systems, like orally disintegrating antipsychotic tablets (ODT), may facilitate medication adherence and help reduce the risk of relapse and hospitalization, no information is available about the comparative cost-effectiveness of standard oral tablets (SOT) vs ODT formulations in the treatment of schizophrenia. This study compared the cost-effectiveness of olanzapine ODT and olanzapine SOT in the usual treatment of outpatients with schizophrenia from a US healthcare perspective. The study also compared olanzapine ODT with risperidone and aripiprazole, two other atypical antipsychotics available in both ODT and SOT formulations. METHODS: Published medical literature and a clinical expert panel were used to populate a 1-year Monte Carlo Micro-simulation model. The model captures clinical and cost parameters including adherence levels, treatment discontinuation by reason, relapse with and without inpatient hospitalization, quality-adjusted life years (QALYs), treatment-emergent adverse events, healthcare resource utilization, and associated costs. Key outcomes were total annual direct cost per treatment, QALY, and incremental cost-effectiveness (ICER) per 1 QALY gained. RESULTS: Based on model projections, olanzapine ODT therapy was more costly ($9808 vs $9533), but more effective in terms of a lower hospitalization rate (15% vs 16%) and better QALYs (0.747 vs 0.733) than olanzapine SOT therapy. Olanzapine ODT was more cost-effective than olanzapine SOT (ICER: $19,643), more cost-effective than risperidone SOT therapy (ICER: $39,966), and dominant (meaning less costly and more effective) than risperidone ODT and aripiprazole in ODT or SOT formulations. LIMITATIONS: Lack of head-to-head randomized studies comparing the three studied atypical antipsychotics required making input assumptions that need further study. CONCLUSIONS: This micro-simulation found that the utilization of olanzapine ODT for the treatment of schizophrenia is predicted to be more cost-effective than any other ODT or SOT formulations of the studied atypical antipsychotic medications.

Striatal mitochondria in subjects with chronic undifferentiated vs. chronic paranoid schizophrenia.

Schizophrenia (SZ) is a heterogeneous disease with a spectrum of symptoms, risk factors, and etiology. Abnormalities in mitochondria, the energy-producing organelles of the cell, have been observed in mixed cohorts of subjects with SZ. The purpose of the present study was to determine if striatal mitochondria were differentially affected in two different DSM-IV subgroups of SZ. Postmortem striatal tissue was examined from normal controls (NC), chronic paranoid SZs (SZP), and chronic undifferentiated SZs (SZU). Tissue was processed for calbindin immunohistochemistry to identify striosomal compartments, prepared for electron microscopy and analyzed using stereological methods. In both caudate and putamen, the density of mitochondria in the neuropil was decreased in SZP compared to both NCs and SZU. In the putamen, both the SZP and the SZU subgroups had fewer mitochondria per synapse than did NCs. When examining patch matrix compartments, striatal compartments associated with different circuitry and function, only the matrix exhibited changes. In the caudate matrix, the SZP subgroup had fewer mitochondria in the neuropil than did the SZU and NCs. In the putamen matrix, the SZP had fewer mitochondria in the neuropil as compared to NCs, but not the SZU. The numbers of mitochondria per synapse in both the SZP and the SZU groups were similar to each other and fewer than that of NCs. A decrease in mitochondrial density in the neuropil distinguishes the SZP from the SZU subgroup, which could be associated with the symptoms of paranoia and/or could represent a protective mechanism against some of the symptoms that are less pronounced in this subtype than in the SZU subgroup such as cognitive and emotional deficits.

Analysis of gene variants previously associated with iloperidone response in patients with schizophrenia who are treated with risperidone.

OBJECTIVE: We examined 6 single nucleotide polymorphisms (SNPs) previously reported to be associated with response to iloperidone therapy for association with response to risperidone therapy. METHOD: Patients with schizophrenia (DSM-IV) were assessed during 2006 and 2007 for response/nonresponse (defined as ≥ 20%/<20% improvement in Positive and Negative Syndrome Scale [PANSS] total score) after 2 weeks of risperidone treatment (2 to 6 mg/d). Responders continued risperidone treatment; nonresponders were randomly assigned to either risperidone or olanzapine treatment (10 to 20 mg/d) for an additional 10 weeks. Associations between change in PANSS total (primary outcome measure), positive, and negative scores and the 6 SNPs were examined in risperidone-treated patients (N = 145). Genotype frequencies and improvement in PANSS total scores were analyzed for those SNPs significantly associated with change in PANSS total score. RESULTS: The SNPs XKR4 rs9643483 and GRIA4 rs2513265 were significantly associated with change in PANSS total response (adjusted P < .05 for both), with the same direction of effect as reported for iloperidone. For patients with nonresponsive genotypes for these SNPs, mean improvement in PANSS total score for African Americans was two-thirds that seen for whites (XKR4: -13.9 versus -21.4; GRIA4: -12.5 versus -20.9). CONCLUSIONS: In this retrospective pharmacogenomic analysis, we found that 2 SNPs previously linked to iloperidone response were also associated with response to risperidone. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00337662.

Responses to antipsychotic therapy among patients with schizophrenia or schizoaffective disorder and either predominant or prominent negative symptoms.

Patients with schizophrenia who have predominant negative symptoms are often considered less responsive to treatment. This analysis of patients with schizophrenia or schizoaffective disorder compares changes in symptom severity between those with predominant versus merely prominent negative symptoms. Prominent negative symptoms were defined by a baseline score of ≥4 on at least 3, or ≥5 on at least 2, of the 7 Positive and Negative Syndrome Scale (PANSS) negative subscale items. Predominant negative symptoms were defined by the foregoing plus a PANSS positive score of <19, a Barnes Akathisia score of <2, a Simpson-Angus score of <4, and a Calgary Depressive Scale score of <9. Adult patients with schizophrenia (n=227) or schizoaffective disorder (n=116) received either olanzapine (10-20mg/day, n=169) or quetiapine (300-700mg/day, n=174) for up to 24weeks. Data for both medications were pooled. Of the 343 patients enrolled in the study, 34.7% met the criteria for predominant negative symptoms, the remaining 65.3% being characterized only by their prominent negative symptoms. Changes in the severity of negative symptoms in both patient types largely followed similar trajectories during treatment, as reflected both in Marder PANSS negative subscale scores and in the Scale for Assessment of Negative Symptoms total and domain scores. Patients with either predominant or prominent negative symptoms therefore appear to respond similarly to atypical antipsychotic treatment. This distinction, incorporating an evaluation of the presence of positive, affective, and extrapyramidal symptoms, may therefore not have prognostic implications for the responsiveness of patients' negative symptoms to treatment.

Rimonabant for neurocognition in schizophrenia: a 16-week double blind randomized placebo controlled trial.

OBJECTIVE: To examine the effect of rimonabant on neurocognitive impairments in people with schizophrenia. METHODS: Participants entered a 16-week double-blind, placebo-controlled, randomized clinical trial. A neurocognitive battery was administered at baseline and end of study. RESULTS: In comparison to rimonabant (20mg/day), placebo-treated participants exhibited a significant improvement on the Repeatable Battery for the Assessment of Neuropsychological Status total score. In contrast, rimonabant was associated with significant improvement on a probabilistic learning task. There were no other significant treatment effects. CONCLUSIONS: Rimonabant did not improve global cognitive functioning, but did improve a specific learning deficit based on response to positive feedback.

Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims.

Teenage suicide is a major public health concern, but its neurobiology is not well understood. Proinflammatory cytokines play an important role in stress and in the pathophysiology of depression-two major risk factors for suicide. Cytokines are increased in the serum of patients with depression and suicidal behavior; however, it is not clear if similar abnormality in cytokines occurs in brains of suicide victims. We therefore measured the gene and protein expression levels of proinflammatory cytokines interleukin (IL)-1ß, IL-6, and tissue necrosis factor (TNF)-α in the prefrontal cortex (PFC) of 24 teenage suicide victims and 24 matched normal control subjects. Our results show that the mRNA and protein expression levels of IL-1ß, IL-6, and TNF-α were significantly increased in Brodmann area 10 (BA-10) of suicide victims compared with normal control subjects. These results suggest an important role for IL-1ß, IL-6, and TNF-α in the pathophysiology of suicidal behavior and that proinflammatory cytokines may be an appropriate target for developing therapeutic agents.

Decline in hospitalization risk and health care cost after initiation of depot antipsychotics in the treatment of schizophrenia.

PURPOSE: To assess change in hospitalization and cost of care from 6 months pre- to 6 months post-initiation on any depot antipsychotic among schizophrenia patients. PATIENTS AND METHODS: Using a large United States commercial claims and encounters database, patients younger than 65 years diagnosed with schizophrenia were identified. Patients initiated on a depot antipsychotic were studied in a mirror-image design to assess change in hospitalization rates, mean duration hospitalized, and hospitalization cost. McNemar's test and paired t-tests compared the proportions of patients hospitalized and the mean duration. Paired t-test and bootstrapping methods compared costs. RESULTS: In these patients (n = 147), psychiatric hospitalizations declined from 49.7% pre-initiation to 22.4% post-initiation (P < 0.001), and the mean hospitalized duration for psychiatric purposes numerically declined from 7.3 to 4.7 days (P = 0.05). Total health care costs declined from $11,111 to $7884 (P < 0.05) driven by reduction in costs for psychiatric hospitalizations from $5384 to $2538 (P < 0.05). CONCLUSION: Initiation of depot antipsychotic therapy appeared to be associated with a decline in hospitalization rates and costs. Current findings suggest that treatment with depot antipsychotics may be a cost-effective option for a subgroup of patients with schizophrenia who are at high risk of nonadherence with their oral antipsychotic medication regimen.

Identification of early changes in specific symptoms that predict longer-term response to atypical antipsychotics in the treatment of patients with schizophrenia.

BACKGROUND: To identify a simple decision tree using early symptom change to predict response to atypical antipsychotic therapy in patients with (Diagnostic and Statistical Manual, Fourth Edition, Text Revised) chronic schizophrenia. METHODS: Data were pooled from moderately to severely ill patients (n = 1494) from 6 randomized, double-blind trials (N = 2543). Response was defined as a ≥ 30% reduction in Positive and Negative Syndrome Scale (PANSS) Total score by Week 8 of treatment. Analyzed predictors were change in individual PANSS items at Weeks 1 and 2. A decision tree was constructed using classification and regression tree (CART) analysis to identify predictors that most effectively differentiated responders from non-responders. RESULTS: A 2-branch, 6-item decision tree was created, producing 3 distinct groups. First branch criterion was a 2-point score decrease in at least 2 of 5 PANSS positive items (Week 2). Second branch criterion was a 2-point score decrease in the PANSS excitement item (Week 2). "Likely responders" met the first branch criteria; "likely non-responders" did not meet first or second criterion; "not predictable" patients did not meet the first but did meet the second criterion. Using this approach, response to treatment could be predicted in most patients (92%) with high positive predictive value (79%) and high negative predictive value (75%). Predictive findings were confirmed through analysis of data from 2 independent trials. CONCLUSIONS: Using a data-driven approach, we identified decision rules using early change in the scores of selected PANSS items to accurately predict longer-term treatment response or non-response to atypical antipsychotic therapy. This could lead to development of a simple quantitative evaluation tool to help guide early treatment decisions. TRIAL REGISTRATION: This is a retrospective, non-intervention study in which pooled results from 6 previously published reports were analyzed; thus, clinical trial registration is not required.

Cost-effectiveness of olanzapine long-acting injection in the treatment of patients with schizophrenia in the United States: a micro-simulation economic decision model.

OBJECTIVE: To compare, from the perspective of third-party payers in the United States health care system, the cost-effectiveness of olanzapine long-acting injection (LAI, depot) with alternative antipsychotic agents including risperidone-LAI, paliperidone-LAI, haloperidol-LAI, and oral olanzapine, in the treatment of patients with schizophrenia who have been non-adherent or partially adherent with oral antipsychotics. RESEARCH DESIGN AND METHODS: A 1-year micro-simulation economic decision model was developed to simulate the dynamics of usual care of patients with schizophrenia who continue, discontinue, switch, or restart their medication. The model uses a range of clinical and cost parameters including adherence levels, relapse with and without hospitalization, quality-adjusted life years (QALYs), treatment discontinuation rates by reason, treatment-emergent adverse events, suicide, health care resource utilization, and direct health care costs. Published medical literature and a clinical expert panel were used to develop baseline model assumptions. OUTCOME MEASURES: Key model outputs include annual total direct cost (US$) per treatment and incremental cost-effectiveness values per additional QALY gained. RESULTS: Model results found that the olanzapine-LAI treatment strategy was more effective (greater QALYs) and less costly than risperidone-LAI, paliperidone-LAI, and haloperidol-LAI. In addition, olanzapine-LAI was both more effective and more costly, with an estimated incremental cost/QALY of $26,824 compared to oral olanzapine. The base-case and multiple sensitivity analyses found olanzapine-LAI to remain within acceptable cost-effective ranges (<$50,000) in terms of incremental cost/QALY gained. CONCLUSIONS: This micro-simulation model finds the olanzapine-LAI treatment strategy to result in better effectiveness and to be a cost-effective alternative compared to oral olanzapine and the LAI formulations of risperidone, paliperidone, and haloperidol in the treatment of non-adherent and partially adherent patients with schizophrenia in the United States. A key limitation is the assumption how LAI therapies compare to oral counterparts due to sparse head-to-head data. Further research is needed to verify baseline assumptions.

Mitochondria in the striatum of subjects with schizophrenia.

OBJECTIVES: Schizophrenia is a severe mental illness that manifests pathology in many brain regions, including the striatum. Among the abnormalities in schizophrenia are those related to mitochondria. The present study sought to determine whether the number of mitochondria was affected at the level of the synapse. METHODS: Human postmortem striatum from schizophrenia subjects and controls was examined at the ultrastructural level. The density of mitochondria and synapses were tabulated using stereology. RESULTS: There were similar overall numbers of mitochondria in the caudate nucleus and putamen of schizophrenia subjects vs. controls, but a differential distribution of existing mitochondria. Schizophrenia subjects had 26?30% fewer mitochondria per synapse compared to controls. This may contribute to the pathophysiology of the illness, may be a medication effect, or an adaptive response to normalize the high number of striatal synapses we have previously found. The higher density of mitochondria in dendrites in the caudate nucleus in certain subgroups of schizophrenia vs. controls (>34%) may be related to more synaptic inputs. CONCLUSIONS: The role of mitochondria in the various symptoms of schizophrenia is still unclear. A comparison of schizophrenia subjects with differing symptoms or treatment response might shed light on whether differences in mitochondrial density are abnormal or adaptive.

Mitochondria in the striatum of subjects with schizophrenia: relationship to treatment response.

Schizophrenia (SZ) is a severe mental illness with neuropathology in many regions, including the striatum. The typical symptoms of this disease are psychosis (such as hallucinations and delusions), cognitive impairments, and the deficit syndrome. Not all patients respond to treatment and, in those who do, only psychotic symptoms are improved. Imaging studies support a biological distinction between treatment response and resistance, but postmortem examinations of this issue are rare. This study tests the hypotheses that abnormalities in mitochondria, the energy producing organelles in the cell, may correlate with treatment response. Postmortem striatal tissue was obtained from the Maryland Brain Collection. The density of mitochondria (in various neuropil compartments) and the number of mitochondria per synapse (all types of synapses combined) were tallied using electron microscopy and stereology in striatum from SZ subjects (rated treatment responsive or not) and normal controls. The number of mitochondria per synapse was significantly different among groups for both the caudate nucleus (P < 0.025) and putamen (P < 0.002). Compared to controls, treatment-responsive SZ subjects had a 37-43% decrease in the number of mitochondria per synapse in the caudate nucleus and putamen. In the putamen, treatment-responsive subjects also had decreases in this measure compared to treatment-resistant subjects (34%). Our results provide further support for a biological distinction between treatment response and treatment resistance in SZ. Because treatment responders have fewer mitochondria per synapse than controls, although the treatment-resistant subjects have similar results to that of controls, fewer mitochondria per synapse may be related to treatment response.