Serotonin Transporter mRNA Expression Is Reduced in the Peripheral Blood Mononuclear Cells of Subjects with Major Depression but Normal in Fibromyalgia.

BACKGROUND: Fibromyalgia (FM) and major depression disorder (MDD) frequently co-occur. Both disorders may share common serotonergic alterations, although there is less evidence of such alterations in FM. It is also unclear as to whether these alterations are persistent over time or transient. The objectives of this study were to (i) examine the changes in mRNA expression of serotonin transporter (SERT) on the surface of peripheral blood mononuclear cells (PBMCs) in FM, MDD, and the FM + MDD subjects compared to healthy controls, and to (ii) evaluate the effect of drug treatment on SERT expression. METHODS: PBMCs were isolated from FM, MDD, FM + MDD, and control subjects. SERT expression was analyzed at the mRNA level via quantitative real-time polymerase chain reaction. Statistical analyses were performed using analyses of variance and linear mixed-effects models. RESULTS: SERT mRNA expression was significantly reduced in MDD subjects compared to controls (p < 0.001), but not in FM nor in FM + MDD subjects. Although the drug treatments improved symptoms in FM, MDD, and FM + MDD subjects, they had no significant effect on SERT mRNA expression. CONCLUSIONS: These results corroborate the role of the SERT in the pathophysiology of MDD, but not in FM, and show that the decreased mRNA expression of SERT is a persistent, rather than transient, phenomenon.

Discontinuation of benralizumab in Canadian patients with severe eosinophilic asthma.

Within 1 year, 15% of Canadian patients with severe asthma discontinue benralizumab. The reasons for discontinuation are not yet characterised. https://bit.ly/3kaRDlp.

Time on therapy and concomitant medication use of mepolizumab in Canada: a retrospective cohort study.

About half of the patients who initiate therapy with mepolizumab discontinue treatment within the first or second year. Concomitant use of short-acting ß2-agonists and oral corticosteroids drops during mepolizumab use. https://bit.ly/3aRISqS.

Real-World Observational Study on the Characteristics and Treatment Patterns of Allergic Asthma Patients Receiving Omalizumab in Canada.

BACKGROUND: Omalizumab is a treatment option for pediatric and adult patients with moderate to severe allergic asthma poorly controlled with standard inhaled therapies. Clinical trials and observational studies have demonstrated the efficacy of omalizumab. There is limited real-world evidence on the characteristics and treatment patterns of Canadian asthma patients receiving omalizumab. OBJECTIVE: We profiled Canadian omalizumab users to estimate time to omalizumab discontinuation and to assess changes in concurrent medication usage before, during, and after therapy. METHODS: This was a retrospective, observational, cohort study that analyzed data from Canadian prescription claims databases. An algorithm was used to select naïve users of omalizumab with an inferred diagnosis of GINA 5-asthma who made a claim for omalizumab from February 1, 2007, to June 2, 2015. Demographic and baseline characteristics were assessed at index. Outcomes examined over the analysis period included (i) daily omalizumab dose per patient and per claim; (ii) omalizumab discontinuation (defined as ≥100-day gap in making omalizumab claims) and its potential predictors (ie, age, sex, province of residence, drug insurer; assessed by Cox Proportional Hazards Model); and (iii) for patients who discontinued omalizumab, changes in concurrent medication usage before, during, and 6 months after omalizumab usage. RESULTS: The final study cohort consisted of 1160 patients (mean age: 45.8 ± 15.2 years; 64.7% female). During the first year of omalizumab therapy, 29.5% of patients discontinued treatment. The singular characteristic that predicted omalizumab discontinuation with statistical significance was age group (20‒34 years vs 12‒19 years; hazard ratio 1.75, 95% confidence interval 1.11-2.76; P<0.05). There were significant reductions in the use of some concurrent inhaled and oral asthma medications during and/or after omalizumab use (P<0.05). CONCLUSION: Nearly one-third of patients who initiated omalizumab in Canada for refractory, moderate to severe allergic asthma discontinued treatment during the first year.

Severe, eosinophilic asthma in primary care in Canada: a longitudinal study of the clinical burden and economic impact based on linked electronic medical record data.

BACKGROUND: Stratification of patients with severe asthma by blood eosinophil counts predicts responders to anti-interleukin (IL)-5 (mepolizumab and reslizumab) and anti-IL-5 receptor α (benralizumab) therapies. This study characterized patients with severe asthma who could qualify for these biologics in a primary care setting. METHODS: We retrospectively selected patients from July 1, 2010, to June 30, 2014, using a linked electronic medical records (EMR) database (IMS Evidence 360 EMR Canada) for > 950,000 patients in primary care in Ontario, Canada. Patients aged ≥ 12 years with ≥ 2 documented asthma diagnoses were identified as having severe asthma based on prescriptions for high-dosage inhaled corticosteroids (ICS) plus either a leukotriene receptor antagonist, long-acting ß2-agonist (LABA), or theophylline filled on the same day. Patients' asthma was considered severe also if they received a prescription for ICS with oral corticosteroids (OCS) or an additional prescription for omalizumab. Patient characteristics, asthma-related medications, and blood eosinophil counts were captured using observed care patterns for the year prior to ICS/LABA and/or OCS prescription. Health care resource use (HCRU) and costs were captured throughout the 1-year follow-up period. RESULTS: We identified 212 patients who met the criteria for severe asthma. These patients required an average of 6.5 physician visits during the 1-year follow-up period (95% confidence interval 5.7-7.3), and 20 (9%) were referred to respiratory specialists. Overall, 56 patients (26%) with severe asthma had complete blood counts, of whom 23 (41%) had blood eosinophil counts ≥ 300 cells/µL and might be considered for anti-eosinophil therapies. Patients with severe asthma and blood eosinophil counts ≥ 300 cells/µL had more respiratory specialist referrals (17% vs. 12%) than patients with blood eosinophils < 300 cells/µL. CONCLUSIONS: Our data suggest that during 2010-2014, Ontario primary care patients with severe asthma and high blood eosinophil counts had greater HRCU than those with lower counts. Approximately 41% of patients with severe asthma could qualify for anti-eosinophil drugs based on blood eosinophil counts. However, the eosinophilic status of most patients was unknown. It is appropriate to increase awareness of the use of blood eosinophil counts to identify patients who could be considered for anti-eosinophil therapies.

Quetiapine fumarate extended-release for the treatment of major depression with comorbid fibromyalgia syndrome: a double-blind, randomized, placebo-controlled study.

OBJECTIVE: Fibromyalgia and major depressive disorder (MDD) frequently co-occur. Quetiapine fumarate extended-release (quetiapine XR) has demonstrated efficacy in the treatment of MDD and has been shown to have analgesic properties in patients with depression. The primary objectives of this study were to evaluate the effects of quetiapine XR on depressive and pain symptoms in patients with MDD and comorbid fibromyalgia, and to assess its safety and tolerability. METHODS: This was an 8-week, single-center, double-blind, randomized, controlled trial. A total of 120 nonpsychotic adult outpatients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria for MDD and whose diagnosis of fibromyalgia was confirmed according to the American College of Rheumatology criteria were enrolled. The primary end point was the mean change from baseline to week 8 on the 17-item Hamilton Depression Rating (HAM-D) scale. Secondary end points included other depression-rating scores, pain scores, fibromyalgia scores, measures of quality of life and global functioning, and adverse events. RESULTS: The mean change in the HAM-D score from baseline to week 8 was significantly greater in the quetiapine XR group compared with the placebo group (-10.0 versus -5.8; P = 0.001). Improvements in most secondary outcomes were also significantly greater in the quetiapine XR group. Quetiapine XR was generally well tolerated. CONCLUSION: This study is the first to demonstrate that measures of depression, pain, and quality of life are significantly improved with quetiapine XR compared with placebo in patients with a dual diagnosis of MDD and fibromyalgia.

Add-on treatment of quetiapine for fibromyalgia: a pilot, randomized, double-blind, placebo-controlled 12-week trial.

Recently, second-generation antipsychotic drugs have attracted interest in the treatment of chronic pain, including fibromyalgia (FM). Preliminary uncontrolled studies have shown that quetiapine treatment may be helpful for FM patients. In this trial, we sought to examine-for the first time-the efficacy and tolerability of quetiapine as a treatment for FM and its associated psychiatric symptoms. This was a 12-week double-blind, randomized, placebo-controlled trial of quetiapine XR as an add-on treatment for FM syndrome. Fifty-one female FM patients were randomized, and a flexible dosage of 50 to 300 mg/d was used. The primary outcome was the change from baseline to end point in the Fibromyalgia Impact Questionnaire total score. Secondary outcomes included mood symptoms, sleep disturbances, and tender points. Using a low dose (mean = 132.2 mg) of quetiapine, we observed significant benefits of drug treatment on sleep, uncertain effects on FM and mood symptoms, but no effects on pain, in a small group of polymedicated FM patients. Quetiapine was generally well tolerated.

A randomized, double-blind, placebo-controlled study of the safety and tolerability of high-dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder.

OBJECTIVE: Quetiapine is often prescribed at higher than approved doses. We investigated the safety, tolerability, and efficacy of quetiapine > 800 mg/d. METHOD: A trial was carried out from October 2003-September 2005 in 19 referral centers. Patients with DSM-IV schizophrenia or schizoaffective disorder were randomized on the basis of persistent symptoms of moderate severity (< 30% improvement in total Positive and Negative Syndrome Scale score after ≥ 4 weeks of quetiapine). The 8 week, double-blind study compared continuation of quetiapine 800 mg/d (n = 43) versus 1,200 mg/d (n = 88). The primary outcome measure was emergent or worsening parkinsonism (Simpson-Angus Scale). Secondary outcomes were adverse events, metabolic side effects, and symptom severity. RESULTS: Mean doses obtained were 799 mg/d and 1,144 mg/d in the 800-mg/d and > 800-mg/d groups, respectively. Emergent or deteriorating parkinsonism in the high-dose group was 3.1% greater (95% CI, -7.8% to 14.0%; P = .76) than in the 800-mg/d group, a value that was within the a priori limit of 16% defined as noninferiority. Both doses of quetiapine were safe and well tolerated. Weight gain was greater in the high-dose group (1.7 kg over 12 weeks; ≥ 7% body weight, n = 11 [12.5%]) versus the 800-mg/d group (1.1 kg over 12 weeks; ≥ 7% body weight, n = 4 [9.3%]). The mean adjusted difference in weight gain (1.3 kg) was greater in the high-dose group (95% CI, 0.0-2.5; P = .044). Symptom severity declined, with no significant difference between groups. CONCLUSIONS: The results did not demonstrate any advantage for use of quetiapine outside the approved dose range. TRIAL REGISTRATION: www.clinicaltrials.gov Identifier: NCT00328978.

Soluble interleukin-2 receptor levels correlated with positive symptoms during quetiapine treatment in schizophrenia-spectrum disorders.

BACKGROUND: Some but not all antipsychotics have been shown to modulate plasma cytokine levels in schizophrenia patients. Thus far, the most consistent finding has been the increase in plasma levels of soluble interleukin (IL)-2 receptor (sIL-2R) associated with clozapine treatment. Quetiapine is a second-generation antipsychotic with a pharmacological profile similar to that of clozapine, but its immunomodulatory effects have not been investigated in schizophrenia yet. The purpose of this exploratory study was to examine the changes in plasma levels of sIL-2R in schizophrenia during quetiapine treatment and association with psychopathology. METHODS: Participants were 29 schizophrenia-spectrum disorder patients (DSM-IV criteria), and 28 healthy controls. Patients had a comorbid substance use disorder (cannabis>alcohol>cocaine), since quetiapine is increasingly used in this population of dual diagnosis. No participant suffered from infection or overt inflammatory diseases. On baseline, patients taking mostly second-generation antipsychotics were switched to quetiapine for a 12-week open-label trial. Five patients were drop-outs. Mean dose of quetiapine for trial completers (n=24) was 466.6mg±227.3. Psychiatric variables were evaluated with the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. Plasma sIL-2R levels were assessed at baseline, weeks 6 and 12 in patients, and in healthy controls, using sandwich immunoassay. Plasma IL-6 and IL-1 receptor antagonist (IL-1RA) were measured for comparison purposes. RESULTS: On baseline, plasma sIL-2R, IL-6 and IL-1RA levels were higher in dual-diagnosis patients, compared to controls. Plasma sIL-2R further increased after quetiapine treatment (p=0.037), while plasma IL-6 and IL-1RA did not change. Clinical improvements were observed in positive, negative and depressive symptoms, and substance abuse severity (all p<0.01). Interestingly, changes in sIL-2R levels during treatment were inversely correlated with changes in positive symptoms (r=-0.524; p=0.009). That is, increases in sIL-2R levels were associated with reductions in positive symptoms. CONCLUSION: These data show that quetiapine elevates, like clozapine, sIL-2R levels in schizophrenia. Furthermore, the results suggest that sIL-2R alterations in schizophrenia rely on complex interplays between antipsychotics and the positive symptoms of the disorder. Future randomized controlled trials involving larger samples of schizophrenia patients are warranted to determine whether changes in plasma sIL-2R are quetiapine-related.

Evolution of Substance use, Neurological and Psychiatric Symptoms in Schizophrenia and Substance use Disorder Patients: A 12-Week, Pilot, Case-Control Trial with Quetiapine.

Neurological and psychiatric symptoms are consequences of substance abuse in schizophrenia and non-schizophrenia patients. The present case-control study examined changes in substance abuse/dependence, and neurological and psychiatric symptoms in substance abusers with [dual diagnosis (DD) group, n = 26] and without schizophrenia [substance use disorder (SUD) group, n = 24] and in non-abusing schizophrenia patients (SCZ group, n = 23) undergoing 12-week treatment with the atypical antipsychotic, quetiapine. Neurological and psychiatric symptoms were evaluated with the Positive and Negative Syndrome Scale, the Calgary Depression Scale for Schizophrenia, the Extrapyramidal Symptoms Rating Scale, and the Barnes Akathisia Rating Scale. At endpoint, DD and SCZ patients were receiving significantly higher doses of quetiapine (mean = 554 and 478 mg/day, respectively), relative to SUD patients (mean = 150 mg/day). We found that SUD patients showed greater improvement in weekly dollars spent on alcohol and drugs and SUD severity, compared to DD patients. At endpoint, there was no significant difference in dollars spent, but DD patients still had a higher mean SUD severity. Interestingly, DD patients had significantly higher parkinsonism and depression than SCZ patients at baseline and endpoint. On the other hand, we found that SUD patients had significantly more akathisia at baseline, improved more than SCZ patients, and this was related to cannabis abuse/dependence. Finally, SUD patients improved more in Positive and Negative Syndrome Scale positive scores than DD and SCZ patients. Taken together, our results provide evidence for increased vulnerability to the adverse effects of alcohol and drugs in schizophrenia patients. They also suggest that substance abuse/withdrawal may mimic some symptoms of schizophrenia. Future studies will need to determine the role quetiapine played in these improvements.

Clinical evolution of substance use disorder patients during treatment with quetiapine: a 12-week, open-label, naturalistic trial.

OBJECTIVE: Substance use disorders (SUDs) are associated with a variety of psychiatric disorders and mood and behavioral instability. Growing evidence suggests that the atypical antipsychotic quetiapine may be useful in the treatment of SUDs. The primary objective of the current open-label trial was to examine the effects of quetiapine on SUD outcomes in patients entering detoxification. METHODS: Thirty-three nonpsychosis SUD patients participated. Patients received quetiapine for a 12-week beginning in detoxification. Craving, quantities used and psychiatric symptoms were evaluated on baseline and at end point. RESULTS: Out of 33 recruited patients, 26 completed > 9 weeks of treatment. Last observation carried forward (LOCF) analyses revealed that craving, SUD severity and quantities used improved during the study. Psychiatric and depressive symptoms also improved. CONCLUSIONS: Our results cannot be attributed per se to the pharmacological effects of quetiapine owing to the open-label design of the study, the small sample size involved and the fact that patients were involved in an intensive therapy program. Nevertheless, our results indicate that quetiapine may be helpful for the treatment of SUD patients entering detoxification. Controlled studies are warranted to determine whether these results are quetiapine-related.

The co-administration of quetiapine or placebo to cognitive-behavior therapy in treatment refractory depression: a preliminary trial.

BACKGROUND: Patients with major depression refractory to repeated pharmacological trials (TRD) may remain symptomatic for many years after their index episode. Augmentation strategies (with lithium or an atypical antipsychotic) or combining an antidepressant with short-term psychotherapy have been used with relative success in these patients. The aim of this study was to assess the effectiveness of the concomitant administration of quetiapine, an atypical antipsychotic, or placebo, to cognitive-behavior therapy (CBT) in TRD. METHODS: Thirty-one patients who met entrance criteria for unipolar major depression (TRD stage II or greater) underwent 3 weeks of lithium augmentation after which non-responders (N = 22) were randomized to receive either quetiapine or placebo as an adjunct to their 12 weekly CBT sessions (quetiapine/CBT or placebo/CBT groups). Primary efficacy measures were the Hamilton and the Montgomery-Asberg rating scales for depression. RESULTS: Overall, there was a significant reduction in both primary efficacy measure scores at LOCF for the 11 patients in the quetiapine/CBT group but not in the placebo/CBT treated patients. Patients in the quetiapine/CBT group, compared to those receiving placebo/CBT, showed a significantly greater degree of improvement on one primary and one secondary efficacy measure, were more likely to complete the trial and, completed a greater number of CBT sessions. CONCLUSION: Although preliminary, our results suggest that the adjunctive administration of quetiapine to CBT may prove useful in the treatment of stage II TRD. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12638696.

Endogenous cannabinoids in patients with schizophrenia and substance use disorder during quetiapine therapy.

Disturbances in the endogenous cannabinoid (ECB) system in schizophrenia may contribute to their enhanced sensitivity to psychoactive substances, and the beneficial effects of second-generation antipsychotics for substance abuse in schizophrenia may involve modulatory effects on ECB. To verify these two assumptions, 29 patients (24 completers) with schizophrenia and substance use disorders (SUD) were treated with quetiapine for 12 weeks, and peripheral ECB levels were measured, using high-performance liquid chromatography/mass spectrometry, in patients (weeks 0, 6 and 12) and 17 healthy volunteers. Baseline anandamide levels were significantly higher in patients, relative to controls. This result is consistent with studies describing ECB dysfunctions in schizophrenia. SUD parameters improved during treatment, but no changes in ECB occurred over time. Improvements in substance abuse were probably not mediated by modulatory effects of quetiapine on ECB. Lastly, baseline anandamide predicted endpoint SUD scores (alcohol/ cannabis). Anandamide is a potential target for medications aimed at relieving SUD in schizophrenia.

Quetiapine extended-release versus immediate-release formulation: a positron emission tomography study.

OBJECTIVE: The pharmacokinetic and pharmacodynamic profile of the immediate-release (IR) formulation of quetiapine is characterized by a rapid peak in plasma level and striatal dopamine D(2) receptor occupancy, followed by a rapid decrease to baseline levels, necessitating the use of twice-daily dosing. An extended-release (XR) formulation of quetiapine is currently being developed to achieve similar efficacy using a once-daily dosing regimen. We compared the central D(2) receptor binding between the IR and XR formulations. METHOD: In this open-label, crossover positron emission tomography study using [(11)C]-raclopride, we compared the central D(2) receptor binding potential at expected peak and trough plasma levels using equivalent daily doses of the IR and XR formulations (300, 600, and 800 mg/day) in 12 subjects. Data were collected from April 2002 to May 2003. RESULTS: The mean plasma level of quetiapine at trough was significantly lower than that at peak for all dose groups of both formulations except for IR 300 and 800 mg (all p values < .05), while the mean plasma level did not differ significantly between formulations at trough and peak. The mean occupancy at peak was significantly higher than that at trough for all dose groups other than IR 800 mg/day (all p values < .05) and did not differ significantly between formulations at trough and peak. CONCLUSION: Once-daily dosing of the XR formulation gives peak and trough plasma levels and central D(2) receptor occupancy comparable to twice-daily dosing of the IR formulation. These data should be considered while determining equivalent doses, as well as switching strategies.

Anhedonia and social adaptation predict substance abuse evolution in dual diagnosis schizophrenia.

The current study sought to identify the variables, derived from the self-medication hypothesis, which predicted substance abuse evolution during a homogeneous 3-month antipsychotic treatment. Twenty-four patients were diagnosed with schizophrenia and substance abuse (mainly cannabis and alcohol). Substance abuse, psychiatric symptoms, anhedonia, and social adjustment were assessed at baseline and study endpoint. Linear regression analyses were performed. Better social adaptation and worse anhedonia predicted substance abuse improvements. Conversely, greater psychoactive substance (PAS) use predicted endpoint positive and depressive symptoms. These results suggest that: (i) substance abuse interferes with psychiatric prognosis in schizophrenia; and (ii) dual diagnosis treatments leading patients to engage in alternative social activities may render substance abuse less appealing. Further studies are warranted to dissociate the causes and consequences of substance abuse in schizophrenia.

Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review.

BACKGROUND: Cytokines play an important role in infection and inflammation and are crucial mediators of the cross-talk between the brain and the immune system. Schizophrenia would be associated with an imbalance in inflammatory cytokines, leading to a decrease in Th1 and an increase in Th2 cytokine secretion. However, data published so far have been inconsistent. The primary objective of the present meta-analysis was to verify whether the cytokine imbalance hypothesis of schizophrenia is substantiated by evidence. METHODS: Cross-sectional studies were included if they assessed in vivo plasma or serum cytokine concentrations and/or in vitro secretion of cytokines by peripheral blood leukocytes from schizophrenia patients and healthy volunteers. RESULTS: Data from 62 studies involving a total sample size of 2298 schizophrenia patients and 1858 healthy volunteers remained for analysis. Ten cytokines were assessed, including the prototypic Th1 and Th2 cytokines gamma interferon (IFN-gamma) and interleukin 4 (IL-4) as well as IL-2, soluble IL-2 receptor (sIL-2R), IL-1beta, IL-1 receptor antagonist (IL-1RA), tumor necrosis factor-alpha (TNF-alpha), IL-6, soluble IL-6 receptor (sIL-6R), and IL-10. The results show that an increase occurs in in vivo IL-1RA, sIL-2R, and IL-6 and a decrease occurs in in vitro IL-2 in schizophrenia. No significant effect sizes were obtained for the other cytokines. CONCLUSIONS: These findings provide the first evidence of establishment of an inflammatory syndrome in schizophrenia, which refutes the current hypothesis of a Th2 slant. Caveats are presented to data interpretation, including the role of stress and the effect of weight gain that develops in schizophrenia.

Quetiapine attenuates spatial memory impairment and hippocampal neurodegeneration induced by bilateral common carotid artery occlusion in mice.

Quetiapine, a new atypical antipsychotic drug, has beneficial effects on cognitive impairment and neuropathological changes in treating chronic neurodegenerative diseases. Our previous studies have demonstrated that quetiapine may have neuroprotective properties. In the present study, we investigated the effects of a 2-week pre-administration of quetiapine (10 mg/kg/day, i.p.) on spatial memory impairment and hippocampal neurodegeneration induced by 60-minute bilateral common carotid artery occlusion (CCAO). Following a 7-day recovery phase from CCAO, the spatial memory of the mice was tested using a modified water maze test. After the behavioural test, the mice were sacrificed and brain sections were stained with NeuN (a neuron-specific soluble nuclear antigen), cresyl violet (Nissl), and Fluoro-Jade B. CCAO significantly induced spatial memory impairment and caused neurodegeneration in the hilus of hippocampus, while quetiapine significantly attenuated these changes. This is the first study showing that quetiapine significantly attenuates CCAO-induced spatial memory impairment and this improvement parallels the alleviative effects of quetiapine on CCAO-induced neurodegeneration in the hilus of hippocampus. The results suggest that quetiapine may have defending effects on the impairments induced by cerebral ischemia, which enhances our understanding about the mechanisms of quetiapine.

Quetiapine attenuates the depressive and anxiolytic-like behavioural changes induced by global cerebral ischemia in mice.

Recently, we have reported that quetiapine, an atypical antipsychotic drug, prevents memory impairment and hippocampus neurodegeneration induced by global cerebral ischemia (GCI). In the present study, we examined the possible effects of quetiapine on other behavioural deficits, including the depressive and anxiolytic-like behavioural consequences of GCI. Mice were treated with quetiapine (5 or 10mg/kg/day; intraperitoneal (i.p.)) for 14 days. On Day 15, the animals were subjected to GCI. GCI resulted in a decrease of striatal tyrosine hydroxylase (TH) immunostaining and induced depressive and anxiolytic-like behavioural changes. The behavioural changes were indicated by a significant increase in the immobility duration in a tail-suspension test, and an increase in the time spent in the light box in a light/dark box test. Pre-administration of quetiapine significantly alleviated the decreased TH immunostaining and attenuated the depressive and anxiolytic-like behavioural changes induced by GCI. These results enhance our understanding about the mechanisms of quetiapine and suggest a wider perspective for the clinical use of quetiapine.

Quetiapine augmentation of treatment-resistant depression: a comparison with lithium.

OBJECTIVE: The prevalence of and morbidity associated with treatment-resistant depression has motivated the exploration of treatment alternatives. In this study, quetiapine was compared with lithium in the augmentation of treatment-resistant depression. RESEARCH DESIGN AND METHODS: Open-label, comparative study in 20 patients with major depression who had failed to respond after 4 weeks of treatment with an antidepressant at the maximal recommended dose. Patients were randomised to either lithium or quetiapine in addition to the maximally dosed antidepressant and any other concurrent medications. Lithium was initiated at 600 mg/day; quetiapine was titrated to 400 mg by day 7. RESULTS: Depression, measured by the Hamilton Depression Rating Scale (HAM-D), significantly improved from baseline in both quetiapine (F(1,90) = 25.11, p < 0.0001) and lithium (F(1,90) = 34.54, p < 0.0001). The difference in improvement between the two groups began at day 14 and was seen at all timepoints thereafter (p < 0.05), with the quetiapine group showing greater improvement than the lithium group. In the Montgomery-Asberg Depression Rating Scale (MADRS) analysis, the difference between the quetiapine and lithium group was significant from day 28 onwards (p < 0.05), with subjects improving more in the quetiapine group than the lithium group. The treatment by week interaction showed a significant difference overall between the two groups (p < 0.0001). The severity of psychomotor retardation showed a significant decrease in the Widlocher Psychomotor Retardation Scale scores in the quetiapine (p < 0.0001) and lithium (p < 0.0001) groups. CONCLUSIONS: In this pilot study, quetiapine was an effective augmenting agent in treatment-resistant depression.

Quetiapine adjunct to selective serotonin reuptake inhibitors or venlafaxine in patients with major depression, comorbid anxiety, and residual depressive symptoms: a randomized, placebo-controlled pilot study.

This double-blind, placebo-controlled study examined the efficacy and tolerability of quetiapine in combination with selective serotonin reuptake inhibitors (SSRIs)/venlafaxine in 58 patients with major depressive disorder, comorbid anxiety symptoms (HAM-A-14 score > or =14), and residual depressive symptoms (HAM-D-17 score > or =18, CGI-S score > or =4). Patients had received an SSRI/venlafaxine (at a predefined therapeutic dose) for > or =6 weeks. Overall, 62% (18/29) of quetiapine- and 55% (16/29) of placebo-treated patients completed the study. The mean change in HAM-D and HAM-A total scores from baseline to Week 8 (primary endpoint) was significantly greater with quetiapine (mean dose 182 mg/day) than placebo: -11.2 vs. -5.5 (P=.008) and -12.5 vs. -5.9 (P=.002), respectively. The onset of quetiapine efficacy (HAM-D/HAM-A/CGI-I) was rapid (by Week 1) and continued through to Week 8. Significant differences (P<.05) from baseline to Week 8 were observed between groups in 7/17 HAM-D (including feelings of guilt, suicide) and 6/14 HAM-A items (including tension, cardiovascular symptoms). Response (> or =50% decrease in total score) was higher for quetiapine than placebo: HAM-D, 48% vs. 28% (not significant, NS); HAM-A, 62% vs. 28% (P=.02). Remission (total score < or =7) was higher for quetiapine than placebo: HAM-D, 31% vs. 17% (NS); HAM-A, 41% vs. 17% (NS). CGI-S, CGI-I, and the Global Assessment Scale showed that quetiapine was significantly more effective than placebo. For quetiapine, adverse events (AEs) were similar to those previously observed; sedation/somnolence/lethargy was the most commonly reported. Here quetiapine was shown to be effective as augmentation of SSRI/venlafaxine therapy in patients with major depression, comorbid anxiety, and residual depressive symptoms, with no unexpected tolerability issues. Further studies are warranted.