Electroconvulsive shock attenuated microgliosis and astrogliosis in the hippocampus and ameliorated schizophrenia-like behavior of Gunn rat.

BACKGROUND: Although electroconvulsive therapy (ECT) is regarded as one of the efficient treatments for intractable psychiatric disorders, the mechanism of therapeutic action remains unclear. Recently, many studies indicate that ECT affects the immune-related cells, such as microglia, astrocytes, and lymphocytes. Moreover, microglial activation and astrocytic activation have been implicated in the postmortem brains of schizophrenia patients. We previously demonstrated that Gunn rats showed schizophrenia-like behavior and microglial activation in their brains. The present study examined the effects of electroconvulsive shock (ECS), an animal counterpart of ECT, on schizophrenia-like behavior, microgliosis, and astrogliosis in the brain of Gunn rats. METHODS: The rats were divided into four groups, i.e., Wistar sham, Wistar ECS, Gunn sham, and Gunn ECS. ECS groups received ECS once daily for six consecutive days. Subsequently, prepulse inhibition (PPI) test was performed, and immunohistochemistry analysis was carried out to determine the activation degree of microglia and astrocytes in the hippocampus by using anti-CD11b and anti-glial fibrillary acidic protein (GFAP) antibody, respectively. RESULTS: We found PPI deficit in Gunn rats compared to Wistar rats, and it was significantly improved by ECS. Immunohistochemistry analysis revealed that immunoreactivity of CD11b and GFAP was significantly increased in Gunn rats compared to Wistar rats. ECS significantly attenuated the immunoreactivity of both CD11b and GFAP in Gunn rats. CONCLUSIONS: ECS ameliorated schizophrenia-like behavior of Gunn rats and attenuated microgliosis and astrogliosis in the hippocampus of Gunn rats. Accordingly, therapeutic effects of ECT may be exerted, at least in part, by inhibition of glial activation. These results may provide crucial information to elucidate the role of activated glia in the pathogenesis of schizophrenia and to determine whether future therapeutic interventions should attempt to up-regulate or down-regulate glial functions.

Analysis of oxidative stress expressed by urinary level of biopyrrins and 8-hydroxydeoxyguanosine in patients with chronic schizophrenia.

AIMS: Previous studies have supported the claim that psychological stress induces the production of reactive oxygen species. Several authors have suggested that patients with psychiatric disorders show high levels of oxidative stress markers. We examined different oxidative stress markers in patients with chronic schizophrenia. METHODS: This study included 29 patients with chronic schizophrenia and 30 healthy volunteers. The concentration of urinary biopyrrins and 8-hydroxydeoxyguanosine (8-OHdG), as measured by enzyme-linked immunosorbent assay, were normalized to the urinary concentration of creatinine. Psychiatric symptoms were assessed by the administration of the Brief Psychiatric Rating Scale (BPRS). RESULTS: The concentration of biopyrrins in patients with chronic schizophrenia was significantly higher when compared with healthy volunteers. The correlation between biopyrrin level and the duration of illness was highly significant. There were no significant differences in the levels of urinary 8-OHdG between the two groups. In schizophrenic patients, the level of urinary biopyrrins showed correlations with BPRS scores, while the level of urinary 8-OHdG did not show correlations with BPRS. CONCLUSIONS: Urinary biopyrrins are increased in patients with chronic schizophrenia while urinary 8-OHdG is not increased. These findings suggest that patients with chronic schizophrenia are under the condition of certain oxidative stresses.

The effects of aging on changes in regional cerebral blood flow in schizophrenia.

AIMS: Although there have been no conclusive pathophysiological findings in support of the degeneration theory in the etiology of schizophrenia to date, results of our neuroimaging studies suggest functional changes in the brains of schizophrenics. We evaluated age-related changes of brain perfusion in medicated patients with schizophrenia. METHOD: In this study, we evaluated age-related changes in brain perfusion in medicated schizophrenia patients (n = 44) and control subjects (n = 37) undergoing (99m)Tc-ethyl cysteinate dimer single-photon emission computed tomography. RESULT: Although the regional cerebral blood flow (rCBF) was found to be reduced in bilateral frontal lobes by analysis with age in the patients with schizophrenia, significant differences compared to controls in age effects on perfusion were found in the patients with schizophrenia in bilateral temporal lobes. Moreover, in multiple regression analysis including age, total time of treatment and overall neuroleptic dose, rCBF was found to be reduced in bilateral frontal and parietal lobes. As a result, cerebral perfusion in temporal lobes with schizophrenia might be related to age rather than medication. CONCLUSION: In this study, the patients with schizophrenia appeared to have significant bilateral temporal hypoperfusion related to age compared with controls. And bilateral temporal rCBF is decreased in patients with schizophrenia and even more in older schizophrenia patients. These changes might be consistent with degenerative changes observed in patients with schizophrenia and be a promising method for the efficient development of a treatment strategy by measuring temporal perfusion in patients with schizophrenia.

The effects of combine treatment of memantine and donepezil on Alzheimer's disease patients and its relationship with cerebral blood flow in the prefrontal area.

BACKGROUND: In this study, we evaluated the effect on cognitive function of memantine, behavioral and psychological symptoms of dementia, and the care burden, in patients with moderate-to-severe Alzheimer's disease (AD). Furthermore, with near-infrared spectroscopy (NIRS), we examined the association between effect of memantine and brain blood flow. METHODS: We evaluated the effect of memantine administration from baseline on Clinical Global Impression-Improvement scale, mini mental state examination (MMSE), Clock Drawing Test (CDT), Neuropsychiatric Inventory (NPI), Japanese version of the Zarit Burden Interview (J-ZBI) and NIRS in two groups, donepezil administration memantine combination group (combination group, n = 19) donepezil administration memantine non-administration group (control group, n = 18) were assessed at weeks 0, 4, 12, and 24. RESULTS: Significant difference was found between the combination group and the control group in the score variation of Clinical Global Impression-Improvement scale, MMSE, CDT, NPI, and J-ZBI. In the NIRS measurements, trend oxyhemoglobin reduced suppression was observed in some channels centered on the superior frontal gyrus. A significant correlation was observed in the scores of MMSE, CDT, NPI, and J-ZBI. In addition, a significant positive correlation was also observed between the number of words in NIRS and scores of MMSE and CDT. CONCLUSIONS: In this study, by administering memantine in AD patients that inhibit the reduction of cerebral blood flow in the prefrontal area and improve clinical symptoms overall cognitive function, behavioral and psychological symptoms of dementia, thereby reducing the care burden of caregivers was suggested.

Evaluation of autonomic nervous system by salivary alpha-amylase level and heart rate variability in patients with schizophrenia.

Several researches indicate that autonomic nervous system (ANS) dysfunction in patients with schizophrenia. Recently, salivary alpha-amylase (sAA) has been employed as a useful marker for ANS function. We investigated the extent of ANS dysfunction by measuring sAA and heart rate variability (HRV) of 25 patients with schizophrenia compared with controls. Schizophrenia group demonstrated a significant increase in sAA and markedly lower parasympathetic nervous system (PNS) activity in the HRV. However, there were no significant differences between two groups in sympathetic nervous system (SNS) activity. We concluded that PNS might be suppressed and the SNS shows relatively high activity in schizophrenia.

Yokukansan promotes hippocampal neurogenesis associated with the suppression of activated microglia in Gunn rat.

BACKGROUND: The pathophysiology of schizophrenia (SCZ) remains unclear, and its treatment is far from ideal. We have previously reported that yokukansan (YKS), which is a traditional Japanese medicine, is effective as an adjunctive therapy for SCZ. However, the mechanisms underlying the action of YKS have not yet been completely elucidated. A recent meta-analysis study has shown that adjuvant anti-inflammatory drugs are effective for SCZ treatment, and it has been proposed that some of the cognitive deficits associated with inflammation may in part be related to inflammation-induced reductions in adult hippocampal neurogenesis. Although certain ingredients of YKS have potent anti-inflammatory activity, no study has determined if YKS has anti-inflammatory properties. METHODS: Using the Gunn rat, which has been reported as a possible animal model of SCZ, we investigated whether YKS affects cognitive dysfunction in an object-location test and the suppression of microglial activation and neurogenesis in the hippocampus. RESULTS: We found that YKS ameliorated spatial working memory in the Gunn rats. Furthermore, YKS inhibited microglial activation and promoted neurogenesis in the hippocampal dentate gyrus of these rats. These results suggest that the ameliorative effects of YKS on cognitive deficits may be mediated in part by the suppression of the inflammatory activation of microglia. CONCLUSIONS: These findings shed light on the possible mechanism underlying the efficacy of YKS in treating SCZ.

Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model.

BACKGROUND: Schizophrenia is a debilitating and complex mental disorder whose exact etiology remains unknown. There is growing amount of evidence of a relationship between neuroinflammation, as demonstrated by microglial activation, and schizophrenia. Our previous studies have proposed that hyperbilirubinemia plays a role in the pathophysiology of schizophrenia. Furthermore, we suggested the Gunn rat, an animal model of bilirubin encephalopathy, as a possible animal model of schizophrenia. However, the effects of unconjugated bilirubin on microglia, the resident immune cell of the CNS, in Gunn rats have never been investigated. In the present study, we examined how microglial cells respond to bilirubin toxicity in adult Gunn rats. METHODS: Using immunohistochemical techniques, we compared the distribution, morphology, and ultrastructural features of microglial cells in Gunn rats with Wistar rats as a normal control. We also determined the ratio of activated and resting microglia and observed microglia-neuron interactions. We characterized the microglial cells in the hippocampal dentate gyrus. RESULTS: We found that microglial cells showed activated morphology in the hilus, subgranular zone, and granular layer of the Gunn rat hippocampal dentate gyrus. There was no significant difference between cell numbers between in Gunn rats and controls. However, there was significant difference in the area of CD11b expression in the hippocampal dentate gyrus. Ultrastructurally, microglial cells often contained rich enlarged rich organelles in the cytoplasm and showed some phagocytic function. CONCLUSIONS: We propose that activation of microglia could be an important causal factor of the behavioral abnormalities and neuropathological changes in Gunn rats. These findings may provide basic information for further assessment of the Gunn rat as an animal model of schizophrenia.

Yokukansan (TJ-54) for treatment of pervasive developmental disorder not otherwise specified and Asperger's disorder: a 12-week prospective, open-label study.

BACKGROUND: Numerous medications have been tested on patients with pervasive developmental disorder not otherwise specified (PDD-NOS) and Asperger's disorder. Although many of these medications have been demonstrated to be useful, no clear primary treatment for PDD-NOS and Asperger's disorder has emerged. Despite the efficacy of some of the medicines, the acceptability and side effects have proven to be barriers to their use. Recent studies indicate that the traditional Japanese herbal medicine yokukansan (TJ-54) may be safe and useful in treating behavioral and psychological symptoms in dementia and some neuropsychiatric disorders. We aimed at evaluating both the efficacy and safety of TJ-54 in patients with well-defined PDD-NOS and Asperger's disorder. METHODS: This was a 12-week prospective, open-label investigation of TJ-54 in 40 children, adolescents, and adults diagnosed with PDD-NOS or Asperger's disorder. Primary outcome measures included the Clinical Global Impressions-Severity of Illness Scale (CGI-S) and the Aberrant Behavior Checklist-Iritability subscale score (ABC-I). RESULTS: Forty subjects, ages 8-40 years (mean 22.7 ± 7.3 years) received a mean final TJ-54 dosage of 6.4 ± 1.3 g/day (range 2.5-7.5 g/day). Full-scale intelligence quotient (IQ) scores ranged from 70 to 110 (mean 88.9 ± 13.2). Thirty-six (90%) of 40 subjects showed fewer interfering symptoms of irritability, including aggression, self-injury, and tantrums, with a final CGI-S of 1 or 2 (normal, not at all ill or borderline mentally ill) and a 80% or greater improvement on the ABC-I. The mean CGI-S score at baseline was 6.8 ± 0.8 whereas scores at end point was 1.9 ± 0.1 (< 0.0001). ABC-I scores ranged from 11 to 29 (mean 17.4 ± 3.66) at baseline, whereas scores at week 12 ranged from 0 to 5 (mean 0.93 ± 0.97) (p <0.0001). TJ-54 was well tolerated. No subject exited the study due to a drug-related adverse event. CONCLUSIONS: These preliminary data suggest that TJ-54 may be effective and well tolerated for treatment of severe irritability, lethargy/withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech in patients with PDD-NOS or Asperger's disorder. However, given the characteristics of this trial, the present findings should be taken cautiously, and larger-scale placebo-controlled studies are needed to elucidate the efficacy and tolerability of TJ-54 in this understudied population.

Self-construal and behavioral motivation systems among patients with depression in Indonesia: A hospital-based study.

Objective: To validate Indonesian versions of two social/cultural psychological scales: the Self-Construal Scale (SCS) that measures independent and interdependent cultural values, and the Behavioral Inhibition (Avoidance) System and Behavioral Approach System (BIS/BAS) that measures motivation focus. We also explored the cultural background for the rising prevalence of depression in Indonesia. Design: Case (hospital)-control (population) study. Setting: Hasanuddin University Hospital (cases) and Makassar city region (controls), Indonesia. Participants: Participants (N = 369) were 165 patients with depression recruited from a university hospital, and 204 healthy controls without a history of mental disorders recruited from locations within a 30-minute walk from the hospital. Outcome measures: Depression was diagnosed by psychiatrists with reference to Indonesian mental disorder guidelines (Pedoman Penggolongan dan Diagnosa Gangguan Jiwa edisi 3). Participants' independent and interdependent cultural values, and neural motivational systems were measured with the SCS and BIS/BAS. Results: Exploratory and confirmatory factor analyses showed that our revised 12-item SCS and the 13-item, three-factor BIS/BAS had a good model fit for the Indonesian population. MANCOVA showed that the SCS Independent subscale and the BAS subscales were significantly associated with depression after adjustment for age, sex, religion, education, and occupation. Conclusion: These findings may guide provision of appropriate treatment for patients based on their social and cultural environment. In addition, this study contributes to understanding underlying reasons for the increasing prevalence of depression in Indonesia, where society is changing from traditional collectivism to global individualism.

Socio-economic-demographic determinants of depression in Indonesia: A hospital-based study.

The association of socio-economic-demographic (SED; e.g., income-related) factors with depression is widely confirmed in the literature. We conducted a hospital-based case-control study of 160 patients with psychiatrist-diagnosed clinical depression. The control group comprised 160 participants recruited from local communities. We used a questionnaire to collect SED data from all participants. We replaced missing values using multiple imputation analyses and further analyzed the pooled data of five imputations. We also recorded the results from the original analysis and each imputation. Univariate analyses showed income was associated with depression. Multiple logistic regression analyses revealed that, among all SED variables, high income (odds ratio = 2.088 [95% confidence interval = 1.178-3.700]; p = 0.012), middle-level (completed junior or senior high school) education (1.688 [1.042-2.734]; p = 0.033) and cohabitating with four or more family members (1.632 [1.025-2.597]; p = 0.039) were significant predictors for the case group. We conclude that cash income is a determinant of depression in hospital outpatients in Indonesia. This study suggests health policy implications toward better hospital access and service for people with depression in middle- or low-income households, and recommends considering high income as correlated with a high risk of depression, owing to socio-cultural changes.

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test.

INTRODUCTION: Recent studies imply that glial activation plays a role in the pathogenesis of psychiatric disorders, such as schizophrenia and major depression. We previously demonstrated that Gunn rats with hyperbilirubinemia show congenital gliosis and schizophrenia-like behavior. METHODS: As it has been suggested that major depression involves glial activation associated with neuroinflammation, we examined whether Gunn rats show depression-like behavior using the forced swimming test (FST) and the tail suspension test (TST). In addition, we quantitatively evaluated both microgliosis and astrogliosis in the hippocampus of Gunn rats using immunohistochemistry analysis of the microglial marker ionized calcium-binding adaptor molecule (Iba) 1 and the astrocytic marker S100B. RESULTS: Both the FST and TST showed that immobility time of Gunn rats was significantly longer than that of normal control Wistar rats, indicating that Gunn rats are somewhat helpless, a sign of depression-like behavior. In the quantification of immunohistochemical analysis, Iba1immunoreactivity in the dentate gyrus (DG), cornu ammonis (CA) 1, and CA3 and the number of Iba1-positive cells in the CA1 and CA3 were significantly increased in Gunn rats compared to Wistar rats. S100B immunoreactivity in the DG, CA1, and CA3 and the number of S100B-positive cells in the DG and CA3 were significantly increased in Gunn rats compared to Wistar rats. CONCLUSION: Our findings suggest that both microglia and astrocyte are activated in Gunn rats and their learned helplessness could be related to glial activation.

Minocycline improves recognition memory and attenuates microglial activation in Gunn rat: a possible hyperbilirubinemia-induced animal model of schizophrenia.

BACKGROUND: Accumulating evidence indicates that neuroinflammation plays a significant role in the pathophysiology of schizophrenia. We previously reported evidence of schizophrenia-like behaviors and microglial activation in Gunn rats. We concluded that the Gunn rat, which exhibits a high concentration of unconjugated bilirubin, may be useful as an animal model of schizophrenia. On the other hand, there have been numerous reports that minocycline is effective in treating schizophrenia. METHODS: In the present study, we investigated the effects of minocycline on performance of behavioral tests (prepulse inhibition (PPI) and novel object recognition test (NORT)) after animals received either 40mg/kg/d of minocycline or vehicle by intraperitoneal (i.p.) injection for 14 consecutive days. Furthermore, we examined the effects of minocycline on microglial activation in the hippocampal dentate gyrus of Gunn rats and Wistar rats. RESULTS: We found that administration of minocycline for 14days significantly increased the exploratory preference in retention sessions and tended to improve the PPI deficits in Gunn rats. Immunohistochemistry analysis revealed that microglial cells in the minocycline-treated Gunn rat group showed less expression of CD11b compared to vehicle-treated Gunn and Wistar groups. CONCLUSIONS: Our findings suggest that minocycline improves recognition memory and attenuates microglial activation in the hippocampal dentate gyrus of Gunn rats. Therefore, minocycline may be a potential therapeutic drug for schizophrenia.

The effects of antipsychotics on behavioral abnormalities of the Gunn rat (unconjugated hyperbilirubinemia rat), a rat model of schizophrenia.

BACKGROUND: There have been reports of a positive relationship between schizophrenia and hyperbilirubinemia. Patients with schizophrenia show a significantly higher frequency of hyperbilirubinemia than patients suffering from other psychiatric disorders and when compared to the general population. Previously we observed that patients suffering from schizophrenia frequently present an elevated unconjugated bilirubin plasma concentration, when admitted to the hospital. In addition it was recently reported that unconjugated bilirubin exhibited neurotoxicity in the developing nervous system. We also reported that Gunn rats, which tend to show a high frequency of hyperbilirubinemia, may be used as an animal model of schizophrenia. In the present study, we assessed the effects of antipsychotics on Gunn rat behavioral abnormalities. METHODS: We examined the behavior of Gunn rats after treatment with risperidone (0.1mg/kg), haloperidol (0.2mg/kg), or aripiprazole (0.4mg/kg) using an open-field test, social interaction test and a prepulse inhibition (PPI) test. RESULTS: The administration of antipsychotics alleviated behavioral abnormalities, mimicking some positive and negative symptoms and cognitive defects of schizophrenia. The pharmacological reaction of Gunn rats to antipsychotics echoes the pharmacological response of humans to such antipsychotics. CONCLUSIONS: Our study suggested that the Gunn rat may be useful as a preclinical model of schizophrenia with which to evaluate the pharmacological properties of antipsychotics. The results obtained to date have been encouraging and warrant further research.

Yokukansan (TJ-54) for irritability associated with pervasive developmental disorder in children and adolescents: a 12-week prospective, open-label study.

BACKGROUND: Autistic disorder is a neuropsychiatric syndrome characterized by deficits in social interaction; qualitative impairments in communication; and restricted, repetitive, and stereotyped patterns of behavior, interests, or activities. It is classified as a type of pervasive developmental disorder (PDD). All PDDs have a qualitative impairment in social relatedness. However, many individuals with PDDs have interfering symptoms, including irritability (aggression, self-injurious behavior, and severe tantrums). Behavioral therapy is often helpful in decreasing these behaviors; however, sometimes adjunctive medications are needed, because of the intensity and severity of irritability. Numerous medications have been tested on patients with PDDs. Although many of these medications have been demonstrated to be useful, no clear main treatment for PDD has emerged. Despite the efficacy of some of the medicines, acceptability and side effects have proven to be barriers to their use. Yokukansan (TJ-54), a traditional Japanese medicine, is composed of seven kinds of dried herbs. It is widely prescribed in clinical situations for treating psychiatric disorders by acting mainly on the glutamatergic and serotonergic nervous system. Recent studies indicate that TJ-54 may be safe and useful in treating behavioral and psychological symptoms in dementia patients. We aimed at evaluating both the efficacy and the safety of TJ-54 in patients with PDDs. METHODS: This was a 12 week prospective, open-label investigation of TJ-54 in 20 children and adolescents ages 6-17 years diagnosed with PDDs. Primary outcome measures included the Clinical Global Impressions-Improvement of Illness Scale (CGI-I), Children's Global Assessment Score (CGAS), and the Aberrant Behavior Checklist (ABC) irritability subscale. RESULTS: Twenty subjects, ages 6-17 years, received TJ-54 in the dosage range of 2.5-7.5 g/day. The CGI-I was significantly improved from 8 weeks (p<0.001). The mean CGAS was 31.92 at baseline, whereas the mean final score at 12 weeks was 54.52 (p<0.001). The ABC irritability/agitation subscale (subscale 1) was significantly improved from 8 weeks, and the hyperactivity/noncompliance subscale (subscale 4) was significantly improved in 12 weeks. TJ-54 was well tolerated. No subject left the study because of a drug-related adverse event. CONCLUSIONS: These preliminary data suggest that TJ-54 may be effective and well tolerated for the treatment of severe irritability/agitation and hyperactivity/noncompliance in children and adolescents ages 6-17 years with PDD. However, given the characteristics of this trial, the present findings should be taken cautiously, and larger-scale placebo-controlled studies are needed to elucidate the efficacy and tolerability of TJ-54 in this understudied population.

Yokukansan (TJ-54) for treatment of very-late-onset schizophrenia-like psychosis: an open-label study.

BACKGROUND: Although schizophrenia affects all age groups, late or very-late-onset schizophrenia-like psychosis has not been well studied, and various treatment issues remain unresolved. The objective of the present study was to evaluate the efficacy and safety of yokukansan (TJ-54), Japanese herbal medicine, monotherapy in a diagnostically homogenous group of elderly patients without cognitive impairment suffering from very-late-onset schizophrenia. METHODS: Forty patients of mean age 73.1±4.8 years, fulfilling both the recent consensus criteria for very late-onset schizophrenia-like psychosis and the DSM-IV-TR criteria for schizophrenia, were assessed by the brief psychiatric rating scale, the clinical global impression scale-severity, and positive and negative syndrome scale at baseline and after 4 weeks administration of TJ-54 (2.5-7.5 g/day). In addition, abnormal movements were evaluated with the Simpson-Angus scale, Barnes Akathisia scale, and abnormal involuntary movement scale. RESULTS: A highly significant (p<0.001) improvement on all measures of psychotic symptomatology was observed in all patients. TJ-54 was very well tolerated by the patients, and no clinically significant adverse effects were observed. Scores on all abnormal movement scales did not differ significantly prior to and after TJ-54 treatment. CONCLUSION: Preliminary results indicate that TJ-54 appears to be an efficacious and safe herbal medicine for treatment of very-late-onset schizophrenia-like psychosis.

Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study.

BACKGROUND: Approximately 25% of patients admitted to a hospital as a result of depression are actually suffering from psychotic depression. Psychotic symptoms can be present in patients with either unipolar depression or bipolar depression and can be difficult to treat. It was reported the second-generation tetracycline may exert potential antidepressant effects through its robust neuroprotective activities, which include neurogenesis, antioxidation, and anti-glutamate excitotoxicity, and may direct regulation of pro-inflammatory agents. METHODS: This was a 6-week, open-label study to evaluate the efficacy and safety of minocycline in combination with antidepressants in adult inpatients (n=25) diagnosed with major depression with psychotic features (psychotic depression) according to DSM-IV-TR. The primary endpoint was the change from baseline in the Hamilton Depression Rating Scale (HAM-D-21) score from baseline to week 6. Secondary endpoints were changes in the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) Scale scores from baseline to week 6. Spontaneously reported adverse events were recorded. RESULTS: The patients' average age was 46.9±10.2 years. Minocyline (150 mg/day) in combination with antidepressants (fulvoxamine, paroxetine, and sertraline) provided significant improvement in depression. Mean (± SD) HAM-D-21 was reduced to 6.7±1.9 at week 6 from a baseline value of 40.4±2.5. Significant improvement of psychotic symptoms (mean±SD) was indicated by the decrease in BPRS scores from baseline (63.3±8.7) to week 6 (4.6±2.4). No serious adverse events occurred. CONCLUSIONS: These preliminary data suggest that minocycline in combination with antidepressants is effective and well tolerated in the treatment of unipolar psychotic depression. Further studies using larger, double-blind, parallel-group design are warranted to confirm these findings.