Treatment of Paroxysmal Perceptual Alteration in Catatonic Schizophrenia by Switching to Aripiprazole from Risperidone: A Case Report.

Paroxysmal perceptual alteration (PPA) is the occurrence of brief and recurrent episodes of perceptual changes. It is mainly caused by the treatment of schizophrenia patients with antipsychotics. However, diagnosis of PPA is not very prevalent among psychiatrists, partly due to underrecognition or misunderstanding that it is a worsening of psychiatric symptoms. If psychiatrists do not understand PPA, they cannot treat it appropriately, and the patient's quality of life is impaired. We present a case of PPA in catatonic schizophrenia that was successfully treated by switching to aripiprazole from risperidone. We suggest that the disappearance of PPA in our case was due to both discontinuing risperidone, which completely blocks D2 receptors, and replacing it with aripiprazole, which is characterized as a partial agonist of D2 receptors. Treatment of PPA will improve medication adherence and quality of life. It is important to recognize PPA as a possible side effect of treatment with antipsychotics.

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.

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 (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.

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 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.

May salivary alpha-amylase level be a useful tool for assessment of the severity of schizophrenia and evaluation of therapy? A case report.

Background. Previous studies suggested dysfunction of the autonomic nervous system (ANS) in schizophrenia patients, but the mechanism remains unclear. Recently, the measurement of salivary alpha-amylase (sAA) has been considered a useful tool for evaluating ANS, especially the sympathoadrenal medullary system. Furthermore, there was a report that patients with schizophrenia showed much higher sAA level than normal controls. Methods. We present the case of a 51-year-old female with catatonic schizophrenia. She needed the treatment of electroconvulsive therapy (ECT). We evaluated her sAA level and her psychiatric symptoms during the treatment. Results. Before ECT treatment, she showed high sAA level. Her sAA level decreased during the course of ECT, and this attenuation was accompanied by improvement of schizophrenic symptoms. Conclusion. We consider that measurement of the sAA level may be one of the useful biological markers for assessment of psychotic state and efficacy of treatment in patients with schizophrenia.

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.

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.

Yi-gan san for treatment of charles bonnet syndrome (visual hallucination due to vision loss): an open-label study.

BACKGROUND: Recent studies indicate that the traditional Japanese herbal medicine yi-gan san (YGS, yokukan-san in Japanese) may be safe and useful for treating behavioral and psychological symptoms in dementia, borderline personality disorder, neuroleptic-induced tardive dyskinesia, and treatment-resistant schizophrenia. Visual hallucinations are common and often distressing consequences of vision loss, particularly in age-related macular degeneration. Charles Bonnet syndrome (CBS) is defined by the triad of complex visual hallucinations, ocular pathology causing visual deterioration, and preserved cognitive status. We aimed at evaluating both the efficacy and safety of YGS in patients with CBS. METHODS: Twenty patients diagnosed with CBS were investigated, according to the diagnostic criteria established by Gold and Rabins and Teunisse. Participants were treated in a 4-week open-label study with YGS at an average daily dose of 5.8 ± 2.6 g (2.5-7.5 g). Psychometric instruments used to assess efficacy included the Neuropsychiatric Inventory, hallucination subscale of the Positive and Negative Syndrome Scale, and Clinical Global Impression. No cases of serious adverse events were attributed to the study's drug therapy. RESULTS: A significant decrease in visual hallucination was observed at 2 and 4 weeks in the Neuropsychiatric Inventory, hallucination subscale of the Positive and Negative Syndrome Scale, and Clinical Global Impression scores. CONCLUSIONS: Yi-gan san may be an effective and safe therapy to control visual hallucination in patients with CBS and should be further tested in double-blind, placebo-controlled trials. Given the design characteristics of this trial, the present findings should be taken cautiously.