Discrepancies Between Nomenclature and Indications of Psychotropics.

INTRODUCTION: While the current nomenclature of psychotropic drugs is disease-based, their approved indications do not always match their classifications. METHODS: Information on approved indications of "second-generation antipsychotics" and "newer antidepressants" that are available in the United States (US), the United Kingdom (UK), France, Germany, and Japan were extracted from their packet inserts. RESULTS: A significant proportion of "atypical antipsychotics" were approved for psychiatric conditions other than psychotic disorders (i. e., bipolar disorder, major depressive disorder, and autistic disorder) as follows: 76.9% in the US, 66.7% in the UK, 66.7% in France, 60.0% in Germany, and 44.4% in Japan. Likewise, more than half of "newer antidepressants" had approved indications for psychiatric conditions other than depression (e. g., panic disorder, obsessive compulsive disorder, social anxiety disorder, general anxiety disorder, and post-traumatic stress disorder): 56.3% in the US, 69.2% in the UK, 69.2% in France, 50.0% in Germany, and 62.5% in Japan. CONCLUSIONS: Our results raise concerns regarding generic terminologies of "antipsychotics" and "antidepressants" since the conventional indication-based nomenclature does not fit well with the official indication.

Factor structure of the targeted inventory on problems in schizophrenia.

OBJECTIVE: The aim of this study was to explore the factor structure of a novel, 10-item rating scale, the Targeted Inventory on Problems in Schizophrenia (TIP-Sz). Determining the factor structure will be useful in the brief evaluation of medication and non-medication treatment of the disease. METHODS: An exploratory factor analysis was performed on TIP-Sz scores obtained from 100 patients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for schizophrenia. RESULTS: THE FACTOR ANALYSIS EXTRACTED FOUR FACTORS THAT WERE DEEMED CLINICALLY PERTINENT, WHICH WE LABELED: disorganization, social cooperativeness, functional capacity, and emotional state. The items exhibited cross-loadings on the first three factors (i.e., some items loaded on more than one factor). In particular, the 'behavioral dyscontrol and disorganization,' 'insight and reality testing,' and 'overall prognostic impression' items had comparable cross-loadings on all of the first three factors. The emotional state factor was distinct from the other factors in that the items loading on it did not cross-load on other factors. CONCLUSION: The TIP-Sz scale comprises factors that are associated with the psychosocial functioning and emotional state of patients, which are important outcome parameters for successful treatment of the disease.

Magnitude of rater differences in assessment scales for schizophrenia.

The magnitude of rater differences, instead of interrater reliability, in the assessment scales of schizophrenia has rarely been investigated and was therefore addressed in this study. Thirty-six patients with schizophrenia were independently assessed by 4 expert physicians, using clinical rating scales including the Positive and Negative Syndrome Scale (PANSS). The scores obtained by the physician in charge (PIC), who had a long close contact with the patients, served as the referent answer for the purpose of this study. The scores rated by the other 3 non-PIC psychiatrists, who had a first formal examination with them, were evaluated for percentage deviance from the referent answer. The results showed that the PIC raters endorsed the numerically highest score in 20 (56%) of the 36 patients, whereas they rated the lowest in only 2 (6%) in the PANSS total score. The non-PIC assessors on the average underrated the PANSS total score by 10%, and such a tendency of underestimating the severity was noted across other clinical scales. Furthermore, the PANSS total score by one of the non-PIC physicians was deviant from the referent answer by at least 20% in 15 (42%) of 36 instances. Importantly, this magnitude of deviance was noted in the context of an intraclass correlation coefficient of 0.92. This unique investigation disclosed clinically pertinent differences among raters, even under an excellent interrater reliability. The magnitude of differences described herein seems to be an underestimation, and the baseline scores by the independent new raters might need to be corrected for those by the PICs.

Augmentation of atypical antipsychotics with valproic acid. An open-label study for most difficult patients with schizophrenia.

OBJECTIVE: Most difficult inpatients with schizophrenia are in serious needs but obviously underrepresented in clinical trials. METHODS: Very challenging patients received open-label treatment with atypical antipsychotics concurrently augmented with valproic acid. The primary outcome was the newly developed Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz). Patients improving more than 20 points were classified as responders. RESULTS: Mean age and illness duration of 28 participants (22 male) were 42 y.o. and 20 years, respectively. They had spent a half of their life admitted after the onset. The average Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity (CGI-S) were very severe at 79 and 6.1, respectively, with the baseline Global Assessment of Functioning (GAF) of as low as 21. As a result of augmentation, there were nine responders, 12 partial responders, and seven non-responders including only two patients who got worse. The main antipsychotics were mostly either risperidone or olanzapine. Mean maximum oral dose and blood level of valproic acid were 1907 mg and 91.7 microg/ml, respectively. Overall significant improvements whilst to an inadequate degree were noted in clinical parameters. Valproate augmentation was generally well tolerated but serious adverse effects included thrombocytopenia, anaemia and sedation/falls. CONCLUSIONS: While these preliminary results need to be tested against tenacious monotherapy or polypharmacy involving clozapine, augmenting atypical antipsychotics with valproic acid can be useful for very severe schizophrenia.

Benzodiazepine and antidepressant use in elderly patients with anxiety disorders: a survey of 796 outpatients in Japan.

Since the literature on benzodiazepine use in elderly patients with anxiety disorders is limited, a large cross-sectional review of psychotropic prescriptions in 796 patients with neurotic disorders (ICD-10) (age range=11-91 years) was conducted across 30 sites in Japan. Use of benzodiazepine-derivative anxiolytics was approximately 70% in all decades without a group difference. The proportion of subjects who received prescriptions for benzodiazepine-derivative anxiolytics in the absence of antidepressants was higher in older age groups (e.g., 27.7% and 43.2% in the third and sixth decades, respectively). On the other hand, antidepressants were less frequently prescribed in older age groups (e.g., 59.8% and 41.5% in the third and sixth decades, respectively). The very high use of anxiolytics in the elderly, especially in the absence of concomitant antidepressant use, is a cause for concern since they are not a preferred long-term treatment strategy given their adverse effects in the elderly.

Novel rating scales for schizophrenia - Targeted Inventory on Problems in Schizophrenia (TIP-Sz) and Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz).

OBJECTIVE: Many rating scales have been in use to evaluate various symptomatic domains, and eventually there are too many scales to be selected and widely utilized in busy real-world settings. Relevant, quick, and user-friendly assessment scales are needed to facilitate measurement-based treatment of schizophrenia. METHODS: The authors created unique convenient assessment scales: Targeted Inventory on Problems in Schizophrenia (TIP-Sz), and Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz). The TIP-Sz consists of 10 items (behavioral dyscontrol/disorganization, hostility/agitation/violence, indifference/affective withdrawal/motor retardation, symptoms on mood/anxiety/obsession/compulsion, insight/reality testing, social competence/independence, adherence to treatment, therapeutic alliance/comfort of therapists on the situation, overall prognostic impression, and subjective well-being/satisfaction with therapy). They are all common and frequently problematic, and each item is rated from 0-10. The FACT-Sz evaluates psychosocial functioning of patients with a score of 0-100, and is judged entirely on an objective basis. Their correlations with the frequently utilized Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), and Clinical Global Impression-Severity subscale were determined. RESULTS: Data on 36 patients, assessed separately by four experienced psychiatrists, were analyzed. Under an excellent interrater reliability among raters (Intraclass correlation coefficients: 0.822-0.966), correlations among the scales were very high (Spearman's rho: 0.825-0.909), and other indicators of the scale were generally good. Specifically, the TIP-Sz and FACT-Sz could be rated at 1/3-1/4 of time to complete the PANSS and GAF. CONCLUSION: The TIP-Sz and FACT-Sz proved to be reliable and valid, which would be of value in daily clinical practice as a minimum standardized assessment set.

Effects of age and age of onset on prescribed antipsychotic dose in schizophrenia spectrum disorders: a survey of 1,418 patients in Japan.

OBJECTIVES: The relationship between age and prescribed antipsychotic dose in patients with schizophrenia has been examined by assuming only a linear correlation in two age subgroups at most. The age of illness onset has also not been under adequate consideration in past prescription surveys. The objective of this study was to better evaluate these age effects on antipsychotic dose prescribed in these patients across a broad age range. METHODS: Review of prescriptions for antipsychotic medications in patients with schizophrenia spectrum disorders was conducted across 30 sites in Tokyo. A total of 1,418 patients (655 inpatients, 763 males, age range: 16.6-90.2 years) were studied. RESULTS: Age had significant effects on prescribed antipsychotic dose; the dose increased with age through the third decade, subsequently plateaued, and decreased after the fifth decade. The age of illness onset also had significant effects on the dose; late-onset schizophrenia (LOS) and very-late-onset schizophrenia-like psychoses (VLOS) patients received lower doses than early onset schizophrenia (EOS) patients. LOS and VLOS patients who did not experience any hospitalization for the previous year were treated with (1/2) and (1/3), respectively, of the dose for EOS of comparable current age. CONCLUSION: Our results suggested biphasic effects of age on antipsychotic dose prescribed in patients with schizophrenia spectrum disorders. The natural history of schizophrenia and physiological aging may contribute to this inverted U-shaped relationship. In addition, our results may add another evidence of distinction among EOS, LOS, and VLOS from a clinical psychopharmacological perspective.

Effectiveness of antipsychotic polypharmacy for patients with treatment refractory schizophrenia: an open-label trial of olanzapine plus risperidone for those who failed to respond to a sequential treatment with olanzapine, quetiapine and risperidone.

OBJECTIVE: To evaluate the effectiveness of antipsychotic polypharmacy in a methodologically sound manner. METHODS: In this open-label study, 17 patients with treatment-refractory schizophrenia, who failed to respond to a sequential monotherapy with olanzapine, quetiapine and risperidone, were subsequently treated with a combination therapy with olanzapine plus risperidone for at least 8 weeks. RESULTS: Seven responded according to the primary endpoint defined as the post-treatment Brief Psychiatric Rating Scale being less than 70% of the pretreatment values, and they were classified as such an average of 10 weeks after the initiation of polypharmacy. Two of them were successful in a later conversion to monotherapy. None dropped out prematurely. Four (out of 13 inpatients) got better enough to be discharged from the hospital, while six patients did not show any response. The Global Assessment of Functioning score improved from 37.1 to 53.0 in responders (mean maximum dose: olanzapine 12.9 mg; risperidone 3.14 mg), while it showed non-significant changes among others (mean maximum dose: olanzapine 14.5 mg; risperidone 5.50 mg). Body weight, prolactin, and total cholesterol increased significantly. CONCLUSIONS: Antipsychotic polypharmacy might be sometimes helpful for difficult populations but at the cost of adverse effects. More studies of antipsychotic combination therapy versus clozapine, augmentation strategies or tenacious longer- term monotherapy are warranted for refractory schizophrenia.

Antipsychotic-induced hyperprolactinemia inhibits the hypothalamo-pituitary-gonadal axis and reduces bone mineral density in male patients with schizophrenia.

OBJECTIVE: An inhibitory effect of hyperprolactinemia on the hypothalamo-pituitary-gonadal axis has been suggested as a mechanism of bone loss in schizophrenia, but this has not been confirmed. In this study, which was conducted in Tokyo, Japan, from February to May 2005, we examined the possible causes of reduced bone mineral density (BMD) in male patients with schizophrenia. METHOD: The BMD of the radius of 74 male patients (aged 31-78 years) who met the diagnostic criteria for DSM-IV schizophrenia was measured by dual-energy x-ray absorptiometry. Levels of prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, estradiol, and 1,25-dihydroxy vitamin D (VitD) were also measured. Pedometers were used to measure the impact of exercise. RESULTS: Study subjects showed lower BMD in all age groups compared with reference values in healthy persons. There was no significant difference in the Z score among low, medium, and high exercise groups. 87% of the subjects had hyperprolactinemia, and VitD levels were normal in all subjects except 1. The high PRL group had lower levels of FSH and LH, and significantly lower levels of estradiol (p < .05), compared with the normal PRL group. In the high PRL group, there was a significant negative correlation between the duration of treatment and the Z score (p < .05). CONCLUSION: Male patients with schizophrenia had lower BMD than normal individuals irrespective of the amount of exercise or the level of VitD. The results support the hypothesis that inhibition of the hypothalamo-pituitary-gonadal axis by hyperprolactinemia contributes to the mechanism of the bone loss and suggest that the longer the duration of hyperprolactinemia, the greater the reduction in BMD.

How effective is it to sequentially switch among Olanzapine, Quetiapine and Risperidone?--A randomized, open-label study of algorithm-based antipsychotic treatment to patients with symptomatic schizophrenia in the real-world clinical setting.

RATIONALE: Evidence on sequential trial with atypical antipsychotics has been scarce. OBJECTIVES: We conducted an algorithm-based antipsychotic pharmacotherapy. MATERIALS AND METHODS: In this open-label study, patients with schizophrenia (DSM-IV) were treated with antipsychotic monotherapy, step-by-step, with each trial lasting up to 8 weeks. At baseline, they were highly symptomatic to score more than 54 in the total Brief Psychiatric Rating Scale (BPRS(1-7)) score. When the posttreatment BPRS score was above 70% of the baseline, they were subsequently treated with another and up to three atypicals. Basically, anticholinergics were prohibited, and only adjunctive allowed was lorazepam. The secondary endpoint was a clinical status good enough to be discharged for 66 inpatients and a successful continuation therapy with the same antipsychotic agent for more than 6 months for 12 outpatients. RESULTS: Three groups of 26 patients each were randomized to Olanzapine, Quetiapine, or Risperidone. Thirty-nine (50%) responded to the first agent (Olanzapine16, Quetiapine9, Risperidone14), and 14 responded to the second. Only two showed response to the third, and 16 failed to respond to all three antipsychotics, with only 7 dropouts. Overall, there were 22 Olanzapine, 14 Quetiapine, and 19 Risperidone responders. Based on the secondary outcome, 20 Olanzapine-treated (average maximum dose, 15.4 mg), 10 Quetiapine-treated (418 mg), and 20 Risperidone-treated (4.10 mg) patients responded. The difference in response as the first choice was significant (p < 0.05). Relative doses of those failing to respond were comparable (Olanzapine 18.3 mg, Quetiapine 564 mg, Risperidone5.47 mg). Extrapyramidal symptoms did not change significantly. CONCLUSIONS: When the first atypical antipsychotic is inadequate, switching to the second is worth trying, although some remain treatment-refractory. Quetiapine may be inferior to Olanzapine and Risperidone in symptomatic patients.

Prediction of medication noncompliance in outpatients with schizophrenia: 2-year follow-up study.

Neuroleptic noncompliance is a major reason for relapse in outpatients with schizophrenia. In a 2-year follow-up study, we used the Japanese version of the Rating of Medication Influences Scale (ROMI-J) to investigate the reasons for compliance and noncompliance in outpatients with schizophrenia. Ninety outpatients who were confirmed by interview to have had good compliance for more than 3 months completed the initial interview, which included the Clinical Global Impressions Scale (CGI), the Brief Psychiatric Rating Scale (BPRS), the Global Assessment of Functioning Scale (GAF), the UKU Side Effect Rating Scale, and the ROMI-J. All the outpatients were followed up for 2 years. At the initial interview, the most frequent reason for compliance was "relapse prevention," while the most frequent reason for noncompliance was "distressed by side effects." Fifteen outpatients who proved to be noncompliant in the follow-up period had higher baseline BPRS "agitation" scores and ROMI-J "no perceived daily benefit" ratings than compliant patients. Sixty-four outpatients who maintained compliance during the follow-up had higher baseline ROMI-J ratings of "fulfillment of life goals" than their noncompliant counterparts. It is important to understand the attitudes of patients with schizophrenia toward drug therapy in order to predict better compliance and provide psychoeducation designed to forestall relapses.

Effectiveness of herbal medicine (Rokumigan and Hachimijiogan) for fatigue or loss of energy in patients with partial remitted major depressive disorder.

Some patients with major depressive disorder (MDD) do not show remission of their depressive symptomatology. We investigated the efficacy of Rokumigan (TJ-87) and Hachimijiogan (TJ-7) in 20 patients with prolonged partial remitted MDD associated with fatigue or loss of energy. In these 20 patients, TJ-7 or TJ-87 was added to the previous regimen for 4 weeks. Six patients were 'much improved', six were 'minimally improved' (responders), and eight showed 'no change' (non-responders), on the Clinical Global Impression Global Improvement scale. All responders had Shofuku-fujin (tenderness or weakness of the lower abdomen). In conclusion, we experienced 12 outpatients with prolonged partial remitted MDD with fatigue or loss of energy, which was successfully treated with TJ-87 or TJ-7.

[Is it valid to concurrently use multiple antipsychotics for patients with schizophrenia?].

The role of antipsychotic polypharmacy in the treatment of schizophrenia remains largely unknown, although such a mode of therapy has frequently been advocated on an empirical basis. This trend has especially been true in Japan. We briefly review current evidence in favor of and against polypharmacy in schizophrenia, then we show the data of revising antipsychotic polypharmacy to monotherapy. The study included 47 patients with chronic schizophrenia. Among the 44 patients assessable, 24 remained stable, 10 got better and 10 got worse after 24 weeks of maintenance monotherapy with the main agent. Overall, there were no significant differences in the Global Assessment of Functioning and the Global Impression of the participants. Conversion to antipsychotic monotherapy was feasible in 22 patients, while another 12 needed low dosages of low-potency agents. The chlorpromazine equivalent amount of antipsychotics was significantly reduced from 1,171 to 952 mg/day in 34 patients who were successful in switching. Although the procedure overall did not help patients much, it is suggested that many instances of antipsychotic polypharmacy are avoidable. Adding medications upon the emergence of symptoms might be an easy way to treat patients. Such an action should be validated in every case, however, and polypharmacy should be tested against prolonged, tenacious monotherapy.

Simplifying psychotropic medication regimen into a single night dosage and reducing the dose for patients with chronic schizophrenia.

RATIONALE: Taking psychotropic medications is frequently problematic from both consumers' and caregivers' perspective. Occasionally missed doses may lead to pervasive non-adherence with relapse a likely outcome. OBJECTIVE: To evaluate the simple medication regimen, all psychotropics were given at night for patients with chronic schizophrenia, who had been taking them at least twice a day for more than 12 weeks before the entry. METHODS: Switching of agents took place in two ways: converting only antipsychotic medications followed by other psychotropics, and changing all psychotropics simultaneously. Any psychotropics of little clinical significance were then cautiously minimized. Final evaluation was made 12 weeks after the competed dose consolidation. Patients finally rated their subjective impression on this intervention. RESULTS: Twenty-five patients were recruited in each treatment arm (50 in total). After switching, 11 got better, 29 remained stable whereas seven got worse, according to the Global Improvement. Three were not assessable. Overall, there were no relevant changes in clinical ratings including adverse effects. However, the chlorpromazine equivalent dose of antipsychotics and the number of total psychotropics were significantly reduced from 957 to 722 mg/day (p<0.0001) and from 4.0 to 3.2 (p<0.0001), respectively. Dose deflation of psychotropics was feasible in 35 subjects (74.5%). Twenty-six (of 40 successful) patients indicated that they favored the night-time regimen mainly because it was less complicated. Sedation in the morning was identified as an important adverse event, which should be addressed by reducing the dose. CONCLUSIONS: The procedure may be of value to counteract a recent trend of psychotropic polypharmacy in schizophrenia.

Revising polypharmacy to a single antipsychotic regimen for patients with chronic schizophrenia.

Antipsychotic polypharmacy has been empirically used and a recent trend in favour of that mode of therapy has been suggested for the treatment of schizophrenia. The clinical efficacy, however, still remains to be clarified. In order to critically evaluate the usefulness of such kind of psychopharmacotherapy, antipsychotic combination regimen (polypharmacy) was switched to a treatment with the single main antipsychotic (monotherapy) in cross-tapered fashion, while approximately maintaining the total amount, for patients with chronic schizophrenia. Patients had been treated with an average of three antipsychotics and maintained with the same antipsychotic polypharmacy regimen for more than 6 months before the entry. They were followed up with an antipsychotic monopharmacy and evaluated at 24 wk after completion of switching. Forty-seven patients were recruited for this study. Of 44 patients for whom evaluation was possible, 24 (54.5%) remained stable, while 10 (22.7%) showed improvement and the same number of patients ended in a deleterious status. Twenty-two patients were converted to antipsychotic monotherapy, while another 12 needed minimal dosing of low-potency agents. Overall, social functioning, evaluated by the Global Assessment of Functioning and the Clinical Global Impression, remained unchanged. Eighteen of 34 successful patients showed adverse effects of the main antipsychotic medication, which necessitated a significant dose reduction. Nine out of 10 deteriorating patients had been treated with a combination of low- and high-potency antipsychotics. It is suggested that many instances of antipsychotic polypharmacy is avoidable. The result is compatible with the current treatment recommendations, which dictate the use of a single antipsychotic agent.

A clinical case series of switching from antipsychotic polypharmacy to monotherapy with a second-generation agent on patients with chronic schizophrenia.

Second-generation antipsychotic medications have become popular as a treatment for schizophrenia. The authors investigated 25 chronic subjects who had previously been treated with high-dose antipsychotic polypharmacy without amelioration. All patients had a history of having been treated with an antipsychotic polypharmacy regimen of the total daily chlorpromazine equivalent dose exceeding 1000 mg/day for more than 6 weeks. They were subsequently switched to a second-generation antipsychotic monotherapy. Other psychotropic medications were simplified at the same time. For successful patients whose symptoms showed at least minimal improvement, the medical chart was reviewed retrospectively. After completed switching, the patients were followed up for 12 weeks, when final evaluation was made. The Global Assessment of Functioning score improved from 32 to 47. The number of antipsychotic medications and total psychotropic medications were significantly reduced from 3.5 to 1.1 and 6.8 to 2.6, respectively. Also, the antipsychotic dose was significantly minimized from 2203 to 619 mg/day. Eleven of eighteen inpatients were discharged and the other four were better enough to be ready for discharge. By showing successful cases, the authors suggest a possibility of antipsychotic monotherapy with a second-generation agent even for those patients who had been treated with high-dose antipsychotic polypharmacy in vain.