Clinical Experience With Intramuscular Clozapine.

Clozapine is the most effective antipsychotic for patients with treatment-refractory schizophrenia, but many refuse to accept oral clozapine therapy. Intramuscular (IM) clozapine represents a convenient alternative for their treatment. The aim of this review is to summarize studies investigating IM clozapine administration. When initially developed, clozapine was also provided as an IM formulation, but the manufacturer later discontinued its production. Recently, IM clozapine became again available as an unlicensed product distributed by the Dutch company Apotheek A15. The use of IM clozapine has been reported in older studies on clozapine's adverse effects. It has also been described in detail in 5 more recent and generally smaller (n = 7 - 59) retrospective studies in patients refusing to take oral clozapine. In addition, its administration has been noted in 5 case reports. IM clozapine has been used at approximately ½ of the dose of oral clozapine due to pharmacokinetic considerations. It has been used in doses of up to 500 mg per day and for up to 99 days of treatment. The majority of patients (between 60 and 100%) were successfully transitioned to oral clozapine within a few days of IM treatment, and improvement in their condition was sustained during the long-term follow-up. Side effects of IM clozapine were similar to those of oral clozapine, but its sedative and cardiovascular effects (hypotension and tachycardia) had faster onset following IM administration. After long-term use, clozapine injections lead to local swelling and to the formation of painful nodules in some patients. In summary, IM clozapine may facilitate successful transition to oral clozapine in most patients, and it definitely represents a valuable tool for addressing refusal of oral clozapine in patients with treatment-refractory schizophrenia. More studies, especially focused on its safety, are, however, needed to better understand the limitations of this novel treatment approach.

A pilot dose-finding clinical trial of creatine monohydrate augmentation to SSRIs/SNRIs/NASA antidepressant treatment in major depression.

Creatine's effects on brain energy metabolism raise the possibility of developing a new therapeutic strategy in depression focusing on the treatment of metabolic hypoactive brain areas. Previous creatine augmentation studies in patients with major depression showed a beneficial effect. Eighteen patients (14 women) with major depression not responding to previous 3 weeks of antidepressant treatment were enrolled into a pilot, dose finding, 4-week double-blind parallel augmentation study where creatine monohydrate 5 or 10 g daily or placebo was added to ongoing SSRIs/SNRIs/NASA treatment. Rating scales included the Hamilton Depression Rating Scale and the Clinical Global Impression Severity scale. Overall, there was no difference between creatine administered at 5 or 10 g daily and its corresponding placebos. Two female patients on creatine augmentation, but none on the placebo, showed early improvement of more than 50% reduction in Hamilton Depression Rating Scale after 2 weeks of creatine treatment. No clinically relevant side effects were reported. This preliminary study seems to suggest that the strategy using creatine augmentation in major depressive women showing no 'real-life response' to 3 weeks of treatment with SSRIs/SNRIs/NASA treatment is of no advantage compared with placebo. However, such creatine augmentation may still induce a more rapid response in a small subgroup of these female patients.

Cognitive rigidity in unipolar depression and obsessive compulsive disorder: examination of task switching, Stroop, working memory updating and post-conflict adaptation.

Obsessive compulsive disorder (OCD) and depressive rumination are both characterized by cognitive rigidity. We examined the performance of 17 patients (9 suffering from unipolar depression [UD] without OCD, and 8 suffering from OCD without UD), and 17 control participants matched on age, gender, language and education, on a battery covering the four main executive functions. Results indicated that, across both disorders, patients required more trials to adjust to single-task conditions after experiencing task switching, reflecting slow disengagement from switching mode, and showed abnormal post-conflict adaptation of processing mode following high conflict Stroop trials in comparison to controls. Rumination, which was elevated in UD and not in OCD, was associated with poor working memory updating and less task preparation. The results show that OCD and UD are associated with similar cognitive rigidity in the presently tested paradigms.

[Factitious disorder by proxy].

Factitious disorder by proxy remains one of the least known and most controversial disorders in psychiatry. The following review refers to the contemporary approach to the disorder, its prevalence, risk factors, diagnostic problems, treatment and coping.

Clinical trials of PUFAs in depression: State of the art.

Omega fatty acid treatment of depression is an unusual story in psychopharmacology in that the use and study of these compounds were advanced in cardiovascular disease before becoming of interest in psychiatry. Given the absence of an easily patentable derivative it is a tribute to the field that enough studies have accumulated for a reasonable review of omega-3 treatment of depression at this time. On the other hand, it is clearly not possible to compare the number of studies, variety of studies and the number of participants in each study with Federal Drug Administration style registration trials of patented antidepressant drugs. Most of the available studies of omega-3 in depression have been investigator initiated and use add-on design. This paper reviews 12 published and as yet unpublished clinical trials (all but one double-blind placebo-controlled) of polyunsaturated fatty acids in unipolar depression, bipolar disorder, and special populations with affective/depressive disorders. While overall results up to this point are encouraging, they are not unanimously positive. Outstanding issues that have not as yet been resolved include the dose of omega-3 necessary and the length of time required for significant response. Moreover, the complex issue of the relationship between two possible active ingredients, eicosapentaenoic acid and docosahexaenoic acid, remains unresolved.

Omega-3 treatment of childhood depression: a controlled, double-blind pilot study.

OBJECTIVE: Major depressive disorder in children may be more common than previously thought, and its therapeutics are unclear. Because of success in a previous study on omega-3 fatty acids in adult major depressive disorder, the authors planned a pilot study of omega-3 fatty acids in childhood major depression. METHOD: Children who entered the study were between the ages of 6 and 12. Ratings were performed at baseline and at 2, 4, 8, 12, and 16 weeks using Children's Depression Rating Scale (CDRS), Children's Depression Inventory (CDI), and Clinical Global Impression (CGI). Children were randomized to omega-3 fatty acids or placebo as pharmacologic monotherapy. Twenty-eight patients were randomized, and 20 completed at least 1 month's ratings. RESULTS: Analysis of variance showed highly significant effects of omega-3 on symptoms using the CDRS, CDI, and CGI. CONCLUSIONS: Omega-3 fatty acids may have therapeutic benefits in childhood depression.

Electroconvulsive therapy-induced symptomatic hypocalcemia in a schizophrenic patient: a case report.

We present a case study of a young schizophrenic 20-year-old female patient, admitted for severe psychotic exacerbation unresponsive to several antipsychotic regimens. She was treated successfully with a course of bilateral electroconvulsive therapy, but developed symptomatic hypocalcemia of short duration after the fifth ECT treatment. There is limited information regarding the phenomenon of ECT-induced acute hypocalcemia. To the best of our knowledge, there are no previous reports of this finding in the literature. A similar phenomenon was reported many years ago in patients with primary affective illness. The possible mechanisms of this potentially life-threatening reaction are not clear and should be evaluated in further studies.

Vitamin B6 versus mianserin and placebo in acute neuroleptic-induced akathisia: a randomized, double-blind, controlled study.

Treatment strategies against acute neuroleptic-induced akathisia (NIA) include anticholinergic (antimuscarinic) agents, dopamine agonists, GABAergic agents, beta-blockers, benzodiazepines, and serotonin antagonists. However, many patients who have acute akathisia fail to respond. In previous studies, mianserin and vitamin B6 were found to be effective in the treatment of acute akathisia. The purpose of this study was to compare the efficacy of B(6), mianserin and placebo in the treatment of acute NIA. Sixty schizophrenia and schizoaffective inpatients who have NIA were randomly divided to receive vitamin B(6) 1,200 mg/d, mianserin 15 mg/d, or placebo for 5 days, in a double-blind design. The Barnes Akathisia Rating Scale, Brief Psychiatric Rating Scale, and Clinical Global Impression were used to assess the severity of NIA and psychotic symptoms. The assessment was made at baseline and daily for the duration of the study. Compared with the placebo group, the vitamin B(6)-treated and mianserin-treated patients showed a significant improvement in the subjective (P < 0.0001), subjective distress (P < 0.0001), and global (P < 0.0001) subscales. The objective subscale did not show significant positive results (P = 0.056), but there was a trend toward symptom amelioration in both groups. A reduction of at least 2 points on the Barnes Akathisia Rating Scale global subscale was noted in the vitamin B(6) group (13/23, 56%) as well as in the mianserin groups (13/20, 65%), and in only one patient in the placebo group (1/17, 6%; P < 0.0005). Our results indicate that high doses of B(6) and a low dose of mianserin may be a useful addition to current treatments of NIA. The efficacy of vitamin B(6) and mianserin suggests that the pathophysiology of acute NIA is heterogeneous with the various subtypes of acute NIA responding differently to the various pharmacological approaches.

Controlled double-blind trial of phenytoin vs. fluoxetine in major depressive disorder.

BACKGROUND: Phenytoin was the first non-sedative anticonvulsant introduced and is still the anticonvulsant most widely used worldwide in neurology. Given the efficacy of the anticonvulsant lamotrigine in the depressed phase of bipolar disorder, a critical theoretical question is whether other anticonvulsants used in treating bipolar disorder might be similarly effective. We therefore undertook a controlled trial of phenytoin versus fluoxetine in major depressive disorder. METHOD: Data were collected from July 2001 to July 2003. Thirty-three subjects entered the study. All patients met DSM-IV criteria for major depressive disorder and scored a minimum of 18 on the 24-item Hamilton Rating Scale for Depression (HAM-D) at baseline. After a 3-day washout of any previous medications, patients were randomly assigned to fluoxetine or phenytoin in identical capsules. Each capsule contained phenytoin 100 mg or fluoxetine 7 mg plus cornstarch. Patients started with 1 tablet daily and increased every other day until they were taking 1 tablet 3 times daily with meals. Blood phenytoin levels were taken after 1 week, 3 weeks, and 6 weeks, and dosage was adjusted to achieve blood levels of 10 to 20 microg/mL, to a maximum dose of 4 capsules per day or a minimum dose of 2 capsules per day. Fluoxetine patients were assigned dummy blood phenytoin levels by the control psychiatrist such that the treating physician would raise the number of capsules to at least 3 per day (20 mg of fluoxetine). RESULTS: Thirty-three patients entered the study, and 28 (N = 14 in each treatment group) completed at least 3 weeks and were included in the data analysis. Patients who dropped out after week 3 (3 patients) were included in the study as last value carried forward. There was no difference between treatment groups in overall rate of response or speed of response. CONCLUSION: The absence of a placebo arm in our study allows for the possibility that neither treatment was more effective than placebo. However, the exclusion of past fluoxetine nonresponders and the minimum HAM-D score at baseline of 18 make this possibility unlikely.

Myo-inositol has no beneficial effect on premenstrual dysphoric disorder.

Inositol, a simple isomer of glucose, which serves as a precursor in the phosphatidyl-inositol (PI) second messenger cycle, was shown to be effective in double-blind, placebo-controlled studies of depression, panic and obsessive compulsive disorders as well as in bulimia. The following study was designed to investigate whether inositol has beneficial effects in another disorder shown to be responsive to SSRIs: premenstrual dysphoric disorder (PMDD). Eleven female patients with PMDD diagnosed according to DSM-IV participated in a cross-over, double-blind, placebo-controlled trial. The active drug was myo-inositol, 12 g daily, whereas placebo was d-glucose administered at the same dose. Each drug was given during the luteal phase only (14 days prior to menses). For each patient treatment alternated between these two drugs for six menstrual cycles. No beneficial effect was demonstrated for inositol over placebo.

[False memory syndrome: state of the art].

The review describes the heated dispute on the present state of recovered traumatic memories. There are two main schools concerning the status of recovered memories of child abuse. One school believes in their authenticity unconditionally. Those who oppose the authenticity claim False Memory Syndrome's existence. They describe it as "a serious form of psychopathology characterized by strongly believed pseudomemories of childhood sexual abuse" and "condition in which a person's identity and interpersonal relationships are centered around a memory of traumatic experience which is objectively false but in which the person strongly believes". This review presents the allegations of both sides involved in the dispute, with updates of scientific and judicial references and relevant recommendations to care takers.

Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder.

OBJECTIVE: Studies have reported that countries with high rates of fish oil consumption have low rates of depressive disorder. The authors studied a specific omega-3 fatty acid, the ethyl ester of eicosapentaenoic acid (E-EPA), as an adjunct to treatment for depressive episodes occurring in patients with recurrent unipolar depressive disorder who were receiving maintenance antidepressant therapy. METHOD: Twenty patients with a current diagnosis of major depressive disorder participated in a 4-week, parallel-group, double-blind addition of either placebo or E-EPA to ongoing antidepressant therapy. Seventeen of the patients were women, and three were men. RESULTS: Highly significant benefits of the addition of the omega-3 fatty acid compared with placebo were found by week 3 of treatment. CONCLUSIONS: It is not possible to distinguish whether E-EPA augments antidepressant action in the manner of lithium or has independent antidepressant properties of its own.

Lack of effect of eicosapentaenoic acid in the Porsolt forced swimming test model of depression.

BACKGROUND: Eicosapentaenoic acid (EPA) is one of the major components of fish oils. Omega-3 fatty acids, particularly EPA, have been hypothesized to play a role in the etiology, pathogenesis and treatment of mood disorders. Clinical studies have shown beneficial effects of omega-3 fatty acids in major depression, bipolar disorder and other psychiatric disorders. OBJECTIVE: The present study design evaluates the effect of EPA in the Porsolt forced swimming test. RESULTS: EPA alone did not reduce the immobility time and did not enhance the anti-immobility effect of a low dose of imipramine. Contrary to the hypothesis, EPA slightly increased the immobility time, and in some experiments tended to reduce the anti-despair effect of imipramine. CONCLUSION: The present results do not provide an animal model for the antidepressant effect of EPA as demonstrated in clinical experiments. The mechanism of EPA antidepressant action is unknown and the Porsolt forced swimming test could be non-sensitive for its antidepressant properties.

Combination of antidepressant drugs: the case of inositol.

Inositol is a second messenger precursor that is effective in depression and obsessive-compulsive disorder via a mechanism different from serotonin reuptake inhibitors. However, controlled trials of inositol combined with serotonin reuptake inhibitors in depression or in reuptake inhibitor resistant depressed patients, or in partially responsive obsessive-compulsive patients, did not reveal added benefit. This is comparable to results with combinations of other antidepressant treatments, such as tricyclics plus monoamine oxidase inhibitors. Copyright 2001 John Wiley & Sons, Ltd.