[Diabetes mellitus and dementia]. / Diabetes mellitus a demence.

Patients with diabetes are at increased risk of developing cognitive impairment in comparison with the general population. Diabetes mellitus increases the risk of dementia (vascular and/or neurodegenerative). Diabetes accelerates the progression from mild cognitive impairment to dementia. It has been estimated that type 2 diabetes or impairment of glucose metabolism might be present in up to 80% of patients with Alzheimer disease. The cognitive dysfunction is associated with poorer ability in diabetes self-care and decreased adherence to antidiabetic treatment.

Treatment retention with risperidone long-acting injection: 24-month results from the Electronic Schizophrenia Treatment Adherence Registry (e-STAR) in six countries.

OBJECTIVE: To assess treatment retention on risperidone long-acting injection (RLAI) and outcomes in schizophrenia patients for whom 24 months of follow-up data in the electronic Schizophrenia Treatment Adherence Registry (e-STAR) were available. RESEARCH DESIGN AND METHODS: e-STAR is an ongoing, international, multicenter, prospective, observational registry assessing use of antipsychotics in patients with schizophrenia or schizoaffective disorder in a normal clinical practice setting. Parameters were assessed prior to and post-initiation of RLAI. Data presented are from six European countries that enrolled patients in e-STAR after they initiated treatment with RLAI. MAIN OUTCOME MEASURES: Clinical and demographic information were collected at baseline and treatment-related data, including RLAI discontinuation, psychiatric hospitalization and medication utilization, were collected prospectively every 3 months. Data collection continued for 24 months, even for patients who discontinued RLAI therapy. Hospitalization and medication utilization were also collected retrospectively by chart review for the 12-month period prior to RLAI initiation. RESULTS: A total of 1659 patients (mean age, 39.2; 18.3% inpatients) completed the study. Twenty-four months after initiating therapy (initial RLAI dose = 33.6 mg) 85% of patients (n = 1410) remained on RLAI (completers) while 15% discontinued therapy. The main reasons for discontinuation were insufficient response (28.5%), patient/family choice (26.1%), adverse events (9.6%) and unacceptable tolerability (6.0%). At baseline, compared to completers, discontinuers were younger (37.4 vs. 39.6 years, p = 0.01), had schizophrenia for a shorter time (10.2 vs. 11.9 years, p = 0.02), had lower Global Assessment of Functioning (GAF) scores (43.5 vs. 48.0, p = 0.0001), higher utilization of benzodiazepines (56.5 vs. 43.3%) and more initiated therapy as inpatients (30 vs. 16%). With RLAI therapy GAF scores improved significantly (p < 0.001) for both groups but the 24-month value for discontinuers was lower than that of completers (55.4 vs. 67.2). Compared to the pre-RLAI initiation period, at 12 months post-initiation completers had greater reductions than discontinuers in the percent of patients hospitalized (66.2% reduction vs. 29.2%) and in the length (68% reduction vs. 0%) and number (80.0 vs. 14.3%) of hospital stays, differences that remained at 24 months. The most common adverse events while patients were taking RLAI were nervous system disorders (6.8%), psychiatric disorders (5.6%), weight increase (3.2%), reproductive system and breast disorders (2.5%) and gastrointestinal disorders (2.1%). CONCLUSIONS: These observational data confirm that RLAI is an effective treatment in schizophrenia and high levels of adherence to therapy offers an opportunity for effective long-term disease management and significant sustained decreases in hospitalization.

[Diabetes mellitus and cognitive impairments]. / Diabetes mellitus a kognitivní poruchy.

Patients with diabetes have an at increased risk of developing cognitive impairment in comparison with the general population. Cognitive dysfunction comprises impairments of executive functions, memory, attention, and psychomotor efficiency. The question of whether recurrent exposure to severe hypoglycaemia promotes long-term cognitive dysfunction is unresolved. The main risk factors for cognitive impairment in diabetes are considered to be chronological age, duration of diabetes, and coexistent microvascular and macrovascular complications. Diabetes should be treated as a risk factor for cognitive impairment. Cognitive dysfunction is associated with poorer ability in diabetes self-care and decreased adherence to antidiabetic treatment.

Acetylcholinesterase inhibitor donepezil in the treatment of cognitive deficit in schizophrenia. Subanalysis of the active branch from Czech extended double blind study.

The article mentions the conclusions of most evidential works investigating donepezil in the treatment of cognitive deficit in schizophrenia. It focuses on an analysis of a sub-group of 20 patients receiving treatment of the donepezil in an extended Czech double-blind placebo controlled study.

Haloperidol blood levels in acute mania with psychosis.

In this study, the authors examined the relationship between steady-state haloperidol blood levels and clinical response in patients with acute psychotic mania. Fifty-four inpatients with acute mania were randomly assigned to receive either haloperidol 25 mg/day or haloperidol 5 mg/day. Each subject also received a concomitant medication: lorazepam 4 mg/day, lithium, or placebo. The relationship between steady-state haloperidol blood levels and clinical improvement was studied using analysis of covariance. There was wide interindividual variation in the haloperidol blood level-dose ratio. Haloperidol blood levels (log-transformed) were found to significantly correlate with clinical response in acute mania. Low-dose haloperidol with concomitant lithium may produce an optimal response in acute mania. Haloperidol blood levels may be clinically useful in identifying patients who are nonresponsive because of low drug levels and, hence, in enhancing optimal haloperidol dosing for acute mania with psychosis.

Pretreatment plasma HVA and haloperidol response in acute mania.

INTRODUCTION: Pretreatment plasma homovanillic acid (HVA) levels have been reported to be a correlate of clinical response to typical antipsychotics for schizophrenic, bipolar manic, and mixed groups of psychotic patients. Biological markers of clinical response to antipsychotics could be useful for optimizing drug treatment. METHOD: Thirty-one consenting acute inpatient subjects between ages 19 and 66 years with a DSM-III-R clinical diagnosis of bipolar disorder, manic with psychotic features were entered into this double-blind study and were randomly assigned to receive either haloperidol 25 mg/day or haloperidol 5 mg for the 3-week study. Subjects also received one of the following concomitant medications: standard lithium, lorazepam 4 mg/day, or placebo. RESULTS: The primary multiple regression analysis, including all subjects on both haloperidol doses, yielded a significant main effect for pretreatment plasma HVA (n=31, F=5.7, P=0.025), indicating that higher pretreatment plasma HVA was predictive of better clinical response. In addition, the interaction between haloperidol dose and pretreatment plasma HVA was also significantly associated with clinical response (F=12.59, P=0.0015). When the two haloperidol doses were analyzed separately, we found that pretreatment plasma HVA was only correlated with clinical response in the low haloperidol 5 mg/day group (n=18, F=11.73, P=0.0038) and was unrelated to clinical response to the high haloperidol 25 mg/day group. LIMITATIONS: The sample size was small. Results may have been confounded by prior antipsychotic treatment and concomitant use of lithium or lorazepam. DISCUSSION: These results suggest that pretreatment plasma HVA could be useful for dosing antipsychotics. Patients with high plasma HVA levels would be good candidates for low-dose treatment because they are more likely to improve on such a dose, while patients with low plasma HVA levels might warrant more rapid dosage escalation.

Costs and outcomes of use of amitriptyline, citalopram and fluoxetine in major depression: exploratory study.

BACKGROUND: The increasing cost of pharmaceuticals in the Czech Republic has led to the restriction on prescriptions of expensive new antidepressants. The aim of the study was to compare the costs and outcomes of using amitriptyline, citalopram and fluoxetine in the treatment of major depression. METHODS: Ninety patients (69 women) with a mean age of 44.5 years (S.D. = 14.3) suffering from major depression were treated with amitriptyline (N = 31), citalopram (N = 29) and fluoxetine (N = 30). Direct medical costs and effectiveness (indicated by the number of hospitalization-free days) were assessed in a prospective, open, intent-to-treat study. RESULTS: Neither cost nor effectiveness were significantly different among the treatment groups. CONCLUSION: Amitriptyline treatment is not less expensive nor more effective than citalopram or fluoxetine therapies. There is no advantage in restricting patients from treatment with SSRIs, which have fewer adverse effects and a decreased risk of a lethal overdosage in comparison with tricyclic antidepressants.

Acute mania: haloperidol dose and augmentation with lithium or lorazepam.

Antipsychotic dosing for acute mania has not been well studied. Combined treatment with lithium and an antipsychotic is the most common treatment, but additional antimanic efficacy of a lithium-antipsychotic combination beyond that of an antipsychotic alone has not been well demonstrated. Furthermore, the possibility that lithium could affect antipsychotic dose requirement is believed to have never been studied. In this study, 63 acutely psychotic bipolar manic inpatients were randomly assigned to receive double-blind treatment with 1 of 2 haloperidol doses, 25 mg/day or 5 mg/day, for 21 days. In addition to haloperidol, subjects were randomly assigned to receive concomitant treatment with placebo, standard lithium, or lorazepam 4 mg/day. The high haloperidol dose produced greater improvement and more side effects than did the low dose. Lithium added to the low dose produced a markedly greater clinical response than did the low dose alone. Lorazepam did not improve the outcome for the patients receiving low-dose haloperidol. The clinical response produced by high-dose haloperidol was not enhanced by adding either lithium or lorazepam. All treatment effects emerged by the fourth day of treatment and persisted. Used alone, a haloperidol dose of 5 mg/day is too low for most manic patients, but concomitant lithium produces a dose-dependent enhancement of haloperidol response. Lorazepam 4 mg/day was insufficient to produce an advantage when added to low-dose haloperidol.

Intra-individual variability and influence of urine collection period on dextromethorphan metabolic ratios in healthy subjects.

The aim of the study was to evaluate intra-individual variability in metabolic ratios (MRs) of dextromethorphan (DM) in healthy volunteers and to compare the MRs in urine collected 0-4, 0-8 and 0-24 h post-dose. Urinary molar ratios of DM to dextrorphan (MR1) and of DM to methoxymorphinan (MR2) were obtained after a single oral 27.5 mg dose of DM hydrobromide to ten healthy male and four female Caucasians (ten extensive metabolizers (EM) and four poor metabolizers (PM) of DM) to probe activities of CYP2D6 and CYP3A, respectively. Seven EM and one PM received DM on three additional occasions within 2 months. For the seven EM, the intra-individual variability (CVw) in the MRs obtained in the three urine collections ranged from 11 to 93% (MR1) and from 8 to 77% (MR2). The mean CVw estimated separately for the 4, 8 and 24 h urines by two-way analysis of variance reached 58, 57 and 44% for the MR1 and 50, 42 and 31% for the MR2, respectively. For all 14 subjects, the log-transformed ratios (MR1) obtained in the 24 h urines were highly correlated with those in either the 8 h (rs = 0.967, P < 0.0001) or 4 h urines (rs = 0.946, P < 0.0001). Correlation between the log-transformed MR2s were weaker (24 h vs. 8 h: rs = 0.829, P < 0.0001, 24 h vs. 4 h: rs = 0.831, P < 0.0001). The MR1s in 4 h and 8 h urines were only 2 and 9% less than those in 24 h urines (median differences) and varied from 48 and 47% below to 85 and 55% above (95% -CI for the differences). However, the MR2s in the 4 h and 8 h urines were shifted towards higher values by 49 and 23% and the corresponding 95% -CI limits were: 16-164% (4 h vs. 24 h) and 30-119% (8 h vs. 24 h). In conclusion, MR1 values in the 4 h urine collection agree well with those in longer collections and their use in epidemiological studies can be recommended. The intra-individual variability of approximately 50% in the MR1 has to be taken into account in clinical studies with within-subject design. Accurate determination of the MR2 requires at least a 24 h period of urine collection.

Fenfluramine challenge test in obsessive-compulsive disorder--first results.

Obsessive-compulsive disorder is a chronic psychiatric illness, affecting up to 3% of the general population, to the middle of 60-th it was supposed to be untreatable. Antidepressant pharmacotherapy is one of the treatment alternatives today. We compared efficacy and safety of citalopram versus clomipramine (serotoninergic antidepressants) in 6 weeks in double blind therapy of obsessive-compulsive disorder. The second objective was to compare prolactin response to a fenfluramine challenge test before the treatment of patients and after 6 weeks of the treatment. In a sample of 14 patients we confirmed significant therapeutic response after 3 weeks of pharmacotherapy, better in obsession than in compulsion. We found low level of adverse effects in the first week of therapy--dry mouth, anxiety, nausea, somnolence, tremor, and sexual adverse events. There were no changes in the laboratory, test EEG, and ECG examinations. Fenfluramine challenge test showed statistically significant decrease of prolactin levels 1 hour after administration of fenfluramine. It was not observed after six weeks of the therapy. Statistically significant negative correlation between prolactin plasma levels at the 6th hour after administration of fenfluramine and obsession item of YBOC Scale was showed after the 3rd and 6th week of the therapy. The correlation was not observed for compulsion item YBOC Scale. Side effects observed during and after the challenge test were anxiety and nervousness and gastrointestinal problems, lasted from 1 hour to 10 hours. These preliminary result could support the idea, that obsessions and compulsions have not necessary the same biological background. The challenge paradigm appears to be a possible way to clarify the pathogenesis of OCD. Our study will continue.

Treatment approaches for acute mania.

Drug treatment of mania is conceptually divided into mood stabilizers and tranquilizers. Indications for each are defined and a graphical decision tree for treatment of acute mania is presented. The anticonvulsants carbamazepine and valproic acid have an efficacy comparable to that of lithium and work in many lithium-refractory patients. They have not, however, been sufficiently studied in maintenance treatment. Guidelines are presented for the selection of a mood stabilizing agent as well as for combining two mood stabilizers. Lithium-refractoriness, a key concept in determining drug choice, is poorly defined in the literature and requires refinement. Among tranquilizers, neuroleptics are used most frequently, but their use should be minimized. Neuroleptic dosing of manic patients is probably too high and exposes patients to an unnecessary risk of side effects including tardive dyskinesia. In patients with no history of substance abuse, benzodiazepines can be used instead of neuroleptics or in augmentation of neuroleptics which can then be used at lower doses.

[Treatment of tardive dyskinesias with 7-methoxytacrine. I]. / Lécba tardivních dyskinéz 7-metoxytakrinem--I.

The 7-metoxytacrine (7-MEOTA) is an original Czech cholinergic agent synthetized in the labs of the Military Medical Academy in Hradec Králové. The treatment of tardive dyskinesias is one of the possible indications of the use of 7-MEOTA in clinical practice. The authors have summed up their experience from the first phase of clinical tests with 7-MEOTA in psychiatrical patients suffering from tardive dyskinesias in long-termed administration of cholinergic agents. The clinical efficiency and tolerance of 7-MEOTA have been evaluated after a single administration of 100 mg of 7-MEOTA per os in 19 patients. A reduction of dyskinesias was observed as early as 4 h following the testing dose. In 5 patients, viz. in 26% a reduction of dyskinesias was observed of more than 50% of the original value of the total score of the testing scale AIMS. Except for a slight decrease of the blood pressure and a mild somnolence in 3 patients no other undesirable effects have been observed. In some patients a slight euphorization effect of 7-MEOTA has been found.

[Treatment of tardive dyskinesias with 7-methoxycrine. II]. / Lécba tardivních dyskinéz 7-metoxytakrinem--II.

In an open clinical study the authors have verified the effectivity and tolerance of 7-metoxytacrine cholinergic agent (7-MEOTA) in a total consisting of 14 patients with schizophrenic or schizoaffective psychoses suffering from tardive dyskinesias in long-termed treatment with neuroleptics. In the whole group consisting of 14 patients the seven days' administration of the experimental preparation in a dose of 100-150 mg pro die was evaluated. The 7-MEOTA preparation was administered to 7 patients for 2 weeks. In the seven and fourteen days' administration a favourable effect of 7-MEOTA on tardive dyskinesias was observed. A fast onset of the efficiency as early as in the first days of the treatment was recorded. In final evaluation a minimal reduction of 50% of the intensity of the dyskinesias (using the AIMS scale) in 29% of the patients treated for a fortnight was found. The 7-MEOTA preparation was well tolerated, no undesirable marked side effects being observed. A transient increase of ALT was found in 1 patient only in the 2nd week of the treatment. In experimental treatment the maintenance neuroleptical therapy was not discontinued. An improvement of the dyskinesias overlasted in some patients as long as 2 month g after the discontinuation of the administration of 7-MEOTA preparation.

[Prevention of suicidal activity in patients with affective disorders by treatment with lithium]. / Ovlivnení sebevrazedné aktivity nemocných s afektevními poruchami lithioprofylaxí.

The authors expressed in 1984 the assumption that lithium is the drug of the phenomenon of suicidal action in affective disorders. In the present paper the authors describe in a group of 56 patients with affective disorders in the course of lithioprophylaxis a marked decline of the suicide rate at the 4% level of significance. Therefore the authors are still in favour of the view that lithium is the drug in suicidal behaviour in affective disorders. This mechanism can be explained by the antiaggressive as well as prophylactic action of lithium. In the authors' opinion it is possible that the mechanism of this action may be conditioned by the interference of lithium with the dysfunction of the central serotonergic system.

Reduction in temporal lobe size in siblings with schizophrenia: a magnetic resonance imaging study.

Twenty-eight individuals with familial schizophrenia, from 16 unrelated families (12 sibling pairs and 4 individuals whose siblings refused scanning), and 21 normal control subjects were examined by cerebral magnetic resonance imaging (MRI). Measurements of the cerebrum, temporal lobes, and cerebral lateral ventricles were obtained using consecutive coronal sections containing these structures. Temporal lobe volume was significantly decreased by approximately 10% in these early onset schizophrenic siblings compared with normal controls. These findings add to recent post-mortem and neuroradiological evidence for morphological alteration in the temporal lobes in schizophrenia.

[Lithium in the prevention of affective disorders: 20 years' experience]. / Lithium v profylaxi afektivních poruch: dvacetiletá zkusenost.

Long term preventive lithium administration results are referred to with the manifestation of a full effect in 23% affective illness-related patients. In 70% of patients, the occurrence of side-effects including those initial ones was stated in no but 40% patients in the course of long term lithium-prophylaxis. This fact testifies about the decrease in number of side-effects during the treatment with lithium. Most frequent side-effects were tremors and diarrhea. No serious renal complications were observed, except the onsets of tardive dyskinesis in on patient after the combined administration of chlorprothixene, amitriptyline and lithium. In three patients, the distant relapses were observed without discontinuation of therapy after the 10-year-lasted successful lithium-prophylaxis. In accord to the long term experience, the authors estimate 0.4 mmol/l lithemia level to be the minimal effective one. They believe the lithium is a reliable thymoprophylactic agent, though in accord with them the other substances with larger therapeutic spectrum are to be searched as well as predictors of an effective lithium-prophylaxis.