Michael Philipp

The Hamilton Anxiety Scale: reliability, validity and sensitivity to change in anxiety and depressive disorders

The Hamilton Anxiety Scale (HAM-A) was tested for reliability and validity in two different samples, one sample (n = 97) defined by anxiety disorders, the other sample (n = 101) defined by depressive disorders. The reliability and the concurrent validity of the HAM-A and its subscales proved to be sufficient. Internal validity tested by latent structure analysis was insufficient. The major problems with the HAM-A are that (1) anxiolytic and antidepressant effects cannot be clearly distinguished; (2) the subscale of somatic anxiety is strongly related to somatic side effects. The applicability of the HAM-A in anxiolytic treatment studies is therefore limited. More specific anxiety scales are needed.

Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology – a double-blind controlled study comparing a selective D2-like antagonist to a mixed D1-/D2-like antagonist

Abstract The benzamide amisulpride (ASP) is a selective D2-like dopamine antagonist, while flupentixol (FPX), a thioxanthene, blocks D2-like, D1-like and 5-HT2 receptors. To evaluate efficacy and safety of ASP and to investigate the importance of an additional D1-like antagonism for antipsychotic effects and extrapyramidal tolerability, a randomized double-blind multi-center study versus FPX as reference drug was performed for 6 weeks in 132 patients suffering from acute schizophrenia (DSM-III-R) with predominant positive symptomatology. Doses were initially fixed (ASP: 1000 mg/day; FPX: 25 mg/day) but could be reduced by 40% in case of side effects (mean daily doses: ASP: 956 mg; FPX: 22.6 mg). Intention-to-treat evaluation demonstrated significant improvement under both medications. The difference between the mean BPRS decreases of both treatment groups was 5.6 points (95% CI: 0.55; 10.65) in favour of ASP. According to CGI, 62% of patients in either drug group were treatment responders. ANCOVA analysis showed that reductions of BPRS (ASP: −42%; FPX: −32%) and SAPS (ASP: −78%; FPX: −65%) were more pronounced under ASP. Due to adverse events, significantly fewer ASP patients (6%) were withdrawn from the study (FPX: 18%). Extrapyramidal tolerability was better in the ASP group, as demonstrated by smaller increases in the Simpson-Angus Scale, the AIMS, and the Barnes Akathisia Scale in ANCOVA analyses with dosage as covariate. ASP appears to be as effective as FPX with regard to antipsychotic effects on positive schizophrenic symptomatology, while extrapyramidal tolerability is better. These conclusions have to be drawn cautiously, as dosage effects on outcome parameters cannot be entirely ruled out. The present results question the notion that additional blockade of D1-like receptors may be necessary to achieve sufficient antipsychotic effects or to improve extrapyramidal tolerability.

Improving depression severity assessment--I. Reliability, internal validity and sensitivity to change of three observer depression scales.

The Hamilton Depression Scale (HAMD) is the most commonly used scale for depression severity assessment and for antidepressant treatment evaluation. Alternative scales have been proposed by Bech and Rafaelsen (BRMS) and by Montgomery and Asberg (MADRS) to try to overcome the shortcomings of HAMD: they are based on different concepts of severity and different scaling procedures. Comparisons with respect to reliability, validity and ability to detect change have been performed using these scales in different samples. The BRMS proved superior. This result makes it necessary to question the usual procedure of testing the efficacy of antidepressants by means of HAMD alone. Problems in defining the severity of depression and in testing the validity of severity scales are discussed.

Improving depression severity assessment—II. Content, concurrent and external validity of three observer depression scales

The Hamilton Depression Scale (HAMD), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Bech-Rafaelsen Melancholia Scale (BRMS) were compared with respect to content, concurrent and external validity in sample of 130 patients with a major depressive episode. The three scales did equally well in concurrent and external validity. The HAMD showed some deficiencies in content validity. The consequences for depression severity assessment are discussed.

Mirtazapine orally disintegrating tablets versus venlafaxine extended release: a double-blind, randomized multicenter trial comparing the onset of antidepressant response in patients with major depressive disorder.

This randomized, multicenter, double-blind study was designed to compare specifically the onset of antidepressant action of mirtazapine orally disintegrating tablets (ODT) with venlafaxine extended-release (XR) formulation in outpatients with major depression. Both treatments were administered in a rapidly escalating dosing regimen. Target doses (mirtazapine ODT, 45 mg OD; venlafaxine XR, 225 mg OD) were reached by day 6 of treatment. On the primary efficacy parameter [the average of the change in HAM-D (17-item) total score on days 5, 8, 11, and 15], mirtazapine ODT was significantly superior to venlafaxine XR (P = 0.008). In addition, calculating the HAM-D score without the sleep items resulted in significant reductions in favor of mirtazapine ODT on days 8 (P = 0.006) and 11 (P = 0.037). The proportion of responders (HAM-D decrease of ≥50% from baseline) was higher in the mirtazapine ODT group on all assessment days, being significant on days 8 (P = 0.002), 11 (P = 0.004), and 22 (P = 0.027). More patients in the mirtazapine ODT group achieved remission (HAM-D total score of ≤7) up to day 29, and the difference was statistically significant on day 15 (P = 0.016). Significant differences in favor of mirtazapine ODT were evident in the CGI of change on days 8 (P = 0.019), 11 (P = 0.004), and 15 (P = 0.031), and the CGI of severity on days 8 (P = 0.014) and 11 (P = 0.033). Both treatments were well tolerated. These results indicate that mirtazapine ODT has a faster onset of antidepressant efficacy than venlafaxine XR in patients with major depressive disorder, and that this effect is independent of its sleep-improving properties.

Development of a rating scale for quantitative measurement of the alcohol withdrawal syndrome.

SummaryThe alcohol withdrawal syndrome consists of autonomic, neurological and mental symptoms. For its assessment, these symptoms have to be rated in a quantitative and valid manner. We developed a new rating scale for mild and moderate alcohol withdrawal states. Difficulty, discrimination coefficient, internal consistency, and the principal component analysis were assessed. External validation was tested on a separate sample of inpatients. Eight of 12 original items fulfilled test-the-oretical criteria. From these a psychosensory and an autonomic factor have been extracted. This instrument can be used repeatedly for clinical assessment as well as for evaluation of the alcohol withdrawal syndrome in clinical drug studies.

The Polydiagnostic Interview: A Structured Interview for the Polydiagnostic Classification of Psychiatric Patients

A structured interview (PODI) for the polydiagnostic evaluation of affective and schizophrenic disorders is presented. The interview includes elements of the Structured Clinical Interview for DSM-III (SCID) and of the Present State Examination (PSE). The central idea of this interview is to break down complex criteria into their elements, to assess a wide area of such elements, and to recombine them by a computer program according to different algorithms that are included in a greater number of operational diagnoses. Reliability data will be presented which show sufficiently high kappa and Yule coefficients for a selected set of diagnostic criteria for depressive, manic and psychotic disorders. The applicability of the PODI was established in about 180 interviews.

Dose escalation vs. continued doses of paroxetine and maprotiline: a prospective study in depressed out-patients with inadequate treatment response

In view of the fact that controlled prospective studies on the benefits of dose escalation of the selective serotonin re‐uptake inhibitor (SSRI) paroxetine are lacking, we conducted a double‐blind, randomized, parallel‐group multicentre study designed to compare the possible benefits of dose escalation of paroxetine and maprotiline in patients suffering from major or minor depression according to modified Research Diagnostic Criteria (RDC) with inadequate treatment response. The study sample consisted of 544 out‐patients with different degrees of severity of depression. Patients received either 20 mg paroxetine (n=271) or 100 mg maprotiline (n=273) for the first 3 weeks in a double‐blind manner. Response after 3 weeks was defined using explicit operationalized criteria. Patients with inadequate treatment response (paroxetine group, n=86; maprotiline group, n=88) were again randomized to either continuation of the previous dosage (paroxetine, n=36; maprotiline, n=48) or increased doses, i.e. 40 mg paroxetine (n=50) or 150 mg maprotiline (n=40), respectively. Intention‐to‐treat and completer analyses were performed. Defining response as a reduction in Hamilton Depression Rating Scale (17‐item version) (HAMD‐17) score of at least 50% from baseline, no significant benefits of dose escalation were found for either paroxetine or maprotiline. Stratification according to baseline severity of depression also revealed no significant benefits of dose escalation. After dose escalation, new adverse events that had not been present during treatment with lower doses rarely occurred. Our results support the view that a dose of 20 mg paroxetine is optimal for the acute treatment of depression in the majority of patients.

Mortality in affective disorders

BACKGROUND To investigate the mortality rates in affective disorders due to unnatural and natural causes with respect to illness subtype and social-demographic features. METHODS Mortality data were determined from a prospective study of 354 outpatients with affective disorders during a follow-up period of 5 years. Death from natural and unnatural causes was compared to sex- and age-specific expectations in the general population. Standardized mortality rates (SMR) in diagnostic subgroups and the influence of social-demographic features were investigated. RESULTS The observed 30 deaths represented nearly three times (SMR, 2.9) the number expected on the basis of age- and sex-standardized reference population rates. Death from natural causes occurred with the same rate as expected (SMR, 1.0), death from unnatural causes was 28.8 times higher than expected. Women with affective disorders had a considerable high risk to die from unnatural causes (SMR, 47.1). A significant excess of unnatural death was found in all subtypes of affective disorders, particularly in recurrent major depressive episodes (SMR, 46.7). LIMITATIONS The sample was restricted in size. Therefore subgroup differences and multiple relationships of risk factors could not be analyzed with high statistical power. CONCLUSIONS The results corroborate earlier findings of excess mortality in major affective disorders and strengthen the view that suffering from recurrent major depression confers per se an important biological risk for suicide. Natural causes of death in affective disorders are comparable to expectations from reference populations. Social-demographic characteristics may contribute to an additional risk of premature death by suicide, particularly in women.

Response to treatment in minor and major depression: results of a double-blind comparative study with paroxetine and maprotiline

Several concepts of minor depression in the sense of acute but less severe symptomatology than major depression have been proposed in the literature, but currently none of them is generally accepted. For the treatment of these conditions, only few recommendations based on empirical data are available. We conducted a randomized double-blind multicentre study in depressed outpatients comparing paroxetine and maprotiline in both patients with minor (n = 245) and major depression (n = 298). For the diagnosis, Research Diagnostic Criteria were used in a modified version. Two response criteria were applied: a reduction of 50% or more in total HAMD-17 scores from baseline (criterion 1), and a reduction of the HAMD-17 total score to 9 points or less (criterion 2). A completer and an endpoint analysis was performed. For patients with minor depression, remarkably high response rates were found for paroxetine (criterion 1: 90.9% completer, 82.1% endpoint; criterion 2: 89.1% completer, 82.4% endpoint) while the respective rates for maprotiline tended to be lower (criterion 1: 80.4% completer, 71.4% endpoint; criterion 2: 84.9% completer; 76.1% endpoint). Response rates in patients with major depression were for paroxetine: criterion 1: 74.3% completer, 62.8% endpoint; criterion 2: 76.4% completer, 65.2% endpoint; and for maprotiline: criterion 1:82.4% completer, 68.5% endpoint; criterion 2: 80.6% completer; 66.0% endpoint, which resembles rates reported from previous antidepressant trials. Both drugs were generally well tolerated. Though no placebo control was carried out, our results suggest that minor depression is a disorder that is very likely to respond to antidepressant pharmacotherapy with paroxetine, but also with maprotiline at a favourable risk/benefit ratio.