Peter Allerup

The panic-associated symptom scale : measuring the severity of panic disorder

The Panic‐Associated Symptom Scale (PASS) is presented as a new measurement of the severity of the core symptoms of panic disorder. This first description addresses the rationale for its design and its scoring, score distributions, test‐retest reliability, correlations within the PASS and with other scales, principal component structure, and response to drug therapy. Data are presented from a large study group of patients with panic disorder (n= 1168). Problems in measuring panic disorder are discussed.

Evaluation of a multifaceted intervention to limit excessive antipsychotic co‐prescribing in schizophrenia out‐patients

Baandrup L, Allerup P, Lublin H, Nordentoft M, Peacock L, Glenthoj B. Evaluation of a multifaceted intervention to limit excessive antipsychotic co‐prescribing in schizophrenia out‐patients.

Exploring regional variation in antipsychotic coprescribing practice: a Danish questionnaire survey.

OBJECTIVE The pharmacologic treatment of schizophrenia is characterized by excessive use of antipsychotic polypharmacy, which reflects a gap between evidence and practice. The aim of the present study was to investigate regional differences in treatment setting characteristics and in physician and nurse attitudes toward antipsychotic polypharmacy and clinical guidelines. METHOD Cross-sectional postal questionnaire survey directed to physicians and nurses at 2 pairs of treatment settings in Denmark, characterized by low and high prevalence of antipsychotic polypharmacy, respectively. The questionnaire investigation was conducted during November 2007 to February 2008. RESULTS Satisfactory response rates were obtained (physicians: 93%; nurses: 87%). The treatment settings with low use of antipsychotic polypharmacy were characterized by raised knowledge/awareness of local antipsychotic treatment guidelines (P = .02 for physicians; P = .01 for nurses). Among physicians, these settings were also characterized by an elevated confidence in these guidelines (P = .01), frequent local educational activities (P < .0001), and increased recent involvement in research (P = .01). Among nurses, a perception of an overwhelming work load (P = .01) and time pressure (P = .003) was significantly more prevalent in treatment settings with high rates of antipsychotic coprescribing, as was the belief in the benefit of antipsychotic polypharmacy augmentation (P = .001). CONCLUSION Albeit no causal relationships can be inferred from this cross-sectional observational study, we recommend the furtherance of a treatment environment characterized by easily accessible clinical guidelines, frequent academic activities, and an unruffled atmosphere.

The Hamilton Depression Scale (HAM-D) and the Montgomery–Åsberg Depression Scale (MADRS). A psychometric re-analysis of the European Genome-Based Therapeutic Drugs for Depression Study using Rasch analysis

The objective of this re-analysis of the European Genome-Based Therapeutic Drugs for Depression Study (GENDEP) was to psychometrically test the unidimensionality of the full Montgomery Åsberg Depression Rating Scale (MADRS10) and the Hamilton Depression Scale (HAM-D17) versus their respective subscales (MADRS5 and HAM-D6) containing the core symptoms of depression severity. Rasch analysis was applied using RUMM 2030 software to assess the overall fit for unidimensionality. Neither the MADRS10 nor the HAM-D17 was found to fit the Rasch model for unidimensionality. The HAM-D6 (containing the items of depressed mood, guilt, work and interests, psychomotor retardation, psychic anxiety, and somatic general) as well as the analogue MADRS5 were tested for unidimensionality by use of the RUMM 2030 programme, and only the HAM-D6 was accepted. When testing for invariance across rating weeks or centres, the RUMM 2030 had to be supplemented with the Friedman two-way analysis of variance by ranks. The HAM-D6 but not the MADRS5 was accepted. It was therefore concluded that the HAM-D6 is a psychometrically valid outcome scale to measure change in clinical trials of antidepressants.

Well-being and depression in individuals with subclinical hypothyroidism and thyroid autoimmunity—A general population study

Abstract Background: The association between subclinical hypothyroidism (SCH), with and without raised thyroid peroxidase antibodies (anti-TPO), and well-being or depression is still controversial, in spite of many studies on the topic. Aims: In this large general population study of 8214 individuals, we aim to clarify the significance of elevated levels of anti-TPO as a marker of poor well-being and depression in euthyroid individuals and individuals with SCH. Methods: In participants from the Danish General Suburban Population Study (GESUS), serum thyroid stimulating hormone (TSH), total triiodothyronine (tT3), free thyroxine (fT4) and anti-TPO was measured. Prevalence of poor well-being and depression was measured using the WHO-5 Well-being questionnaire and WHO MDI [Major (ICD-10) Depression Inventory] questionnaire. Results: Raw score for well-being or depression overall and stratified for sex was not more significantly different in euthyroid individuals than in individuals with SCH, with or without high anti-TPO, except that euthyroid women with elevated anti-TPO had better well-being (P = 0.03) compared with euthyroid women with anti-TPO within the reference range. Conclusion: Elevated anti-TPO levels cannot be used as a general marker of poor well-being or depression in the general population.

Striatal D2/3 Binding Potential Values in Drug-Naïve First-Episode Schizophrenia Patients Correlate With Treatment Outcome

One of best validated findings in schizophrenia research is the association between blockade of dopamine D2 receptors and the effects of antipsychotics on positive psychotic symptoms. The aim of the present study was to examine correlations between baseline striatal D2/3 receptor binding potential (BPp) values and treatment outcome in a cohort of antipsychotic-naïve first-episode schizophrenia patients. Additionally, we wished to investigate associations between striatal dopamine D2/3 receptor blockade and alterations of negative symptoms as well as functioning and subjective well-being. Twenty-eight antipsychotic-naïve schizophrenia patients and 26 controls were included in the study. Single-photon emission computed tomography (SPECT) with [123I]iodobenzamide ([123I]-IBZM) was used to examine striatal D2/3 receptor BPp. Patients were examined before and after 6 weeks of treatment with the D2/3 receptor antagonist amisulpride. There was a significant negative correlation between striatal D2/3 receptor BPp at baseline and improvement of positive symptoms in the total group of patients. Comparing patients responding to treatment to nonresponders further showed significantly lower baseline BPp in the responders. At follow-up, the patients demonstrated a negative correlation between the blockade and functioning, whereas no associations between blockade and negative symptoms or subjective well-being were observed. The results show an association between striatal BPp of dopamine D2/3 receptors in antipsychotic-naïve first-episode patients with schizophrenia and treatment response. Patients with a low BPp have a better treatment response than patients with a high BPp. The results further suggest that functioning may decline at high levels of dopamine receptor blockade.

The Validity of the WHO-5 as an Early Screening for Apathy in an Elderly Population.

Aim. The objective of our study has been to evaluate the WHO-5 as a new early screening instrument for apathy in a group of elderly persons. Methods. The WHO-5 was compared to the Geriatric Depression Scale (GDS-15). The GDS contains five items measuring well-being and ten items measuring depression. The internal validity of the WHO-5 (total score being a sufficient statistic) was evaluated with both parametric and nonparametric item response theory models. The external validity of the WHO-5 and the GDS was evaluated by ROC using depression as index of validity. Results. The item response theory analyses confirmed that the total score of the WHO-5 is a sufficient statistic. The ROC analysis shows an adequate sensitivity (61%) and specificity (84%). The GDS15 and its two subscales obtained low sensitivity (25–42%), but high specificity (90–98%). Conclusion. The WHO-5 was found both internally and externally valid when considering decreased positive well-being to be an early indication of apathy reflecting that the wind has begun to be taken out of the “motivation sail.”

Electrical kindling of rats treated discontinously or continuously with haloperidol

Intermittent as opposed to continuous treatment of rats with haloperidol resulted in a long-lasting potentiation of oral activity. To examine if this behavioural sensitization to discontinuous neuroleptic treatment facilitates seizure development in electrical kindling, rats treated either intermittently or continuously with haloperidol for 15 weeks were kindled in the nucleus amygdala. Development of kindled seizures was significantly faster in the intermittently treated group (P < 0.01) than in controls or continuously treated rats. Furthermore, discontinuously treated animals displayed electroencephalographic afterdischarges in the substantia nigra from the beginning of treatment. The findings of cross-sensitivity between electrical amygdala kindling and pharmacological sensitization and of early appearance of epileptiform nigral activity have implications for the pathogenesis of both conditions. We suggest that depressed gamma-aminobutyric acid activity in substantia nigra could be a common mechanism.

Extrastriatal dopamine D2/3 receptors and cortical grey matter volumes in antipsychotic-naïve schizophrenia patients before and after initial antipsychotic treatment.

Abstract Objectives: Long-term dopamine D2/3 receptor blockade, common to all antipsychotics, may underlie progressive brain volume changes observed in patients with chronic schizophrenia. In the present study, we examined associations between cortical volume changes and extrastriatal dopamine D2/3 receptor binding potentials (BPND) in first-episode schizophrenia patents at baseline and after antipsychotic treatment. Methods: Twenty-two initially antipsychotic-naïve patients underwent magnetic resonance imaging (MRI), [123I]epidepride single-photon emission computerised tomography (SPECT), and psychopathology assessments before and after 3 months of treatment with either risperidone (N = 13) or zuclopenthixol (N = 9). Twenty healthy controls matched on age, gender and parental socioeconomic status underwent baseline MRI and SPECT. Results: Neither extrastriatal D2/3 receptor BPND at baseline, nor blockade at follow-up, was related to regional cortical volume changes. In post-hoc analyses excluding three patients with cannabis use we found that higher D2/3 receptor occupancy was significantly associated with an increase in right frontal grey matter volume. Conclusions: The present data do not support an association between extrastriatal D2/3 receptor blockade and extrastriatal grey matter loss in the early phases of schizophrenia. Although inconclusive, our exclusion of patients tested positive for cannabis use speaks to keeping attention to potential confounding factors in imaging studies.

Escitalopram versus nortriptyline: How to let the clinical GENDEP data tell us what they contained

GENDEP is an acronym for Genome-based Therapeutic Drugs for Depression. The GENDEP trial is a partially randomized multi-centre clinical study comparing the antidepressive effect of escitalopram and nortriptyline. In their first report (1) the authors made a factor analysis across all three primary outcome rating scales. This produced three factors with items from the different scales. When using these factors, the GENDEP data were not able to discriminate with clinical significance between the antidepressive effects of the two therapeutic drugs for depression (2). We have made an attempt to let the data from the Hamilton Depression Scale (HAM-D), which was actually the first listed GENDEP primary outcome scale, tell us what they really show when using clinimetrically based analyses (3). We have consequently used both the full HAM-D17 and its sixitem subscale (HAM-D6) which measures the pure antidepressive effect (3). These six items are those which experienced psychiatrists use to give global assessments of depression severity (3). The HAM-D6 includes the core symptoms of depressed mood, guilt, work and interests, psychomotor retardation, psychic anxiety and general somatic. In several drug trials, the HAM-D6, in contrast to HAMD17, has been able to detect the pure antidepressive effect of antidepressants (3). In our GENDEP analysis we focused on the 765 patients with major depression who had a complete rating scale data set at baseline. After 8 weeks of therapy 569 patients were completers (74%) and after 12 weeks, 496 patients (65%), this is quite acceptable (3). In total, 427 of the 765 patients received escitalopram (mean dose 18 mg daily) and 338 received nortriptyline (mean dose 105 mg daily). At baseline 38 patients had doubtful depression (HAM-D17 < 13); 92 patients had a mild depression (HAM-D17 = 13–17); 405 patients had moderate depression (HAM-D17 = 18–24) and 230 patients had severe depression (HAM-D17 = 25–52). The distributions of patients receiving escitalopram or nortriptyline within these four categories were equal. Rasch analysis (3) of the HAM-D6 across the GENDEP rating occations showed acceptable transferability. Based on the HAM-D6 as a continuous outcome measure, effect size statistics were used for the evaluation of response to treatment (3). Furthermore, any drug–drug difference reported through computing number needed to treat (NNT) was used for obtainment of remission after 12 weeks of therapy, applying a HAMD6 cut-off score of <5 (3). The intention to treat approach was applied when evaluating response (effect size) and remission (NNT). The last observation carried forward method (LOCF) was used, but for effect size the mixed model was also used. The results showed an effect size of 0.31 (LOCF) and 0.28 (mixed model) in favour of escitalopram. This level is of clinical significance when comparing two different classes of drugs for depression (4). We found a remission rate of 70% for mild depression in the escitalopram-treated patients and 46% in the nortriptylinetreated patients, resulting in an NNT of 5. For moderate depression the remission rates were 49% and 34%, respectively, resulting in an NNT of 7. For severe depression the remission rates were 42% and 22%, respectively, resulting in an NNT of 5. These NNT ranges between 5 and 7 are of clinical significance and equal an effect size of approximately 0.3 (3). In other words, the superiority of escitalopram over nortriptyline was independent of baseline depression severity (5). By making the GENDEP data set tell us what they actually are about rather than making factor analysis tell them how they ought to have behaved, we were able to demonstrate the superiority of escitalopram over nortriptyline in pure antidepressive effect, no matter whether the data were analysed as continuous measures (effect size) or categorical measures (remission).