High-dose selective serotonin reuptake inhibitors in OCD: a systematic retrospective case notes survey.

This article presents a systematic, retrospective case-note survey of a specialist obsessive-compulsive disorder (OCD) outpatient service. We explore the frequency of 'high-dose' selective serotonin reuptake inhibitor (SSRI) prescribing and describe clinical outcomes in a naturalistic clinical setting. Patients receiving high doses were compared with 'control' cases at the following three time-points: referral, initiation of high-dose SSRI and last clinical assessment.Twenty-six (13.5%) out of 192 patients received high-dose treatment for 3-364 weeks (mean 81.5 weeks; SD = ±95.1). At referral, high-dose patients were significantly more likely than controls to be male, and to have received Cognitive Behavioural Therapy (CBT), although illness severity and complexity did not differ. At initiation of dose escalation, however, high-dose patients were significantly more symptomatic than controls (Yale-Brown Obsessive Compulsive Scale score [Y-BOCS 25.4 vs. 17.7]). At the last assessment, patients on high-dose treatment showed significant within-group improvements (Y-BOCS 25.35 vs. 20.95), although endpoint scores for the high-dose group remained significantly higher than control patients treated for a matched period (Y-BOCS 21.0 vs. 15.5), suggesting enduring treatment-resistance. Frequency of adverse effects did not significantly differ between the two groups. Our results suggest that high-dose SSRI was associated with clinical improvement and well-tolerated in a particularly refractory OCD sample.

Commentary on STAR*D: a summary and UK perspective.

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) program attempted to determine whether some treatment sequences are better than others in the management of depression. Application of the findings to UK treatment settings is difficult because depression is an inhomogeneous condition and to regard it as a unitary entity, to which a unitary stratagem can be applied, is possibly misguided.

Defining remission by cut off score on the MADRS: selecting the optimal value.

BACKGROUND: Remission from major depression may be conceptualised in terms of a cut-off score on an appropriate rating scale. Candidate values proposed hitherto have not been directly validated. METHOD: The relationship between The Clinical Global Impression Scale for Severity (CGI-S) and the Montgomery-Asberg Depression Rating Scale (MADRS) was explored in 684 major depressed patients (1114 observations). The value on the MADRS which had greatest concordance with remission, as defined by the CGI-S, was computed using two models. Concordance between clinician and patient judgements of global illness were also compared. RESULTS AND CONCLUSION: The two models yielded optimal definitions of remission of <9 and <10 on the MADRS. Either value offers a workable operationalisation of remission and there is little to choose between them. CLINICAL RELEVANCE: The data confirm that MADRS <10 should provide the clinician with a valid, and reasonably objectifiable, target for remission

How does the threshold score to enter a major depression trial influence the size of the available patient population for study?

BACKGROUND: This paper describes the relationship between entry criteria and eligible population for inclusion in Major Depression (MD) clinical trials. Inclusion criteria for a MD study typically require patients to pass a threshold score on a depression rating scale, most commonly the HAM-D or MADRS. A Score To Enter (STE) of > or = 17 on the HAM-D 17-item scale is a typical value, although higher values (i.e. > or = 22 or even > or = 25 points) are often used. It is commonly supposed that patients with higher baseline scores form a more sensitive sample for discriminating active drug from placebo. METHOD: We present data from a sample of depressed hospital outpatients and describe their general characteristics. We then introduce a model, based upon this sample, which predicts the impact of STE on eligible trial population. RESULTS AND CONCLUSION: A small increase in STE has a marked effect on eligible population: an increase in HAM-D (17 item) STE from 17 to 21 and 25 reduces the eligible population by 42 and 76%, respectively. These predictions are reasonably robust when our model is validated with known clinical trial data. CLINICAL RELEVANCE: Our findings have major implications for planning and managing Major Depression trials as higher STEs substantially restrict the proportion of patient eligible for study.

Risk assessment for people with mental health problems: a pilot study of reliability in working practice.

INTRODUCTION: This paper describes a pilot study of reliability in the risk assessment of people with mental health problems. Specifically, we explore the evidence for professional and gender bias in ratings, in addition to the general level of agreement between raters. METHOD: Six professional groups (psychiatrists, junior psychiatric doctors, nurses, community psychiatric nurses, social workers and occupational therapists) participated in the study and rated 159 patients on a nine-item scale which assessed different components of risk. RESULTS: Contrary to some earlier work, we found no clear evidence that any one group consistently rated more extremely than any other group. Women were more cautious than men in their ratings, and this concurs with previous studies. Finally, a reliability study of randomly selected pairs of raters showed only moderate levels of agreement and, in some instances, the levels of disagreement were high enough to warrant concern. CONCLUSION: These findings are discussed in the context of current risk assessment practice and the problems associated with investigating reliability in naturalistic settings and designing appropriate rating tools for risk. (Int J Psych Clin Pract 2002; 6: 73-81).

A randomized, double-blind controlled comparison of nefazodone and paroxetine in the treatment of depression: safety, tolerability and efficacy in continuation phase treatment.

We investigated the safety, tolerability and efficacy of nefazodone and paroxetine in the continuation phase of treatment of depression. The study comprised a double-blind, parallel-group comparison over 4 months, of patients who had previously improved following random allocation to nefazodone or paroxetine during an 8-week acute treatment study. Assessments included Clinical Global Impression Scales, Hamilton Rating Scales for Depression and Anxiety, Montgomery-Asberg Depression Rating Scale and the Patient Global Assessment Scale, in addition to a review of reported adverse events, vital sign measurements, electrocardiograms and clinical laboratory tests. One hundred and eight patients participated in the continuation study (53 received paroxetine, 55 nefazodone) and 73 completed treatment. No clinically relevant differences in antidepressant efficacy were seen. Headache and somnolence were the most common reported adverse events in both treatment groups. Both nefazodone and paroxetine maintain their efficacy in continuation treatment, and both are generally well tolerated.

Efficacy, safety and tolerability of combined administration of lithium and selective serotonin reuptake inhibitors: a review of the current evidence. Hertfordshire Neuroscience Research Group.

Several case reports have engendered concern about the safety of coadministering lithium and selective serotonin reuptake inhibitor (SSRI) antidepressants and there are theoretical reasons to suppose that lithium and serotonergic antidepressants may be associated with dangerous interactions. Systematic reports regarding combination therapy with lithium and SSRI antidepressants were assimilated for the purpose of this review. Although there are many publications, few are directly informative as to safety and tolerability. A total of 503 patients are considered in systematic reports and, among these, no serious or life-threatening adverse events can be identified. Such data as there are demonstrate little potential for toxic interactions between lithium and SSRIs, although new, non-serious, adverse events do frequently arise. The evidence for the efficacy of addition of lithium to SSRIs in treatment refractory depression is only provisional.

A protocol for the pharmacologic treatment of major depression. A field test of a potential prototype.

BACKGROUND: Much attention is being given to developing clinical practice guidelines for management of mental health disorders. The aim of this study was to field test a prototype protocol for the pharmacologic treatment of Major Depression. METHOD: The protocol consisted of four, six week, treatment phases with critical choices in therapy defined by scores on the MADRS (Montgomery Asberg Depression Rating Scale). Observational data as collected on the behaviour of the protocol in terms of relevance, acceptability, ease of use and effectiveness. RESULTS: Effectiveness of the protocol was good for those patients who were retained within it, with three quarters of them attaining remission. However more than half of all patients dropped out-non attendance and adverse events being the most common reasons for this. CONCLUSION: The protocol for the treatment of Major Depression appeared relevant, easy to use and potentially effective. LIMITATION: Problems with non-adherence by both doctors and patients posed major challenges to the protocol's design. Such difficulties demonstrate the need to field test any proposed design as preconceptions about a protocol's performance may be misplaced. CLINICAL RELEVANCE: The protocol tested represents progress towards the goal of developing optimal strategies for the use of pharmacotherapeutic agents in the treatment of depression.

Depression rating scales can be related to each other by simple equations.

We present evidence that scores on the Montgomery, Hamilton and Beck depression scales are strongly intercorrelated and can be equated to each other. These scales were administered on 107 occasions to patients with major depression. The correlations between scores on each scale were much higher than has been previously reported and, furthermore, the relationships were always well described by a linear function. The close correlations could not be explained by rater biases. We were able to provide validation data for two of the rating scales, demonstrating that our simple models generalize well to a novel dataset. The knowledge that there is a robust relationship between the three scales has practical value for both clinicians and researchers.

A preliminary study to examine the adequacy of long-term treatment of depression and the extent of recovery in general practice.

About 1% of patients in general practice take antidepressants for long periods. Many receive repeat prescriptions, without review. It might be assumed that these patients are well and are on adequate maintenance treatment. Our findings refute this assumption; of 78 patients on long-term repeats, only a third were in remission and a fifth had Beck Depression Inventory scores suggesting persisting syndromal major depression. Subtherapeutic dosing of classic tricyclics was the norm rather than the exception. Patients on long term antidepressant treatment need regular review and adequate treatment to ensure remission is maintained.

A review of the psychomotor effects of paroxetine.

All 10 placebo-controlled studies of the psychomotor effects of paroxetine are reviewed. The total number of subjects is 195. The majority of studies show little or no effect of paroxetine on psychomotor function. No adverse effects are apparent at the dose of 20 mg/day, although minor impairments can be identified at 40 mg/day. An overview of the data indicates that at the standard therapeutic dose of 20 mg/day, paroxetine has no psychomotor or behavioural toxicity.

Recovery from depressive illness does fit an exponential model.

A very large number of therapeutic trials of antidepressant drugs have been reported in the scientific literature. Until now, the comparison of one drug with another, or with placebo, has been performed typically by comparing the scores on depression rating scales of the two groups of patients at fixed points of time after the beginning of therapy. It was postulated in 1989 that the curves of the recovery scores followed an exponential curve of the formula y = ae-bx + c. This hypothesis was tested in a double-blind controlled trial of the antidepressant minaprine, with the use of the scores on the Hamilton Rating Scale for Depression (HAM-D). We found that the correlation coefficient, Pearson's r, between the log of the HAM-D value and the week number of the study was -0.99. This gives a coefficient of determination of 0.98, which makes it clear that the model adequately fits the data. We conclude that the use of the formula gives a method of testing the statistical significance of the difference between treatments as a valuable alternative to traditional tests. We believe that this would give a much more sensitive discrimination between treatments because all of the data points are used to calculate a single parameter--the slope of the curve.

Safety and tolerability of combined treatment with moclobemide and SSRIs: a systematic study of 50 patients.

Fifty major depressed patients, resistant to multiple pharmacotherapies, were treated by the addition of moclobemide (up to 600 mg/day) to paroxetine or fluoxetine (20 mg/day) for 6 weeks in an open study to assess tolerability. There were 188 adverse events: insomnia, dizziness, headache, nausea, dry mouth and myoclonic jerks were the most common. Many events were rated as severe. The high rate of adverse events suggest that there are clinically significant pharmacodynamic interactions between moclobemide and SSRIs. However the uncontrolled data on effectiveness is encouraging and the combination deserves further consideration as a strategy for treating intractable depression.

A multicenter double-blind comparison of nefazodone and paroxetine in the treatment of outpatients with moderate-to-severe depression.

BACKGROUND: The efficacy, safety, and tolerance of nefazodone and paroxetine in the treatment of depressed outpatients were compared in a randomized, double-blind parallel group study at 20 centers in the United Kingdom and Republic of Ireland. METHOD: The study population comprised 206 outpatients meeting DSM-III-R criteria for a moderate-to-severe nonpsychotic major depressive episode. Patients considered to be at serious risk of suicide were excluded from participation in the study. After a drug-free baseline phase of 1 to 4 weeks, patients were randomly assigned to treatment with either nefazodone or paroxetine. Outcome measures for efficacy included the Clinical Global Impressions scales, Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, Montgomery-Asberg Depression Rating Scale, and Patient Global Assessment scale. Tolerance and safety were assessed using spontaneously reported adverse events, vital signs, and laboratory investigations. RESULTS: There were no significant differences between the groups in clinical outcome. Analysis of the efficacy measures revealed a consistent and continuous improvement in both groups. A similar proportion of patients in each group discontinued treatment owing to adverse events: 15 (14%) in the nefazodone group and 13 (13%) in the paroxetine group. CONCLUSION: Nefazodone and paroxetine have similar efficacy and tolerability in the treatment of outpatients with major depression.

Safety and tolerability of combined treatment with moclobemide and SSRIs: a preliminary study of 19 patients.

Nineteen major depressed patients, resistant to previous pharmacotherapies, were treated by the addition of moclobemide (up to 600 mg/day) to paroxetine or fluoxetine (20 mg/day) for 6 weeks in an open study to assess the adverse events and tolerability. There were 77 emergent events, insomnia, headache, nausea and dizziness being the most common. Many events were rated as severe. The high rate of adverse events suggests that there may be clinically significant interactions between moclobemide and SSRIs. However, the uncontrolled data on effectiveness is encouraging and the combination deserves further attention as a strategy for treating intractable major depression.

Comparison of long-term benzodiazepine users in three settings.

BACKGROUND: Most studies of chronic benzodiazepine users consider selected populations which may be unrepresentative. This study was undertaken to examine possible differences between groups. METHOD: Subjects chosen were benzodiazepine users in general practice, a hospital clinic, and attending TRANX trials. Descriptive data were collected on characteristics and outcome. RESULTS: TRANX trial patients had the best outcome (P = 0.027). Hospital cases used high doses of anxiolytic benzodiazepines; concomitant mental disorder, including schizophrenia, was common. General practice cases were older and mainly used hypnotics (P < 0.05). CONCLUSIONS: Because groups of benzodiazepine users are different, there cannot be one single management approach. Cases require individual medical assessment.

Tolerability of combined treatment with lithium and fluoxetine: 14 cases treated under open conditions.

Fourteen cases of depression resistant to multiple treatments were treated by lithium augmentation of fluoxetine. Tolerability of the treatment was poor. Lithium and fluoxetine may be a possible treatment for resistant depression but there is caution regarding tolerability and toxicity with the relatively high doses of lithium used in this series.

Tolerability of combined treatment with lithium and paroxetine: 19 cases treated under open conditions.

Nineteen patients resistant to paroxetine monotherapy were treated by lithium augmentation for 6 weeks to assess tolerability. Although the addition of lithium increased the number of adverse events, none were serious. The combination of lithium and paroxetine is safe enough to warrant further investigation as a treatment for resistant depression.

Suicidal ideation as a presenting complaint. Associated diagnoses and characteristics in a casualty population.

A prospective study was conducted of all referrals to the emergency psychiatric service of an inner-London hospital over one year. There were 53 individuals who presented with the specific and spontaneous complaint of suicidal ideation without any accompanying act of self-harm. The main diagnoses in this group were personality disorders (40%) and alcohol dependence (15%); only 13% were suffering from depressive illness. Members of the group differed from the other 369 presenters to the service in that they were less likely to be accorded a diagnosis of a defined mental illness, twice as likely to have a criminal record, and more likely to have a previous history of deliberate self-harm. A quarter of the suicidal complainants were admitted to hospital following assessment.