Ketamine as the anaesthetic for electroconvulsive therapy: the KANECT randomised controlled trial - CORRIGENDUM.

This notice describes a correction to the above mentioned paper.

Ketamine as the anaesthetic for electroconvulsive therapy: the KANECT randomised controlled trial.

BackgroundKetamine has recently become an agent of interest as an acute treatment for severe depression and as the anaesthetic for electroconvulsive therapy (ECT). Subanaesthetic doses result in an acute reduction in depression severity while evidence is equivocal for this antidepressant effect with anaesthetic or adjuvant doses. Recent systematic reviews call for high-quality evidence from further randomised controlled trials (RCTs).AimsTo establish if ketamine as the anaesthetic for ECT results in fewer ECT treatments, improvements in depression severity ratings and less memory impairment than the standard anaesthetic.MethodDouble-blind, parallel-design, RCT of intravenous ketamine (up to 2 mg/kg) with an active comparator, intravenous propofol (up to 2.5 mg/kg), as the anaesthetic for ECT in patients receiving ECT for major depression on an informal basis. (Trial registration: European Clinical Trials Database (EudraCT): 2011-000396-14 and clinicalTrials.gov: NCT01306760)ResultsNo significant differences were found on any outcome measure during, at the end of or 1 month following the ECT course.ConclusionsKetamine as an anaesthetic does not enhance the efficacy of ECT.

Differences in Cognitive Outcomes After ECT Depending on BDNF and COMT Polymorphisms.

OBJECTIVE: The study aimed to explore cognitive outcomes after electroconvulsive therapy (ECT) depending on which version of common single nucleotide polymorphisms the patient expressed for brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT). METHODS: A total of 87 patients from the clinical ECT service in Aberdeen, Scotland, were included in the study. Cognitive function testing (using Spatial Recognition Memory task from the Cambridge Neuropsychological Test Automated Battery and Mini-Mental State Examination) and mood ratings (Montgomery-Åsberg Depression Rating Scale) were performed before ECT, after 4 treatments, at the end of ECT and 1 and 3 months after the end of treatment. These scores were compared depending on BDNF and COMT variant at each time point using the Student t test and using a time series generalized least squares random effects model. RESULTS: No differences were found between the val and met versions of the BDNF or COMT polymorphism in either cognitive or mood outcomes at any time point during ECT treatment or up to 3 months of follow-up. CONCLUSIONS: This study did not detect significant differences in cognitive or mood outcomes between patients who have the val66val or met versions of the BDNF polymorphism. Our results suggest that these polymorphisms will not be helpful in clinical practice for predicting cognitive outcomes after ECT.

Electroconvulsive therapy reduces frontal cortical connectivity in severe depressive disorder.

To date, electroconvulsive therapy (ECT) is the most potent treatment in severe depression. Although ECT has been successfully applied in clinical practice for over 70 years, the underlying mechanisms of action remain unclear. We used functional MRI and a unique data-driven analysis approach to examine functional connectivity in the brain before and after ECT treatment. Our results show that ECT has lasting effects on the functional architecture of the brain. A comparison of pre- and posttreatment functional connectivity data in a group of nine patients revealed a significant cluster of voxels in and around the left dorsolateral prefrontal cortical region (Brodmann areas 44, 45, and 46), where the average global functional connectivity was considerably decreased after ECT treatment (P < 0.05, family-wise error-corrected). This decrease in functional connectivity was accompanied by a significant improvement (P < 0.001) in depressive symptoms; the patients' mean scores on the Montgomery Asberg Depression Rating Scale pre- and posttreatment were 36.4 (SD = 4.9) and 10.7 (SD = 9.6), respectively. The findings reported here add weight to the emerging "hyperconnectivity hypothesis" in depression and support the proposal that increased connectivity may constitute both a biomarker for mood disorder and a potential therapeutic target.

Anticonvulsant Mechanisms of Electroconvulsive Therapy and Relation to Therapeutic Efficacy.

BACKGROUND: Electroconvulsive therapy (ECT) is held to confer anticonvulsant effects, although the role of rise in seizure threshold upon clinical effect is uncertain. This study investigated the relationship in a large, consecutive, retrospective sample of patients receiving ECT in Aberdeen. We have tested the hypotheses of previous authors to further examine the relationship between seizure and therapeutic effect as well as discuss the potential underlying neurobiological mechanisms. METHODS: All patients receiving ECT at the Royal Cornhill Hospital between 2000 and the end of 2008 were identified from the Scottish ECT Accreditation Network. Electroconvulsive therapy was administered twice weekly with a bifrontotemporal electrode placement using routine dosage schedules. Data were gathered from the Scottish ECT Accreditation Network and case notes regarding ECT course and clinical effect. RESULTS: The seizure threshold increased in 219 (94.4%) patients, stayed the same in 13 (5.6%) patients, and decreased in 0 patient (n = 232). No significant relationship was present between change in seizure threshold and change in Montgomery-Asberg Depression Rating Scale score (P = 0.39; Kendall τ b r = 0.047; n = 182), although responders did display greater increase in seizure threshold than nonresponders. CONCLUSIONS: Electroconvulsive therapy confers anticonvulsant effects in a consecutive sample of real-life patients. Neither initial seizure threshold nor magnitude of seizure threshold increase is a predictor of clinical response to ECT. A rise in seizure threshold is not essential for therapeutic effect but may represent an important marker of underlying neuronal state. The evidence reviewed in this article supports a link between neuroplastic effects of ECT and the evidenced rise in seizure threshold.

A comparison of three methods of assessing differential item functioning (DIF) in the Hospital Anxiety Depression Scale: ordinal logistic regression, Rasch analysis and the Mantel chi-square procedure.

PURPOSE: It is important for clinical practice and research that measurement scales of well-being and quality of life exhibit only minimal differential item functioning (DIF). DIF occurs where different groups of people endorse items in a scale to different extents after being matched by the intended scale attribute. We investigate the equivalence or otherwise of common methods of assessing DIF. METHOD: Three methods of measuring age- and sex-related DIF (ordinal logistic regression, Rasch analysis and Mantel χ(2) procedure) were applied to Hospital Anxiety Depression Scale (HADS) data pertaining to a sample of 1,068 patients consulting primary care practitioners. RESULTS: Three items were flagged by all three approaches as having either age- or sex-related DIF with a consistent direction of effect; a further three items identified did not meet stricter criteria for important DIF using at least one method. When applying strict criteria for significant DIF, ordinal logistic regression was slightly less sensitive. CONCLUSIONS: Ordinal logistic regression, Rasch analysis and contingency table methods yielded consistent results when identifying DIF in the HADS depression and HADS anxiety scales. Regardless of methods applied, investigators should use a combination of statistical significance, magnitude of the DIF effect and investigator judgement when interpreting the results.

The monitoring of longer term prescriptions of antidepressants: observational study in a primary care setting.

BACKGROUND: There is little evidence to guide the frequency of review for patients taking antidepressants in the longer term. OBJECTIVES: To measure the frequency with which patients on longer term courses of antidepressants have their treatment monitored in primary care and to identify patient characteristics associated with the frequency of monitoring. METHODS: A cohort of patients who were receiving antidepressants continuously for at least two years was identified from four general practices. Data were collected from patients' general medical records. The dates of all GP consultations and whether they included a documented review of antidepressant therapy were recorded, along with patient characteristics hypothesized to influence the frequency of monitoring. RESULTS: The frequency of antidepressant review consultations and proportion of participants being reviewed during a specific year of antidepressant therapy decreased with increasing year of antidepressant therapy. Individuals who receive antidepressants for an overt mental health reason; undergo more dose and drug changes; and who are referred to the community mental health team have their antidepressant therapy reviewed more often during the first five years of antidepressant therapy. CONCLUSION: As many patients on longer term courses of antidepressants are not being appropriately reviewed, a 'chronic disease management approach' to depression in primary care is advocated.

MADRS symptom subtypes in ECT-treated depressed patients: relationship to response and subsequent ECT.

OBJECTIVE: This study aimed to explore the relationship of Montgomery-Åsberg Depression Rating Scale (MADRS) symptom subtypes with response to electroconvulsive therapy (ECT) and subsequent ECT treatment within 12 months. METHODS: A consecutive sample of 414 patients with depression receiving ECT in the North East of Scotland was assessed by retrospective chart review. Response rate was defined as greater than or equal to 50% decrease in pretreatment total MADRS score or a posttreatment total MADRS less than or equal to 10. Principal component analyses were conducted on a sample with psychotic features (n = 124) and a sample without psychotic features (n = 290). Scores on extracted factor subscales, clinical and demographic characteristics were assessed for association with response and subsequent ECT treatment within 12 months. Where more than 1 variable was associated with response or subsequent ECT, logistic regression analysis was applied. RESULTS: MADRS symptom subtypes formed 3 separate factors in both samples. Logistic regression revealed older age and high "Despondency" subscale score predicted response in the nonpsychotic group. Older age alone predicted response in the group with psychotic features. Nonpsychotic patients subsequently re-treated with ECT were older than those not prescribed subsequent ECT. No association of variables emerged with subsequent ECT treatment in the group with psychotic features. Being of older age and the presence of psychotic features predicted response. Presence of psychotic features alone predicted subsequent retreatment. CONCLUSIONS: Subscale scores of the MADRS are of limited use in predicting which patients with depression will respond to ECT, with the exception of "Despondency" subscale scores in patients without psychotic features.

Usefulness of treatment reports for electroconvulsive therapy.

OBJECTIVES: Electroconvulsive therapy (ECT) is often given by a specialist ECT team on behalf of a patient's treating psychiatrist. A key aspect of this interface is the communication between these care teams. This study describes the introduction of an ECT treatment report at the Royal Cornhill Hospital in Aberdeen. The aim of the current study was to evaluate whether these reports were useful to psychiatrist. METHODS: The report was designed to provide feedback to the treating psychiatrists on a range cognitive (Mini Mental State Examination, spatial recognition memory on the Cambridge Automated Neuropsychological Testing Battery, Squire Subjective Memory Scale, and Prospective And Retrospective Memory Questionnaire) and mood scores (Montgomery Åsberg Depression Rating Scale) routinely collected by the ECT team. The reports contain the patient's score and the mean of all patients treated in the service. A questionnaire was sent to all treating psychiatrists to evaluate the usefulness of the reports. RESULTS: A 76% response rate was obtained. The reports were well received by treating teams, among whom 78.9% thought they were necessary, 74% thought they were easy to understand, and 79% thought the report was informative. A minority 47.4% thought the report influenced clinical practice, and only 31.3% showed the report to patients. CONCLUSIONS: From the results of our evaluation, the provision of an "ECT Treatment Report" providing a summary of the routinely collected mood and cognitive rating data was useful for psychiatrists prescribing ECT. It is thus likely that such a report would be useful in other ECT services.

Socioeconomic status of patients receiving electroconvulsive therapy.

This study describes the relationship between socioeconomic deprivation and electroconvulsive therapy (ECT) prescription and outcomes. Two research questions are addressed in this study: (1) Does the rate of ECT prescription increase with deprivation? and (2) Does deprivation influence ECT outcomes? Electroconvulsive therapy outcomes, of consecutive patients from Aberdeen, were compared across socioeconomic groups determined by the Scottish Index of Multiple Deprivation (SIMD) quintiles. A primary care sample, invited to complete the Hospital Anxiety and Depression Scale (HADS), was used for comparison. The proportion of patients in the most affluent quintile (32%) was greater than that in the least affluent (9%): this reflects the distribution of the local population, unlike the prevalence of depressive disorder, as demonstrated in our primary care group. Severity of depressive symptoms in patients receiving ECT was no different across the socioeconomic groups: before ECT (χ = 8.056; df = 4; P = 0.09), after ECT (χ = 6.035; df = 4; P = 0.197); nor was the total change in score (χ = 4.367; df = 4; P = 0.359). There were no differences among the SIMD quintiles for the number of ECT treatments administered (χ = 6.076; df = 4; P = 0.194) or the number of courses of ECT each patient had during contact with the service (χ = 6.505; df = 4; P = 0.164).Socioeconomic deprivation has no effect on the rate of ECT prescription or treatment outcomes despite a higher proportion of patients with severe depressive symptoms in the least affluent groups in a local community sample.

Continuity and monitoring of antidepressant therapy in a primary care setting.

BACKGROUND: Little is currently known about the continuity and monitoring of antidepressant treatment at individual patient level in primary care. AIMS: To assess continuity of antidepressant therapy in a UK primary care setting at the individual patient level and whether this therapy is conducted with appropriate review. Methods A systematic analysis was undertaken in two general practices in Aberdeen, Scotland of primary care records of adults initiated on an antidepressant for a new episode of depression or anxiety within a 12-month period and followed up for three years. Demographic and clinical details were recorded. Uni- and multivariate analyses were performed. Results The sample consisted of 191 patients. Median duration of treatment for the first episode was 180 (inter-quartile range (IQR)=60, 429) days, with 29% of patients receiving an antidepressant for 60 days or less. Age and previous receipt of antidepressants contributed significantly to predicting treatment duration (p <0.01); effect size (R(2) =0.1). The median interval between antidepressant review consultations increased progressively with increasing treatment duration. There were no significant predictors of frequency of antidepressant review. Conclusion Depression management could be improved by assertive review (and better characterisation) of patients who discontinue early; and by scheduled reassessment of treatment in the second and subsequent years of continuation therapy.

Psychometric comparison of PHQ-9 and HADS for measuring depression severity in primary care.

BACKGROUND: The 2004 National Institute for Health and Clinical Excellence (NICE) guidelines highlight the importance of assessing severity of depression in primary care. AIM: To assess the psychometric properties of the Patient Health Questionnaire (PHQ-9) and the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) for measuring depression severity in primary care. DESIGN OF STUDY: Psychometric assessment. SETTING: Thirty-two general practices in Grampian, Scotland. METHOD: Consecutive patients referred to a primary care mental health worker completed the PHQ-9 and HADS at baseline (n = 1063) and at the end of treatment (n = 544). Data were analysed to assess reliability, robustness of factor structure, convergent/discriminant validity, convergence of severity banding, and responsiveness to change. RESULTS: Both scales demonstrated high internal consistency at baseline and end of treatment (PHQ-9 alpha = 0.83 and 0.92; HADS-D alpha = 0.84 and 0.89). One factor emerged each for the PHQ-9 (explaining 42% of variance) and HADS-D (explaining 52% of variance). Both scales converged more with each other than with the HADS anxiety (HADS-A) subscale at baseline (P<0.001) and at end of treatment (P = 0.01). Responsiveness to change was similar: effect size for PHQ-9 = 0.99 and for the HADS-D = 1. The HADS-D and PHQ-9 differed significantly in categorising severity of depression, with the PHQ-9 categorising a greater proportion of patients with moderate/severe depression (P<0.001). CONCLUSION: The HADS-D and PHQ-9 demonstrated reliability, convergent/discriminant validity, and responsiveness to change. However, they differed considerably in how they catergorised severity. Given that treatment decisions are made on the basis of severity, further work is needed to assess the validity of the scales' severity cut-off bands.

Schizophrenia illness severity is associated with reduced loss aversion.

Loss aversion, whereby losses weigh more heavily than equal-sized gains, has been demonstrated in many decision-making settings. Previous research has suggested reduced loss aversion in schizophrenia, but with little evidence of a link between loss aversion and schizophrenia illness severity. In this study, 20 individuals with schizophrenia and 16 control participants, matched by age and sex, played two versions of the Iterated Prisoners' Dilemma, one version with only positive payoffs and another version in which negative payoffs were possible, with the second version being derived from the first by subtracting a constant value from all payoffs. The control group demonstrated significantly lower cooperation rates under negative payoffs, compared with the version with only positive payoffs, indicative of loss aversion. The patient group on average showed no loss aversion response. Moreover, the extent of loss aversion in patients was found to be negatively correlated with schizophrenia illness severity, with less ill patients showing loss aversion more similar to controls. Results were found to be robust to the inclusion of potential confounding factors as covariates within rigorous probit regression analyses. Reduced loss aversion is a feature of schizophrenia and related to illness severity.

Ketamine pre-treatment dissociates the effects of electroconvulsive stimulation on mossy fibre sprouting and cellular proliferation in the dentate gyrus.

Electroconvulsive stimulation (ECS), the experimental analogue of electroconvulsive therapy (ECT), has been shown to produce both functional and structural effects in the hippocampal formation in infrahuman species. These changes may relate to the antidepressant and cognitive effects of ECT observed in patients treated for severe depressive disorders. Recent studies have described both enhanced neurogenesis in the dentate gyrus of the hippocampus and sprouting of mossy fibre projections from granule cells. The behavioural significance of these effects remains uncertain. In this study, we examined whether ketamine, a clinically available non-competitive NMDA receptor channel blocker, could block both of these "trophic" effects. Rats were given a course of eight spaced ECS or sham treatments under either halothane or ketamine anaesthesia. The thymidine analogue bromodeoxyuridine was administered to assess the degree of hippocampal cell proliferation and mossy fibre sprouting was quantified using the Timm staining method. Pre-treatment with ketamine dissociated these effects such that mossy fibre sprouting was attenuated significantly, while cell proliferation was unaffected. This dissociation may prove useful in determining the behavioural significance of these hippocampal changes, if any, for either the antidepressant or cognitive consequences of ECT.

Psychometric properties of the 16-item Quick Inventory of Depressive Symptomatology: a systematic review and meta-analysis.

Effective management of depression is predicated upon reliable assessment. The Quick Inventory of Depressive Symptomatology (QIDS) is a depression severity scale with both self-rated (QIDS-SR16) and clinician-rated (QIDS-C16) versions. Although widely used in research, the psychometric properties of the QIDS16 have not been systematically reviewed. We performed a systematic review of studies of the psychometric properties (factor structure, internal consistency, convergent validity, discriminant validity, test-retest reliability and responsiveness to change) of the QIDS-SR16 or QIDS-C16. Six databases were searched: MEDLINE, EMBASE, PsycINFO, CinAHL, Web of Science and the Cochrane Central Register of Controlled Trials. Findings were summarised, bias assessed and correlations with reference standards were pooled. 37 studies (17,118 participants) were included in the review. Both versions of the QIDS16 were unidimensional. Cronbach's alpha ranged from 0.69 to 0.89 for the QIDS-SR16 and 0.65 to 0.87 for the QIDS-C16. The QIDS-SR16 correlated moderately to highly with several depression severity scales. Seven studies were pooled where QIDS-SR16 was correlated with the HRSD-17 (r = 0.76, CI 0.69, 0.81) in patients diagnosed with depression. Four studies examined convergent validity with the QIDS-C16. Four studies examined discriminant validity, for the QIDS-SR16 alone. Eighteen studies had at least one author who was a co-author of the original QIDS16 study. Most studies were conducted in the USA (n = 26). The QIDS-SR16 and the QIDS-C16 are unidimensional rating scales with acceptable internal consistency. To justify the use of the QIDS16 scale in clinical practice, more research is needed on convergent and discriminant validity, and in populations outside the USA.

Enhanced evoked responses after early adversity and repeated platform exposure: the neurobiology of vulnerability?

BACKGROUND: There is a long-standing clinical awareness of the significance of adverse early experiences and subsequent stress in the evolution of psychiatric disorder. METHODS: We investigated the impact of a single episode of preweaning maternal separation on in vivo electrophysiologic responses in the hippocampus of the mature rat after repeated exposure to an open elevated platform. RESULTS: Only rats that had experienced both maternal separation followed by stressful platform exposure when mature had significantly increased granule cell response to perforant path stimulation, compared with control rats. Rats exposed to either maternal separation or the elevated platform in adulthood alone did not differ significantly from control rats. CONCLUSIONS: Adverse early experience seems to induce functional changes in the hippocampus that remain latent until activated by stress in adulthood. Such electrophysiologic changes might represent a neural substrate for vulnerability to stress-associated psychopathology.

Brain plasticity and antidepressant treatments: new cells, new connections.

It is now a decade since we first wrote about the impact of antidepressant agents on plastic processes in the hippocampus (Stewart and Reid, 1993). Since then, the roles of various forms of brain plasticity have moved centre stage in efforts to understand the pathophysiology of depressive disorder. Here, we review the background to current views relating cytoarchitectural and synaptic changes to the aetiology and treatment of affective disease.

Why do patients discontinue antidepressant therapy early? A qualitative study.

BACKGROUND: Current guidelines for antidepressant prescribing are that treatment should be continued following the resolution of symptoms: six months after a first episode and for at least two years for those with previous episodes. Despite this, sub-optimal treatment duration still predominates. Patients have negative and positive views on antidepressants, which change throughout their treatment journey. OBJECTIVES: To explore views and experiences of patients recently initiated on antidepressants (within six months), and to consider the influences on early discontinuation. METHODS: A qualitative interview study was used in four general practices in the North East of Scotland. A purposive sample of primary care patients, newly initiated on antidepressants, was interviewed to explore views and experiences with antidepressant therapy. Interviews were audio-recorded and transcribed verbatim. Thematic analysis was conducted using a consensus coding frame developed by two researchers. RESULTS: Twenty-nine patients participated. Three main factors influencing discontinuation were identified: ownership, knowledge and support. The treatment journey was characterized by four important time points where health care intervention may be helpful. CONCLUSION: Health care professionals would benefit from exploring patient knowledge and views on depression and antidepressants at an early stage in treatment. Patients would welcome active involvement in treatment decision making, the provision of information and ongoing support.

Efficacy and tolerability of antidepressants for sub-threshold depression and for mild major depressive disorder.

BACKGROUND: It is commonly assumed that robust evidence exists for the lack of efficacy of antidepressants at the milder end of the depression severity spectrum. In light of specific limitations of existing reviews, we assess if antidepressants are efficacious and tolerable for sub-threshold or mild major depressive disorder (MDD). METHOD: Systematic review and meta-analysis of randomised controlled trials of adults with sub-threshold depression or mild MDD (initial baseline symptom severity of HRSD≤20) comparing an antidepressant with placebo or treatment as usual (TAU) however defined. A pre-specified protocol was published (Prospero reference: CRD42013004505). RESULTS: 8 trials were included: 5 trials (453 participants) of sub-threshold depression and 3 trials (502 participants) of mild MDD. Trials of sub-threshold depression exhibited low risk of bias whereas those of mild MDD exhibited high risk. Two trials of sub-threshold depression were pooled (n=102) to assess efficacy and favoured antidepressants over placebo statistically but the difference was small and unlikely to be clinically meaningful: mean difference -1.39 (-2.41, -0.36). Due to heterogeneity, no trials of mild MDD could be pooled for efficacy. There was no difference between antidepressant treatment and placebo for drop out due to adverse events. The maximum proportion in those receiving antidepressants dropping out due to adverse events was 17%, with indication of a dose effect. LIMITATIONS: Not all data from identified trials could be included in the meta-analyses due to a lack of availability of relevant data. CONCLUSION: There is insufficient evidence to support or contest the efficacy of antidepressant medication for sub-threshold depression or mild MDD. More trials, with adequate follow up, are required to address this question.

Differential item functioning of the HADS and PHQ-9: an investigation of age, gender and educational background in a clinical UK primary care sample.

BACKGROUND: The Patient Health Questionnaire (PHQ-9) and Hospital Anxiety and Depression Scale (HADS) are commonly used measures in clinical practice and research. It is important that such scales measure the trait they purport to measure and that the impact of other measurement artefacts is minimal. Differential item functioning of these scales by gender, educational background and age is currently assessed. METHODS: Severity of depression and anxiety symptoms were measured in primary care patients referred to mental health workers using the PHQ-9 and HADS. Each scale was assessed for Differential Item Functioning (DIF) and Differential Test Function (DTF) by gender, educational background and age. Minimum n per analysis=895. DIF was assessed with Mantel's χ(2), Liu-Agresti cumulative common odds ratio (LA LOR) and the standardised LA LOR (LA LOR-Z). DTF was assessed in relation to ν(2). RESULTS: PHQ-9, HADS Depression Sub-scale (HADS-D) and HADS Anxiety Subscale (HADS-A) lacked bias in terms of gender and educational background (ν(2)<0.07). However, both PHQ-9 and HADS-D exhibited bias with regard to age: PHQ-9 ν(2)=0.103 (medium effect); HADS-D ν(2)=0.214 (large effect). PHQ-9 items exhibiting DIF by age covered: anhedonia, energy and low mood. HADS-D items exhibiting DIF by age covered psychomotor retardation and interest in appearance. LIMITATIONS: No assessment of other potential DIF contributors was made. CONCLUSIONS: PHQ-9, HADS-D and HADS-A generally do not exhibit bias for gender and educational background. However bias was observed in PHQ-9 and HADS-D for age. Caution should be exercised interpreting scores both in clinical practice and research.