Thyroid hormone treatment in the management of treatment-resistant unipolar depression: a systematic review and meta-analysis.

BACKGROUND: Treatment with thyroid hormones is occasionally used in the management of treatment-resistant depression. However, the evidence supporting this treatment is not fully established. The aim of this study was to systematically review the literature on the effect of adjunctive thyroid hormone in the management of treatment-resistant unipolar depression and to provide a pooled estimate of its efficacy. METHODS: The study is registered with PROSPERO (reg. no. CRD42018108088) and followed the PRISMA guidelines. Searches were carried out on June 24, 2019, in PubMed, EMBASE, and PsycINFO. Each record was screened independently by at least two reviewers. In instances of discrepancies, consensus was reached upon discussion. Pooled efficacy estimates were calculated based on response rates (decrease of ≥50% on the primary outcome measure) using random effect statistics. RESULTS: The search yielded 1355 records. Based on the screening of these records, we identified 10 studies that met the inclusion criteria (total number of patients = 663). The comparison of response to thyroid hormones vs. placebo resulted in an odds ratio of 1.56 (95% CI: 0.50-4.84). Similarly, the comparison of response to thyroid hormones vs. lithium resulted in an odds ratio of 1.91 (95% CI: 0.85-4.26). Thus, adjunctive therapy with thyroid hormones was not superior to placebo or lithium in the management of treatment-resistant unipolar depression. CONCLUSION: According to this review and meta-analysis, there is not sufficient evidence to support the use of adjunctive thyroid hormones for treatment-resistant unipolar depression.

Face and predictive validity of the ClockΔ19 mouse as an animal model for bipolar disorder: a systematic review.

Mice carrying the circadian locomotor output cycles Kaput delta 19 N-ethyl-N-nitrosoure (ENU) mutation (ClockΔ19) are used as an animal model for bipolar disorder (BD). We aimed to systematically review the face validity (phenotypical and pathophysiological resemblance with BD) and predictive validity (responsiveness to treatments used in BD) of this model in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. We carried out a systematic search of the databases PubMed and Embase, combining search terms covering BD and ClockΔ19. The 22 studies included in the review (from a total of 1281 identified records) show that the behavioral phenotype of the ClockΔ19 mouse is characterized by hyperactivity, decreased anxiety-like behavior, decreased depression-like behavior and increased preference for rewarding stimuli. This is highly consistent with mania in humans. Moreover, the ClockΔ19 mouse exhibits rapid mood cycling (a manic-like phenotype during the day followed by euthymia at night), which is consistent with BD. Chronic administration of lithium, a drug with well established mood-stabilizing effect in humans with BD, reverses the majority of the bipolar-like traits and most of the neurobiological abnormalities observed in the ClockΔ19 mouse. In conclusion, the ClockΔ19 mouse has substantial face validity as an animal model for BD. The predictive validity of the ClockΔ19 mouse has primarily been investigated via studies using lithium challenge. Therefore, further studies are needed to determine how the ClockΔ19 mouse responds to other mood-stabilizing treatments of BD such as valproate, lamotrigine, carbamazepine, oxcarbazepine, antipsychotics, electroconvulsive therapy and various light interventions.

In utero exposure to selective serotonin reuptake inhibitors and development of mental disorders: a systematic review and meta-analysis.

OBJECTIVE: Several studies have investigated whether in utero exposure to selective serotonin reuptake inhibitors (SSRIs) is associated with increased risk of developing mental or behavioural disorders. The aim of this study was to perform a systematic review and meta-analysis based on this literature. METHODS: A systematic search of eligible literature in PubMed, EMBASE, and PsycINFO and subsequent meta-analysis was conducted in adherence with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline. RESULTS: A total of 20 studies were included in the review, and results from 18 of these were meta-analyzed. We found a statistically significant positive association between in utero exposure to SSRIs and mental or behavioural disorders such as autism spectrum disorder (hazard ratio (HR) = 1.27; 95% confidence interval (CI) = 1.10-1.47), attention-deficit/hyperactivity disorder (HR = 1.33; 95% CI = 1.06-1.66) and mental retardation (HR = 1.41; 95% CI = 1.03-1.91). Confounding by indication was identified in five of seven studies investigating this aspect. CONCLUSION: Exposure to SSRIs in utero is associated with increased risk of developing mental or behavioural disorders. However, these associations do not necessarily reflect a causal relationship since the results included in this meta-analysis are likely affected by residual confounding by indication, which is likely to account for some (or all) of the positive association.

Predicting mechanical restraint of psychiatric inpatients by applying machine learning on electronic health data.

OBJECTIVE: Mechanical restraint (MR) is used to prevent patients from harming themselves or others during inpatient treatment. The objective of this study was to investigate whether incident MR occurring in the first 3 days following admission could be predicted based on analysis of electronic health data available after the first hour of admission. METHODS: The dataset consisted of clinical notes from electronic health records from the Central Denmark Region and data from the Danish Health Registers from patients admitted to a psychiatric department in the period from 2011 to 2015. Supervised machine learning algorithms were trained on a randomly selected subset of the data and validated using an independent test dataset. RESULTS: A total of 5050 patients with 8869 admissions were included in the study. One hundred patients were mechanically restrained in the period between one hour and 3 days after the admission. A Random Forest algorithm predicted MR with an area under the curve of 0.87 (95% CI 0.79-0.93). At 94% specificity, the sensitivity was 56%. Among the ten strongest predictors, nine were derived from the clinical notes. CONCLUSIONS: These findings open for the development of an early warning system that may guide interventions to reduce the use of MR.

Patterns and predictors of conversion to bipolar disorder in 91 587 individuals diagnosed with unipolar depression.

OBJECTIVE: Conversion from unipolar depression (UD) to bipolar disorder (BD) is a clinically important event that should lead to treatment modifications. Unfortunately, recognition of this transition is often delayed. Therefore, the objective of this study was to identify predictors of diagnostic conversion from UD to BD. METHOD: Historical prospective cohort study based on 91 587 individuals diagnosed with UD in Danish hospital psychiatry between 1995 and 2016. The association between a series of potential predictors and the conversion from UD to BD during follow-up (702 710 person-years) was estimated by means of Cox regression with death as competing risk. RESULTS: During follow-up, 3910 individuals with UD developed BD. The cumulative incidence of conversion was slightly higher in females (8.7%, 95% CI: 8.2-9.3) compared to males (7.7%, 95% CI: 7.0-8.4). The strongest predictor of conversion from UD to BD was parental history of BD (adjusted hazard ratio (aHR) = 2.60, 95% CI: 2.20-3.07)). Other predictors included psychotic depression at the index UD episode (aHR = 1.73, 95% CI: 1.48-2.02), a prior/concomitant non-affective psychosis (aHR = 1.73, 95% CI: 1.51-1.99), and in-patient treatment at the index episode (aHR = 1.76, 95% CI: 1.63-1.91). CONCLUSION: Diagnostic conversion from UD to BD is predicted by severe depression requiring in-patient treatment, psychotic symptomatology, and parental history of BD.

The validity and sensitivity of PANSS-6 in treatment-resistant schizophrenia.

OBJECTIVE: To test the validity and sensitivity of the six-item version (PANSS-6) of the 30-item Positive and Negative Syndrome Scale (PANSS-30) in treatment-resistant schizophrenia (TRS). METHOD: Using data from the clozapine phase (2E) of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, we investigated the following: (i) The scalability of PANSS-6 and PANSS-30; (ii) The correlation between PANSS-6 and PANSS-30 total scores; (iii) Whether PANSS-6 could identify cross-sectional symptom remission; and (iv) The efficacy of clozapine, olanzapine, risperidone and quetiapine in TRS using the 'speed of change' on PANSS-6 and PANSS-30 (change in total score per week) as outcome measures. RESULTS: We found that (i) only PANSS-6 and not PANSS-30 was scalable; (ii) The correlation between PANSS-6 and PANSS-30 total scores was high (Spearman coefficient: 0.85), (iii) PANSS-6 accurately identified cross-sectional symptom remission as defined by the Andreasen et al. criteria; and (iv) The only antipsychotic that caused improvement (speed of change significantly lower than 0 during the first three months of treatment) was clozapine, both when using PANSS-6 (speed of change: -0.50 points/week; 95%CI: -0.84, -0.17) and PANSS-30 (speed of change: -1.41 points/week; 95%CI: -2.80, -0.02) as outcome measures. CONCLUSION: PANSS-6 validly measures severity, remission and antipsychotic efficacy in TRS.

A Systematic Review of the Clinimetric Properties of the 6-Item Version of the Hamilton Depression Rating Scale (HAM-D6).

BACKGROUND: In a study aimed at identifying the items carrying information regarding the global severity of depression, the 6-item Hamilton Depression Rating Scale (HAM-D6) was derived from the original 17-item version of the scale (HAM-D17). Since then, the HAM-D6 has been used in a wide range of clinical studies. We now provide a systematic review of the clinimetric properties of HAM-D6 in comparison with those of HAM-D17 and the Montgomery Asberg Depression Rating Scale (MADRS). METHODS: We conducted a systematic search of the literature in PubMed, PsycInfo, and EMBASE databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Studies reporting data on the clinimetric validity of the HAM-D6 and either the HAM-D17 or MADRS in non-psychotic unipolar or bipolar depression were included in the synthesis. RESULTS: The search identified 681 unique records, of which 51 articles met the inclusion criteria. According to the published literature, HAM-D6 has proven to be superior to both HAM-D17 and MADRS in terms of scalability (each item contains unique information regarding syndrome severity), transferability (scalability is constant over time and irrespective of sex, age, and depressive subtypes), and responsiveness (sensitivity to change in severity during treatment). CONCLUSIONS: According to the published literature, the clinimetric properties of HAM-D6 are superior to those of both the HAM-D17 and MADRS. Since the validity of HAM-D6 has been demonstrated in both research and clinical practice, using the scale more consistently would facilitate translation of results from one setting to the other.

The mortality rate of electroconvulsive therapy: a systematic review and pooled analysis.

OBJECTIVE: Electroconvulsive therapy (ECT) remains underutilized because of fears of cognitive and medical risks, including the risk of death. In this study, we aimed to assess the mortality rate of ECT by means of a systematic review and pooled analysis. METHOD: The study was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. The ECT-related mortality rate was calculated as the total number of ECT-related deaths reported in the included studies divided by the total number of ECT treatments. RESULTS: Fifteen studies with data from 32 countries reporting on a total of 766 180 ECT treatments met the inclusion criteria. Sixteen cases of ECT-related death were reported in the included studies yielding an ECT-related mortality rate of 2.1 per 100 000 treatments (95% CI: 1.2-3.4). In the nine studies that were published after 2001 (covering 414 747 treatments), there was only one reported ECT-related death. CONCLUSION: The ECT-related mortality rate was estimated at 2.1 per 100 000 treatments. In comparison, a recent analysis of the mortality of general anesthesia in relation to surgical procedures reported a mortality rate of 3.4 per 100 000. Our findings document that death caused by ECT is an extremely rare event.

PANSS-6: a brief rating scale for the measurement of severity in schizophrenia.

OBJECTIVE: The 30-item Positive and Negative Syndrome Scale (PANSS-30) is the most widely used rating scale in schizophrenia, but too long for clinical use. Shorter PANSS versions have been proposed, including the PANSS-14 and PANSS-8. However, none of these PANSS versions has been validated using the parametric Rasch rating scale model, which evaluates 'scalability'. Scalability means that each item in a rating scale provides unique information regarding syndrome severity and is a statistical prerequisite for using the total score as a measure of overall severity. METHOD: Based on data from two randomized placebo-controlled trials in schizophrenia, we tested the scalability of PANSS-30, PANSS-14 and PANSS-8 by means of the parametric Rasch rating scale model. Furthermore, we tested whether a scalable PANSS version could separate efficacy of haloperidol and sertindole from placebo. RESULTS: Neither PANSS-30, PANSS-14 nor PANSS-8 was scalable. However, PANSS-6, consisting of the items: P1-Delusions, P2-Conceptual disorganization, P3-Hallucinations, N1-Blunted Affect, N4-Social withdrawal, N6-Lack of spontaneity and flow of conversation, was scalable. Furthermore, PANSS-6 captured superior symptom reduction and higher remission rates during treatment with haloperidol and sertindole vs. placebo. CONCLUSION: PANSS-6 is a short schizophrenia severity rating scale that adequately separates antipsychotic efficacy from that of placebo.

Rating scales measuring the severity of psychotic depression.

OBJECTIVE: Unipolar psychotic depression (PD) is a severe and debilitating syndrome, which requires intensive monitoring. The objective of this study was to provide an overview of the rating scales used to assess illness severity in PD. METHOD: Selective review of publications reporting results on non-self-rated, symptom-based rating scales utilized to measure symptom severity in PD. The clinical and psychometric validity of the identified rating scales was reviewed. RESULTS: A total of 14 rating scales meeting the predefined criteria were included in the review. These scales grouped into the following categories: (i) rating scales predominantly covering depressive symptoms, (ii) rating scales predominantly covering psychotic symptoms, (iii) rating scales covering delusions, and (iv) rating scales covering PD. For the vast majority of the scales, the clinical and psychometric validity had not been tested empirically. The only exception from this general tendency was the 11-item Psychotic Depression Assessment Scale (PDAS), which was developed specifically to assess the severity of PD. CONCLUSION: In PD, the PDAS represents the only empirically derived rating scale for the measurement of overall severity of illness. The PDAS should be considered in future studies of PD and in clinical practice.

Measuring psychotic depression.

OBJECTIVE: Psychotic depression (PD) is a highly debilitating condition, which needs intensive monitoring. However, there is no established rating scale for evaluating the severity of PD. The aim of this analysis was to assess the psychometric properties of established depression rating scales and a number of new composite rating scales, covering both depressive and psychotic symptoms, in relation to PD. METHOD: The psychometric properties of the rating scales were evaluated based on data from the Study of Pharmacotherapy of Psychotic Depression. RESULTS: A rating scale consisting of the 6-item Hamilton melancholia subscale (HAM-D6 ) plus five items from the Brief Psychiatric Rating Scale (BPRS), named the HAMD-BPRS11 , displayed clinical validity (Spearman's correlation coefficient between HAMD-BPRS11 and Clinical Global Impression - Severity (CGI-S) scores = 0.79-0.84), responsiveness (Spearman's correlation coefficient between change in HAMD-BPRS11 and Clinical Global Impression - Improvement (CGI-I) scores = -0.74--0.78) and unidimensionality (Loevinger's coefficient of homogeneity = 0.41) in the evaluation of PD. The HAM-D6 fulfilled the same criteria, whereas the full 17-item Hamilton Depression Scale failed to meet criteria for unidimensionality. CONCLUSION: Our results suggest that the HAMD-BPRS11 is a more valid measure than pure depression scales for evaluating the severity of PD.

The Diagnostic Apathia Scale predicts the ability to return to work following depression or anxiety.

OBJECTIVE: The aim of this study was to evaluate the validity of a new apathy rating scale in predicting the ability to return to work (RTW) in patients with depression or anxiety a year after discharge from a psychiatric hospital. METHODS: We evaluated 56 patients with depression or anxiety, who participated in an on-going randomised clinical trial using RTW as primary outcome. The degree of apathy was measured by the Diagnostic Apathia Scale, which contains six items covering the following neuropsychological symptoms: concentration/memory problems, difficulties in decision making, lassitude, tiredness/fatigue, insomnia, and reduced ability to work and engage in personal interests. The scale was analysed for psychometric validity (scalability) and for its ability to predict RTW. Finally, the predictive validity of the Diagnostic Apathia Scale regarding RTW was compared with scales measuring severity of depression/anxiety symptoms, disability, and psychological well-being. RESULTS: The Diagnostic Apathia Scale displayed sufficient scalability, that is, the total score was a psychometrically valid measure of apathy. Only the Diagnostic Apathia Scale, and not the scales measuring severity of symptoms, disability, or psychological well-being, had predictive validity regarding RTW. Thus, 76% with 'clinically significant apathy' at baseline were unable to RTW versus 50% of the patients without apathy (p<0.05). CONCLUSION: The Diagnostic Apathia Scale was found to have an acceptable predictive validity in terms of patients' ability to RTW 1 year after discharge from hospitalisation for depression or anxiety.

Persistent delusional theme over 13 episodes of psychotic depression.

OBJECTIVE: Unipolar psychotic depression (PD) is a highly debilitating condition, which needs intense monitoring and treatment. Among patients with recurrent PD, delusions tend to be very similar or identical over several separate episodes during the course of illness, but case-reports illustrating this clinical phenomenon in detail are lacking from the literature. METHODS: Case report describing the 45-year-old Ms. J, who has experienced multiple episodes of PD. The report is based on a review of her medical file. RESULTS: The delusional theme of Ms. J's initial episode of PD reappeared at several subsequent episodes. During the majority of admissions, Ms. J was treated with electroconvulsive therapy, which resulted in significant improvement in the depressive, psychotic and catatonic features. CONCLUSION: Ms. J's case illustrates that PD can be a stable phenotype over many episodes and that it is important to recognize psychotic symptoms in order to prescribe the best possible treatment.

The association between physical illness and major depressive episode in general practice.

OBJECTIVE: Physical illness and depression are associated. However, it remains unclear whether this association is sufficiently strong to merit systematic screening for depression among primary care patients suffering from physical illness. In the present study, we investigated the strength of the association between physical illness and depression among patients in general practice. METHOD: Four thousand two hundred and seventy-one consecutive primary care patients completed a diagnostic depression questionnaire. The general practitioner evaluated the patients' physical health, which was then compared to their diagnostic status of depression. RESULTS: Physical illness was associated with the presence of depression. Two hundred and thirty-six patients (5.5%) fulfilled diagnostic criteria for depression. Fourteen of these suffered from extreme physical illness, 27 from at least severe physical illness and 96 from at least moderate physical illness. The number needed to screen decreased with increasing severity and chronicity of the physical illness. CONCLUSIONS: Depression is relatively common in primary care patients suffering from physical illness, particularly if the illness is severe and chronic. However, relatively few depressed patients suffer from a comorbid physical illness. Screening for depression among patients with physical illness may therefore only have a modest impact on the under-recognition of depression in general practice.