Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project.

OBJECTIVE: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. METHOD: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. RESULTS: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge 'impairment' (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. CONCLUSION: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.

No change in neuropsychological functioning after receiving repetitive transcranial magnetic stimulation treatment for major depression.

Early studies of transcranial magnetic stimulation (TMS) have shown no adverse effects on neuropsychological function. However, further research using higher TMS intensities as well as a greater number of TMS pulses and with larger sample sizes is needed. We studied 68 patients with major depressive disorder who were randomized to receive either 15 sessions of sham or real TMS at 110% of the estimated prefrontal cortex threshold to the left dorsolateral prefrontal cortex. Each session consisted of 32 5-second trains of 10-Hz repetitive TMS at 110% adjusted motor threshold. A total of 24,000 pulses were given. Neuropsychological function was assessed before and immediately after TMS treatment with a battery of 8 tests. Using a higher TMS intensity as well as a greater number of pulses and having a larger sample size compared with most previous studies, this study found no negative neuropsychological effects of TMS. Changes in neuropsychological function were unrelated to changes in depression.

Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report.

BACKGROUND: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. OBJECTIVE: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. METHODS: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). RESULTS: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. CONCLUSIONS: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03887715.

Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of quality of life outcome measures in clinical practice.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an effective and safe therapy for major depressive disorder (MDD). This study assessed quality of life (QOL) and functional status outcomes for depressed patients after an acute course of TMS. METHODS: Forty-two, U.S.-based, clinical TMS practice sites treated 307 outpatients with a primary diagnosis of MDD and persistent symptoms despite prior adequate antidepressant pharmacotherapy. Treatment parameters were based on individual clinical considerations and followed the labeled procedures for use of the approved TMS device. Patient self-reported QOL outcomes included change in the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the EuroQol 5-Dimensions (EQ-5D) ratings from baseline to end of the acute treatment phase. RESULTS: Statistically significant improvement in functional status on a broad range of mental health and physical health domains was observed on the SF-36 following acute TMS treatment. Similarly, statistically significant improvement in patient-reported QOL was observed on all domains of the EQ-5D and on the General Health Perception and Health Index scores. Improvement on these measures was observed across the entire range of baseline depression symptom severity. CONCLUSION: These data confirm that TMS is effective in the acute treatment of MDD in routine clinical practice settings. This symptom benefit is accompanied by statistically and clinically meaningful improvements in patient-reported QOL and functional status outcomes.

Sexual functioning in patients with recurrent major depressive disorder enrolled in the PREVENT study.

The incidence of treatment-emergent sexual dysfunction in the acute and continuation phases of the prevention of recurrent episodes of depression with venlafaxine ER for two years (PREVENT) study was assessed. Adult outpatients with recurrent major depressive disorder were randomly assigned to receive venlafaxine extended release (ER; 75-300 mg/day) or fluoxetine (20-60 mg/day). Sexual dysfunction was assessed using items from the 17-item Hamilton Rating Scale for Depression (HAM-D(17)) and the Inventory of Depressive Symptomatology-Self-Report (IDS-SR). The baseline rates of sexual dysfunction based on the HAM-D(17) and IDS-SR items were 57.9% and 48.8%, respectively. The rates of new-onset sexual dysfunction for the venlafaxine ER-treated (44.8%, HAM-D(17); 38.4%, IDS-SR) and fluoxetine-treated patients (52.9%, HAM-D(17); 50.0%, IDS-SR) were similar; approximately 80% of the cases resolved during treatment. Treatment response was associated with lower rates of new-onset sexual dysfunction compared with nonresponse. The patients who remitted were the least likely to experience sexual dysfunction during antidepressant treatment.

Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice.

BACKGROUND: Few studies have examined the effectiveness of transcranial magnetic stimulation (TMS) in real-world clinical practice settings. METHODS: Forty-two US-based clinical TMS practice sites treated 307 outpatients with Major Depressive Disorder (MDD), and persistent symptoms despite antidepressant pharmacotherapy. Treatment was based on the labeled procedures of the approved TMS device. Assessments were performed at baseline, week 2, at the point of maximal acute benefit, and at week 6 when the acute course extended beyond 6 weeks. The primary outcome was change in the Clinician Global Impressions-Severity of Illness from baseline to end of acute phase. Secondary outcomes were change in continuous and categorical outcomes on self-report depression scales (9-Item Patient Health Questionnaire [PHQ-9], and Inventory of Depressive Symptoms-Self Report [IDS-SR]). RESULTS: Patients had a mean ± SD age of 48.6 ± 14.2 years and 66.8% were female. Patients received an average of 2.5 (± 2.4) antidepressant treatments of adequate dose and duration without satisfactory improvement in this episode. There was a significant change in CGI-S from baseline to end of treatment (-1.9 ± 1.4, P < .0001). Clinician-assessed response rate (CGI-S) was 58.0% and remission rate was 37.1%. Patient-reported response rate ranged from 56.4 to 41.5% and remission rate ranged from 28.7 to 26.5%, (PHQ-9 and IDS-SR, respectively). CONCLUSION: Outcomes demonstrated response and adherence rates similar to research populations. These data indicate that TMS is an effective treatment for those unable to benefit from initial antidepressant medication.

A new machine learning-derived screening measure for differentiating bipolar from unipolar mood disorders.

BACKGROUND: While there are several accepted screening measures for identifying those with a bipolar disorder, variations in overall classification rates argue for the pursuit of a more discriminating measure. Extant measures, as well as the DSM-5, rate each diagnostic criterion as having equivalent weighting values; an approach which may compromise diagnostic assignment if symptoms vary considerably in their diagnostic sensitivity. We therefore sought to develop a new measure and examine whether a weighted rating scale was superior to one assigning equivalent weightings to each item. METHODS: An international sample of 165 bipolar patients and a comparison sample of 29 unipolar patients completed a measure assessing 96 putative manic/hypomanic symptoms. A previous machine learning analysis had identified the twenty most discriminating items. In this study, analysis was undertaken involving only the ten most discriminating items. RESULTS: Whether items were scored as each having equivalent value or as weighted by their machine learning-generated values, classificatory accuracy was extremely high (in the order of 96%). Analyses also identified optimal cut-off scores. High classificatory accuracy was also obtained when scores for separate bipolar I and bipolar II groups were compared with scores from the unipolar group. LIMITATIONS: The sample consisted of comparatively few unipolar patients. CONCLUSIONS: The ten-item set allows a new measure for researchers to evaluate, while the items should assist clinician assessment as to whether a patient has a bipolar or unipolar mood disorder.

Categorical differentiation of the unipolar and bipolar disorders.

There has been a longstanding debate as to whether the bipolar disorders differ categorically or dimensionally, with some dimensional or spectrum models including unipolar depressive disorders within a bipolar spectrum model. We analysed manic/hypomanic symptom data in samples of clinically diagnosed bipolar I, bipolar II and unipolar patients, employing latent class analyses to determine if separate classes could be identified. Mixture analyses were also undertaken to determine if a unimodal, bimodal or a trimodal pattern was present. For both a refined 15-item set and an extended 30-item set of manic/hypomanic symptoms, our latent class analyses favoured three-class solutions, while mixture analyses identified trimodal distributions of scores. Findings argue for a categorical distinction between unipolar and bipolar disorders, as well as between bipolar I and bipolar II disorders. Future research should aim to consolidate these results in larger samples, particularly given that the size of the unipolar group in this study was a salient limitation.

Differentiating mania/hypomania from happiness using a machine learning analytic approach.

BACKGROUND: This study aimed to improve the accuracy of bipolar disorder diagnoses by identifying symptoms that help to distinguish mania/hypomania in bipolar disorders from general 'happiness' in those with unipolar depression. METHODS: An international sample of 165 bipolar and 29 unipolar depression patients (as diagnosed by their clinician) were recruited. All participants were required to rate a set of 96 symptoms with regards to whether they typified their experiences of manic/hypomanic states (for bipolar patients) or when they were 'happy' (unipolar patients). A machine learning paradigm (prediction rule ensembles; PREs) was used to derive rule ensembles that identified which of the 94 non-psychotic symptoms and their combinations best predicted clinically-allocated diagnoses. RESULTS: The PREs were highly accurate at predicting clinician bipolar and unipolar diagnoses (92% and 91% respectively). A total of 20 items were identified from the analyses, which were all highly discriminating across the two conditions. When compared to a classificatory approach insensitive to the weightings of the items, the ensembles were of comparable accuracy in their discriminatory capacity despite the unbalanced sample. This illustrates the potential for PREs to supersede traditional classificatory approaches. LIMITATIONS: There were considerably less unipolar than bipolar patients in the sample, which limited the overall accuracy of the PREs. CONCLUSIONS: The consideration of symptoms outlined in this study should assist clinicians in distinguishing between bipolar and unipolar disorders. Future research will seek to further refine and validate these symptoms in a larger and more balanced sample.

Repetitive Transcranial Magnetic Stimulation in the Treatment of Bipolar Depression: Experience From a Clinical Setting.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive Food and Drug Administration (FDA)-approved treatment for unipolar treatment-resistant depression (TRD). rTMS has been utilized clinically to treat bipolar TRD; however, there remains a lack of evidence and support for effectively utilizing this intervention for bipolar TRD. We retrospectively analyzed data from a group of patients who were treated with rTMS for unipolar or bipolar TRD and describe a case example to further delineate management techniques for employing rTMS in the treatment of bipolar TRD. METHODS: Records of 71 patients treated with rTMS for unipolar (n=54) or bipolar (n=17) TRD between 2008 and 2017 were reviewed. The primary outcome of depression severity, the Quick Inventory of Depressive Symptomatology, was completed at baseline and after every 5 sessions throughout the course of 30 treatments. Secondary outcomes involved a comparison of outcomes and clinical characteristics within and between the bipolar and unipolar TRD groups. RESULTS: In the total sample, patients' depression improved significantly over the course of treatment. Patients with bipolar TRD showed greater response and remission rates over the course of treatment compared with patients with unipolar TRD, but this difference was not statistically significant. Both groups showed a similar pattern of depression response over treatment time. No manic or hypomanic episodes occurred during any patient's course of rTMS treatment. A case example is provided discussing the timing of rTMS in a patient with bipolar depression to decrease the likelihood of treatment-induced hypomania. LIMITATIONS: Limitations included the small overall sample size, the smaller size of the patient group with bipolar TRD compared with the group with unipolar TRD, and the naturalistic setting of this study. CONCLUSIONS: Our data suggest that rTMS may be equally effective and safe for patients with both unipolar and bipolar depression. Patients with bipolar TRD showed a similar response profile over treatment time compared with patients with unipolar TRD.

The bipolar disorders: A case for their categorically distinct status based on symptom profiles.

BACKGROUND: It is unclear whether the bipolar disorders (i.e. BP-I/BP-II) differ dimensionally or categorically. This study sought to clarify this issue. METHODS: We recruited 165 patients, of which 69 and 96 had clinician-assigned diagnoses of BP-I and BP-II respectively. Their psychiatrists completed a data sheet seeking information on clinical variables about each patient, while the patients completed a different data sheet and scored a questionnaire assessing the prevalence and severity of 96 candidate manic/hypomanic symptoms. RESULTS: We conducted a series of analyses examining a set (and two sub-sets) of fifteen symptoms that were significantly more likely to be reported by the clinically diagnosed BP-I patients. Latent class analyses favoured two-class solutions, while mixture analyses demonstrated bimodality, thus arguing for a BP-I/BP-II categorical distinction. Statistically defined BP-I class members were more likely when manic to have experienced psychotic features and over-valued ideas. They were also more likely to have been hospitalised, and to have been younger when they received their bipolar diagnosis and first experienced a depressive or manic episode. LIMITATIONS: The lack of agreement between some patients and managing clinicians in judging the presence of psychotic features could have compromised some analyses. It is also unclear whether some symptoms (e.g. grandiosity, noting mystical events) were capturing formal psychotic features or not. CONCLUSIONS: Findings replicate our earlier study in providing evidence to support the modelling of BP-I and BP-II as categorically discrete conditions. This should advance research into aetiological factors and determining optimal (presumably differing) treatments for the two conditions.

Olanzapine/fluoxetine combination vs. lamotrigine in the 6-month treatment of bipolar I depression.

To determine the efficacy and tolerability of olanzapine/fluoxetine combination (OFC) compared with lamotrigine (Lam) for long-term treatment of bipolar I depression, this 25-wk, randomized, double-blind study compared OFC (6/25, 6/50, 12/25, or 12/50 mg/d, n=205) with Lam titrated to 200 mg/d (n=205) in patients with bipolar I disorder, depressed. A protocol-specified analysis of 7-wk outcomes was previously reported. Outcome measures included Clinical Global Impressions-Severity of Illness (CGI-S) (primary), Montgomery-Asberg Depression Rating Scale (MADRS), and Young Mania Rating Scale (YMRS) scores. OFC-treated patients had significantly greater improvement than Lam-treated patients over 25 wk on CGI-S (p=0.008), MADRS (p=0.005), and YMRS (p<0.001) scores, and from baseline across visits from week 5 (titration complete) to the end of the study on CGI-S (p=0.043), MADRS (p=0.017), and YMRS (p=0.001) scores. Of patients in remission after the 7-wk acute phase, there was no significant difference between treatment groups in the incidence of relapse (MADRS >15, p=0.528). Rate of treatment-emergent mania was not significantly different by treatment (p=0.401). OFC-treated patients had more frequent (p<0.05) somnolence, increased appetite, dry mouth, sedation, weight gain, and tremor; Lam-treated patients had more frequent insomnia. There was a significant difference in incidence of treatment-emergent cholesterol > or = 240 (p<0.001) and in weight gain of > or = 7% (p<0.001) in favour of the Lam group. Patients with bipolar I depression had significantly greater symptom improvement over 25 wk on OFC compared with Lam. There was no treatment difference in incidence of relapse. OFC-treated patients had more treatment-emergent adverse events and greater incidence of weight gain and hypercholesterolaemia.

Tachyphylaxis after repeated antidepressant drug exposure in patients with recurrent major depressive disorder.

OBJECTIVE: The aim of this post hoc analysis was to examine whether tachyphylaxis occurs after repeated courses of antidepressant drug therapy. METHOD: 276 patients with major depressive disorder (MDD) were treated with sertraline (150-200 mg daily) for 8 weeks. Patients with persistent MDD after sertraline therapy were randomized to continuation therapy with either sertraline plus atomoxetine (n = 72) or sertraline plus placebo (n = 74) for 8 additional weeks. Logistic regression was used to test the hypothesis that an increase in prior antidepressant drug exposure is associated with a reduced responsiveness to sertraline therapy. RESULTS: The number of prior antidepressant drug exposures was negatively associated with response to initial sertraline therapy (odds ratio = 0.81, p = 0.0035). The odds ratio indicates a 19.9% reduced likelihood of response with each prior antidepressant treatment trial. In contrast, the number of prior antidepressant treatment trials was not associated with response to continuation sertraline plus atomoxetine or sertraline plus placebo therapy. CONCLUSION: This observation supports the hypothesis that tachyphylaxis may develop after repeated antidepressant drug trials.

The symptom-specific efficacy of antidepressant medication vs. cognitive behavioral therapy in the treatment of depression: results from an individual patient data meta-analysis.

A recent individual patient data meta-analysis showed that antidepressant medication is slightly more efficacious than cognitive behavioral therapy (CBT) in reducing overall depression severity in patients with a DSM-defined depressive disorder. We used an update of that dataset, based on seventeen randomized clinical trials, to examine the comparative efficacy of antidepressant medication vs. CBT in more detail by focusing on individual depressive symptoms as assessed with the 17-item Hamilton Rating Scale for Depression. Five symptoms (i.e., "depressed mood" , "feelings of guilt" , "suicidal thoughts" , "psychic anxiety" and "general somatic symptoms") showed larger improvements in the medication compared to the CBT condition (effect sizes ranging from .13 to .16), whereas no differences were found for the twelve other symptoms. In addition, network estimation techniques revealed that all effects, except that on "depressed mood" , were direct and could not be explained by any of the other direct or indirect treatment effects. Exploratory analyses showed that information about the symptom-specific efficacy could help in identifying those patients who, based on their pre-treatment symptomatology, are likely to benefit more from antidepressant medication than from CBT (effect size of .30) versus those for whom both treatments are likely to be equally efficacious. Overall, our symptom-oriented approach results in a more thorough evaluation of the efficacy of antidepressant medication over CBT and shows potential in "precision psychiatry" .

Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the prevention of relapse and recurrence in major depression.

This study followed treatment responders from a randomized controlled trial of adults with major depression. Patients treated with medication but withdrawn onto pill-placebo had more relapse through 1 year of follow-up compared to patients who received prior behavioral activation, prior cognitive therapy, or continued medication. Prior psychotherapy was also superior to medication withdrawal in the prevention of recurrence across the 2nd year of follow-up. Specific comparisons indicated that patients previously exposed to cognitive therapy were significantly less likely to relapse following treatment termination than patients withdrawn from medication, and patients previously exposed to behavioral activation did almost as well relative to patients withdrawn from medication, although the difference was not significantly different. Differences between behavioral activation and cognitive therapy were small in magnitude and not significantly different across the full 2-year follow-up, and each therapy was at least as efficacious as the continuation of medication. These findings suggest that behavioral activation may be nearly as enduring as cognitive therapy and that both psychotherapies are less expensive and longer lasting alternatives to medication in the treatment of depression.

Psychotic symptoms in patients with bipolar mania.

BACKGROUND: Psychosis has been identified in as many as 68% of patients with bipolar mania. This analysis identified psychotic symptoms in these patients. METHODS: Data were from two placebo-controlled, 3-week studies in patients with an acute episode of bipolar mania. Symptoms were identified by the 30-item Positive and Negative Syndrome Scale (PANSS; item ratings, 1 = absent to 7 = extremely severe), the Young Mania Rating Scale, and the Global Assessment Scale. RESULTS: Psychotic features at study entry were diagnosed in 264 (51.3%) of the 515 patients. At baseline, these patients had significantly more severe scores on the PANSS, Young Mania Rating Scale, and Global Assessment Scale than patients without psychotic features. Patients with psychotic features had mean (+/-SD) scores of mild (3) or greater on six PANSS items: grandiosity (4.5+/-1.4), delusions (4.4+/-1.4), lack of judgment/insight (4.1+/-1.5), excitement (3.9+/-1.3), suspiciousness/persecution (3.1+/-1.6), and hostility (3.1+/-1.5). Grandiosity symptoms of delusional proportions (scores > or = 4) were noted in 205 (78%) of patients with a diagnosis of psychotic features and in 113 (45%) patients without the diagnosis. LIMITATIONS: The study was not specifically designed to assess patients with psychotic features and the PANSS was developed to evaluate symptoms of schizophrenia. CONCLUSIONS: These findings support prior reports indicating high rates of psychosis in patients with bipolar mania and identify the most prominent symptoms in these patients.

Long-term tolerability and effectiveness of duloxetine in the treatment of major depressive disorder.

To examine the long-term safety, tolerability, and effectiveness of duloxetine in the treatment of major depressive disorder in a naturalistic study design meant to mimic clinical practice. Data were from the long-term, open-label, extension phase that followed a 12-week acute-treatment, multicenter study of adult outpatients with major depressive disorder. After the first week of the acute phase, all patients were treated with at least 60 mg daily duloxetine, which could be titrated to a maximum dose of 120 mg daily. Outcome measures were collected at monthly visits and included spontaneously reported adverse events, weight, vital signs, and the 17-item Hamilton Depression Rating scale. Seventy-two of the 177 (40.7%) patients who entered the extension phase of this study completed the study. The mean duration of participation in the extension was 305 days, with total exposure ranging from 68 to 707 days. Of the 177 patients who entered the extension, only 12 or 13 (7.0%) showed clinically significant worsening of depression that led to study discontinuation. The mean 17-item Hamilton Depression Rating scale score remained below 7 throughout the extension. A total of 21/177 patients (11.9%) discontinued due to adverse events during extension treatment. The adverse events causing discontinuation during the extension, with the exception of weight gain, were generally not unique to the extension phase, with 11/21 patients (52.0%) discontinuing due to adverse events that were first reported during acute treatment. Weight gain was reported as a reason for discontinuation during extension treatment in 4/177 (2.3%) patients. In this open-label study, efficacy was maintained for most patients. The adverse events causing discontinuation during the extension phase were generally not unique to the extension phase. Few patients experienced significant weight gain.