Psychotic major depression: challenges in clinical practice and research.

Psychotic major depression is an under-researched and under-identified disorder. We highlight the major challenges both in clinical practice and in conducting research with people with this disorder. We also suggest which major issues need addressing to move treatment and knowledge of this disorder forward. Declaration of interest M.H. and A.H.Y. both report grants from the National Institute for Health Research (NIHR).

Multiple-therapy-resistant major depressive disorder: a clinically important concept.

Many novel therapeutic options for depression exist that are either not mentioned in clinical guidelines or recommended only for use in highly specialist services. The challenge faced by clinicians is when it might be appropriate to consider such 'non-standard' interventions. This analysis proposes a framework to aid this decision.Declaration of interestIn the past 3 years R.H.M.W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, LivaNova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. D.M.B.C. has received fees from LivaNova for attending an advisory board. In the past 3 years A.J.C. has received fees for lecturing from Astra Zeneca and Lundbeck; fees for consulting from LivaNova, Janssen and Allergan; and research grant support from Lundbeck.In the past 3 years A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. In the past 3 years A.L.M. has received support for attending seminars and fees for consultancy work (including advisory board) from Medtronic Inc and LivaNova. R.M. holds joint research grants with a number of digital companies that investigate devices for depression including Alpha-stim, Big White Wall, P1vital, Intel, Johnson and Johnson and Lundbeck through his mindTech and CLAHRC EM roles. M.S. is an associate at Blueriver Consulting providing intelligence to NHS organisations, pharmaceutical and devices companies. He has received honoraria for presentations and advisory boards with Lundbeck, Eli Lilly, URGO, AstraZeneca, Phillips and Sanofi and holds shares in Johnson and Johnson. In the past 3 years P.R.A.S. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending an advisory board) from life sciences companies including Corcept Therapeutics, Indivior and LivaNova. In the past 3 years P.S.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has received funding for investigator initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth.

The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment.

Bipolar affective disorder is a common neuropsychiatric disorder. Although its neurobiological underpinnings are incompletely understood, the dopamine hypothesis has been a key theory of the pathophysiology of both manic and depressive phases of the illness for over four decades. The increased use of antidopaminergics in the treatment of this disorder and new in vivo neuroimaging and post-mortem studies makes it timely to review this theory. To do this, we conducted a systematic search for post-mortem, pharmacological, functional magnetic resonance and molecular imaging studies of dopamine function in bipolar disorder. Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania. In bipolar depression imaging studies show increased dopamine transporter levels, but changes in other aspects of dopaminergic function are inconsistent. Puzzlingly, pharmacological evidence shows that both dopamine agonists and antidopaminergics can improve bipolar depressive symptoms and perhaps actions at other receptors may reconcile these findings. Tentatively, this evidence suggests a model where an elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal dopamine transporter (DAT) levels would lead to reduced dopaminergic function and depression. Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder. The limitations of this model include its reliance on pharmacological evidence, as these studies could potentially affect other monoamines, and the scarcity of imaging evidence on dopaminergic function. This model, if confirmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in mania and DAT blockade in bipolar depression.

Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.

Assessing and addressing cognitive impairment in bipolar disorder: the International Society for Bipolar Disorders Targeting Cognition Task Force recommendations for clinicians.

OBJECTIVES: Cognition is a new treatment target to aid functional recovery and enhance quality of life for patients with bipolar disorder. The International Society for Bipolar Disorders (ISBD) Targeting Cognition Task Force aimed to develop consensus-based clinical recommendations on whether, when and how to assess and address cognitive impairment. METHODS: The task force, consisting of 19 international experts from nine countries, discussed the challenges and recommendations in a face-to-face meeting, telephone conference call and email exchanges. Consensus-based recommendations were achieved through these exchanges with no need for formal consensus methods. RESULTS: The identified questions were: (I) Should cognitive screening assessments be routinely conducted in clinical settings? (II) What are the most feasible screening tools? (III) What are the implications if cognitive impairment is detected? (IV) What are the treatment perspectives? Key recommendations are that clinicians: (I) formally screen cognition in partially or fully remitted patients whenever possible, (II) use brief, easy-to-administer tools such as the Screen for Cognitive Impairment in Psychiatry and Cognitive Complaints in Bipolar Disorder Rating Assessment, and (III) evaluate the impact of medication and comorbidity, refer patients for comprehensive neuropsychological evaluation when clinically indicated, and encourage patients to build cognitive reserve. Regarding question (IV), there is limited evidence for current evidence-based treatments but intense research efforts are underway to identify new pharmacological and/or psychological cognition treatments. CONCLUSIONS: This task force paper provides the first consensus-based recommendations for clinicians on whether, when, and how to assess and address cognition, which may aid patients' functional recovery and improve their quality of life.

Hair cortisol and childhood trauma predict psychological therapy response in depression and anxiety disorders.

OBJECTIVE: Around 30-50% of patients with depression and anxiety disorders fail to respond to standard psychological therapy. Given that cortisol affects cognition, patients with altered hypothalamic-pituitary-adrenal (HPA) axis functioning may benefit less from such treatments. To investigate this, reliable pretreatment cortisol measures are needed. METHOD: N = 89 outpatients with depression and anxiety disorders were recruited before undergoing therapy within an Improving Access to Psychological Therapies (IAPT) service. Three-month hair cortisol was determined, and the Childhood Trauma Questionnaire was administered. Patients were classified as responders if they showed significant decreases in depression (>= 6 points on the Patient Health Questionnaire) or anxiety (>= 5 points on the Generalised Anxiety Disorder Scale). RESULTS: Non-responders in terms of depression (57%) had lower pretreatment hair cortisol concentrations (P = 0.041) and reported more physical abuse (P = 0.024), sexual abuse (P = 0.010) and total trauma (P = 0.039) when compared to responders. Non-responders in terms of anxiety (48%) had lower pretreatment hair cortisol (P = 0.027), as well as higher levels of emotional abuse (P = 0.034), physical abuse (P = 0.042) and total trauma (P = 0.048). CONCLUSION: If future research confirms hair cortisol to be a predictor of psychological therapy response, this may prove a useful clinical biomarker which identifies a subgroup requiring more intensive treatment.

Mixed states in bipolar and major depressive disorders: systematic review and quality appraisal of guidelines.

OBJECTIVE: This systematic review provided a critical synthesis and a comprehensive overview of guidelines on the treatment of mixed states. METHOD: The MEDLINE/PubMed and EMBASE databases were systematically searched from inception to March 21st, 2018. International guidelines covering the treatment of mixed episodes, manic/hypomanic, or depressive episodes with mixed features were considered for inclusion. A methodological quality assessment was conducted with the Appraisal of Guidelines for Research and Evaluation-AGREE II. RESULTS: The final selection yielded six articles. Despite their heterogeneity, all guidelines agreed in interrupting an antidepressant monotherapy or adding mood-stabilizing medications. Olanzapine seemed to have the best evidence for acute mixed hypo/manic/depressive states and maintenance treatment. Aripiprazole and paliperidone were possible alternatives for acute hypo/manic mixed states. Lurasidone and ziprasidone were useful in acute mixed depression. Valproate was recommended for the prevention of new mixed episodes while lithium and quetiapine in preventing affective episodes of all polarities. Clozapine and electroconvulsive therapy were effective in refractory mixed episodes. The AGREE II overall assessment rate ranged between 42% and 92%, indicating different quality level of included guidelines. CONCLUSION: The unmet needs for the mixed symptoms treatment were associated with diagnostic issues and limitations of previous research, particularly for maintenance treatment.

Short-term and long-term measures of cortisol in saliva and hair in atypical and non-atypical depression.

BACKGROUND: Atypical depression may show lowered rather than raised short-term cortisol levels. Atypical major depressive episodes (A-MDE) may also be more closely linked to environmental factors and show overlap with somatic symptom disorders. Hair specimens allow measuring long-term cortisol levels. METHODS: Twenty-seven A-MDE and 44 NA-MDE patients and 40 matched controls were tested. Measures of hair cortisol concentration [HCC] covering the previous 3 months and short-term cortisol parameters (six saliva specimens to assess the cortisol awakening response [CAR] and total daily cortisol output calculated as the area under the curve [AUCg]) were taken alongside measures of environmental factors and clinical variables. RESULTS: There were no differences in HCC between the three groups (P = 0.8), and no difference in the CAR (P = 0.95). However, A-MDE showed lowered short-term cortisol output (AUCg) compared to controls (P = 0.04). A-MDE patients also reported a higher number of daily hassles, and higher levels of fatigue and impaired concentration than NA-MDE. CONCLUSIONS: Normal long-term (HCC) and reduced short-term (AUCg) cortisol levels in A-MDE could suggest a disrupted long-term cortisol rhythm, perhaps affected by environmental factors or by certain symptoms, such as mid-nocturnal insomnia. However, other underlying explanations for these findings should also be investigated in the future.

A morphometric signature of depressive symptoms in unmedicated patients with mood disorders.

OBJECTIVE: A growing literature indicates that unipolar depression and bipolar depression are associated with alterations in grey matter volume. However, it is unclear to what degree these patterns of morphometric change reflect symptom dimensions. Here, we aimed to predict depressive symptoms and hypomanic symptoms based on patterns of grey matter volume using machine learning. METHOD: We used machine learning methods combined with voxel-based morphometry to predict depressive and self-reported hypomanic symptoms from grey matter volume in a sample of 47 individuals with unmedicated unipolar and bipolar depression. RESULTS: We were able to predict depressive severity from grey matter volume in the anteroventral bilateral insula in both unipolar depression and bipolar depression. Self-reported hypomanic symptoms did not predict grey matter loss with a significant degree of accuracy. DISCUSSION: The results of this study suggest that patterns of grey matter volume alteration in the insula are associated with depressive symptom severity across unipolar and bipolar depression. Studies using other modalities and exploring other brain regions with a larger sample are warranted to identify other systems that may be associated with depressive and hypomanic symptoms across affective disorders.

Subcortical volumetric abnormalities in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Methodological recommendations for cognition trials in bipolar disorder by the International Society for Bipolar Disorders Targeting Cognition Task Force.

OBJECTIVES: To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus-based guidance paper for the methodology and design of cognition trials in bipolar disorder. METHODS: The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face-to-face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved. RESULTS: Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non-study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach. CONCLUSIONS: This ISBD task force guidance paper provides the first consensus-based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies.

Childhood trauma and mixed episodes are associated with poor response to lithium in bipolar disorders.

OBJECTIVES: Reliable predictors of response to lithium are still lacking in bipolar disorders (BDs). However, childhood trauma has been hypothesized to be associated with poor response to lithium. METHODS: We included 148 patients with BD, euthymic when retrospectively and clinically assessed for response to lithium and childhood trauma using reliable scales. RESULTS: According to the 'Alda scale', the sample consisted in 20.3% of excellent responders, 49.3% of partial responders and 30.4% of non-responders to lithium. A higher level of physical abuse significantly correlated with a lower level of response to lithium (P = 0.009). As compared to patients not exposed to any abuse, patients with at least two trauma abuses (emotional, physical or sexual) were more at risk of belonging to the non-responders group (OR = 4.91 95% CI (1.01-27.02)). Among investigated clinical variables, lifetime presence of mixed episodes and alcohol misuse were associated with non-response to lithium. Multivariate analyses demonstrated that physical abuse and mixed episodes were independently associated with poor response to lithium (P = 0.005 and P = 0.013 respectively). CONCLUSIONS: Childhood physical abuse might be involved in a poor future response to lithium prophylaxis, this effect being independent of the association between clinical expression of BD and poor response to lithium.

Aggressiveness in depression: a neglected symptom possibly associated with bipolarity and mixed features.

OBJECTIVE: To evaluate aggressiveness during a major depressive episode (MDE) and its relationship with bipolar disorder (BD) in a post hoc analysis of the BRIDGE-II-MIX study. METHOD: A total of 2811 individuals were enrolled in this multicenter cross-sectional study. MDE patients with (MDE-A, n = 399) and without aggressiveness (MDE-N, n = 2412) were compared through chi-square test or Student's t-test. A stepwise backward logistic regression model was performed. RESULTS: MDE-A group was more frequently associated with BD (P < 0.001), while aggressiveness was negatively correlated with unipolar depression (P < 0.001). At the logistic regression, aggressiveness was associated with the age at first depressive episode (P < 0.001); the severity of mania (P = 0.03); the diagnosis of BD (P = 0.001); comorbid borderline personality disorder (BPD) (P < 0.001) but not substance abuse (P = 0.63); no current psychiatric treatment (P < 0.001); psychotic symptoms (P = 0.007); the marked social/occupational impairment (P = 0.002). The variable most significantly associated with aggressiveness was the presence of DSM-5 mixed features (P < 0.001, OR = 3.815). After the exclusion of BPD, the variable of lifetime suicide attempts became significant (P = 0.013, OR = 1.405). CONCLUSION: Aggressiveness seems to be significantly associated with bipolar spectrum disorders, independently from BPD and substance abuse. Aggressiveness should be considered as a diagnostic criterion for the mixed features specifier and a target of tailored treatment strategy.

Study protocol for a randomised pragmatic trial comparing the clinical and cost effectiveness of lithium and quetiapine augmentation in treatment resistant depression (the LQD study).

BACKGROUND: Approximately 30-50% of patients with major depressive disorder can be classed as treatment resistant, widely defined as a failure to respond to two or more adequate trials of antidepressants in the current episode. Treatment resistant depression is associated with a poorer prognosis and higher mortality rates. One treatment option is to augment an existing antidepressant with a second agent. Lithium and the atypical antipsychotic quetiapine are two such add-on therapies and are currently recommended as first line options for treatment resistant depression. However, whilst neither treatment has been established as superior to the other in short-term studies, they have yet to be compared head-to-head in longer term studies, or with a superiority design in this patient group. METHODS: The Lithium versus Quetiapine in Depression (LQD) study is a parallel group, multi-centre, pragmatic, open-label, patient randomised clinical trial designed to address this gap in knowledge. The study will compare the clinical and cost effectiveness of the decision to prescribe lithium or quetiapine add-on therapy to antidepressant medication for patients with treatment resistant depression. Patients will be randomised 1:1 and followed up over 12 months, with the hypothesis being that quetiapine will be superior to lithium. The primary outcomes will be: (1) time to all-cause treatment discontinuation over one year, and (2) self-rated depression symptoms rated weekly for one year via the Quick Inventory of Depressive Symptomatology. Other outcomes will include between group differences in response and remission rates, quality of life, social functioning, cost-effectiveness and the frequency of serious adverse events and side effects. DISCUSSION: The trial aims to help shape the treatment pathway for patients with treatment resistant depression, by determining whether the decision to prescribe quetiapine is superior to lithium. Strengths of the study include its pragmatic superiority design, broad inclusion criteria (external validity) and longer follow up than previous studies. TRIAL REGISTRATION: ISRCTN registry: ISRCTN16387615 , registered 28 February 2016. ClinicalTrials.gov: NCT03004521 , registered 17 November 2016.

Relationships between mixed features and borderline personality disorder in 2811 patients with major depressive episode.

OBJECTIVE: The study focused on the relationship between mixed depression and borderline personality disorder (BPD). METHOD: The sample comprised 2811 patients with a major depressive episode (MDE). Clinical characteristics were compared in patients with (BPD+) and without (BPD-) comorbid BPD and in BPD+ with (MXS+) and without (MXS-) mixed features according to DSM-5 criteria. RESULTS: A total of 187 patients (6.7%) met the criteria for BPD. A DSM-IV-TR diagnosis of bipolar disorder (BD) was significantly more frequent in patients with BPD+ than in patients with BPD. Patients with BPD+ were significantly younger and reported lower age at onset than BPD-. Patients with BPD+ also showed more hypomania/mania in first-degree relatives in comparison with patients with BPD-, as well as more psychiatric comorbidity, mixed features, atypical features, suicide attempts, prior mood episodes and antidepressant-induced hypo/manic switches. Mixed features according to DSM-5 criteria were observed in 52 (27.8%) BPD+. In comparison with MXS-, MXS+ were significantly younger at age of onset and at prior mood episode and had experienced more mood episodes and hypo/manic switches with antidepressant treatments. CONCLUSION: Major depressive episode patients with comorbid BPD reported a high prevalence of mixed features and BD. The presence of DSM-5 mixed features in MDE patients with BPD may be associated with complex course and reduced treatment response.

Neurocognitive intra-individual variability in mood disorders: effects on attentional response time distributions.

BACKGROUND: Attentional impairment is a core cognitive feature of major depressive disorder (MDD) and bipolar disorder (BD). However, little is known of the characteristics of response time (RT) distributions from attentional tasks. This is crucial to furthering our understanding of the profile and extent of cognitive intra-individual variability (IIV) in mood disorders. METHOD: A computerized sustained attention task was administered to 138 healthy controls and 158 patients with a mood disorder: 86 euthymic BD, 33 depressed BD and 39 medication-free MDD patients. Measures of IIV, including individual standard deviation (iSD) and coefficient of variation (CoV), were derived for each participant. Ex-Gaussian (and Vincentile) analyses were used to characterize the RT distributions into three components: mu and sigma (mean and standard deviation of the Gaussian portion of the distribution) and tau (the 'slow tail' of the distribution). RESULTS: Compared with healthy controls, iSD was increased significantly in all patient samples. Due to minimal changes in average RT, CoV was only increased significantly in BD depressed patients. Ex-Gaussian modelling indicated a significant increase in tau in euthymic BD [Cohen's d = 0.39, 95% confidence interval (CI) 0.09-0.69, p = 0.011], and both sigma (d = 0.57, 95% CI 0.07-1.05, p = 0.025) and tau (d = 1.14, 95% CI 0.60-1.64, p < 0.0001) in depressed BD. The mu parameter did not differ from controls. CONCLUSIONS: Increased cognitive variability may be a core feature of mood disorders. This is the first demonstration of differences in attentional RT distribution parameters between MDD and BD, and BD depression and euthymia. These data highlight the utility of applying measures of IIV to characterize neurocognitive variability and the great potential for future application.

Neurocognitive functioning in bipolar depression: a component structure analysis.

BACKGROUND: Previous studies of neurocognitive performance in bipolar disorder (BD) have focused predominantly on euthymia. In this study we aimed to compare the neurocognitive profile of BD patients when depressed with healthy controls and explore the component structure of neurocognitive processes in these populations. METHOD: Cognitive tests of attention and executive function, immediate memory, verbal and visuospatial learning and memory and psychomotor speed were administered to 53 patients with a SCID-verified diagnosis of BD depression and 47 healthy controls. Test performance was assessed in terms of statistical significance, effect size and percentile standing. Principal component analysis (PCA) was used to explore underlying cognitive factor structure. RESULTS: Multivariate analysis revealed an overall group effect, depressed BD patients performing significantly worse than controls. Patients performed significantly worse on 18/26 measures examined, with large effect sizes (d > 0.8) on tests of speed of processing, verbal learning and specific executive/working memory processes. Almost all tests produced at least one outcome measure on which ∼25-50% of the BD sample performed at more than 1 standard deviation (s.d.) below the control mean. Between 20% and 34% of patients performed at or below the fifth percentile of the control group in working memory, verbal learning and memory, and psychomotor/processing speed. PCA highlighted overall differences between groups, with fewer extracted components and less specificity in patients. CONCLUSIONS: Overall, neurocognitive test performance is significantly reduced in BD patients when depressed. The use of different methods of analysing cognitive performance is highlighted, along with the relationship between processes, indicating important directions for future research.

Cannabis use and first-episode psychosis: relationship with manic and psychotic symptoms, and with age at presentation.

BACKGROUND: Cannabis use has been reported to be associated with an earlier onset of symptoms in patients with first-episode psychosis, and a worse outcome in those who continue to take cannabis. In general, studies have concentrated on symptoms of psychosis rather than mania. In this study, using a longitudinal design in a large naturalistic cohort of patients with first-episode psychosis, we investigated the relationship between cannabis use, age of presentation to services, daily functioning, and positive, negative and manic symptoms. METHOD: Clinical data on 502 patients with first-episode psychosis were collected using the MiData audit database from seven London-based Early Intervention in psychosis teams. Individuals were assessed at two time points--at entry to the service and after 1 year. On each occasion, the Positive and Negative Syndrome Scale, Young Mania Rating Scale and Global Assessment of Functioning Scale disability subscale were rated. At both time points, the use of cannabis and other drugs of abuse in the 6 months preceding each assessment was recorded. RESULTS: Level of cannabis use was associated with a younger age at presentation, and manic symptoms and conceptual disorganization, but not with delusions, hallucinations, negative symptoms or daily functioning. Cannabis users who reduced or stopped their use following contact with services had the greatest improvement in symptoms at 1 year compared with continued users and non-users. Continued users remained more symptomatic than non-users at follow-up. CONCLUSIONS: Effective interventions for reducing cannabis use may yield significant health benefits for patients with first-episode psychosis.