Mood Disorders and Addictions: A shared biology? Dr. Paul Stokes Clinical Senior Lecturer, Centre for Affective Disorders, Department of Psychological Medicine
Disclosures No relevant disclosures: No paid lectures for pharmaceutical companies No membership of industry advisory boards No shareholdings in pharmaceutical companies No current or previous industry grant income
Overview 1. Prevalence of co-morbid addictions in mood disorders 2. Impact on clinical outcomes in bipolar disorder 3. Mechanisms Dopamine and reward GABA-A dysfunction 4. Treatment Mood stabilisers Atypical antipsychotics
PREVALENCE
Lifetime prevalence of addiction in mood disorders 70 60 50 8X 40 30 20 10 0 % Lifetime prevalence Odds Ratio ECA study Regier et al JAMA 1990
Lifetime prevalence of alcohol dependence in mood disorders 35 30 6X 25 20 15 10 5 0 Normal Unipolar MDD Bipolar 1 Bipolar 2 Schizophrenia Anxiety disorders % Alcohol dependence Odds ratio ECA study Regier et al JAMA 1990
Risk of alcohol dependence in bipolar disorder higher for women than men Frye et al. Am J Psychiatry 2003
Lifetime prevalence of any drug dependence in mood disorders 30 25 11X 20 15 % Drug dependence Odds ratio 10 5 0 Normal Unipolar MDD Bipolar 1 Bipolar 2 Schizophrenia Anxiety disorders ECA study Regier et al JAMA 1990
Lifetime prevalence of comorbid drug abuse in bipolar disorder Prevalence estimates vary widely between individual drug classes Bipolar Disorder Cocaine: 6%-39% Cannabis: 15%-64% Opiates: 3%-25% Sedatives: 5%-31% UK national population Cocaine: 9% Cannabis: 31% Opiates: 1% Sedatives: 3% Cassidy et al. Bipolar Disorders 2001 British Crime Survey, Home Office, UK
Bipolar disorder and nicotine addiction US National Comorbidity survey found that Bipolar Disorder had the highest rates of cigarette smoking of any mental disorder: Bipolar Disorder 3x higher rates MDD 1.5 x increased rates Non affective psychosis 2 x higher rates Lasser et al JAMA 2000
Behavioural addiction symptoms more common in Bipolar disorder: 33% reach cut off for at least one behavioural addiction Significantly higher rating scale scores for: Pathological gambling Compulsive buying Sexual and work addiction Di Nicola et al Journal of Affective Disorders 2010
Zurich Cohort study (20 year follow-up): Manic symptoms associated with: 4x risk of alcohol dependency 5x risk of cannabis abuse/dependence 11x risk of benzodiazepine abuse/dependence BP2 associated with: 21 x risk of alcohol dependence 14x risk of benzodiazepine abuse/dependence No increased risk of cannabis dependence Merikangus et al Archives Gen Psychiatry 2008
IMPACT ON CLINICAL OUTCOMES
Alcohol misuse associated with more severe mania Acute mania complicated by current alcohol misuse associated with: Higher numbers of manic symptoms Increased risk profile: More mood lability Higher impulsivity levels Increased risk of violence Increased rates of other drug abuse Salloum et al Bipolar Disorders 2002
Remission after an episode of mania less likely in patients with prior substance use Particularly alcohol or cannabis use Remission more likely in those treated with Valproate or Carbamezepine than Lithium Goldberg et al J Clin Psych 1999
Co-morbid drug use increases risk of suicide in Bipolar Disorder 40 35 30 25 20 15 % Suicide attempts 10 5 0 Overall Drug use disorder No drug use Dalton et al. Bipolar Disorders 2003
Other impacts Co-morbid substance use disorders in bipolar disorder associated with: Poorer adherence to medication (Keck et al. 1998) Poorer outcomes (Keck et al. 1998) Higher relapse rates (Tohen et al 1990) Probability of not relapsing over 4 years in 24 first episode BD patients (Tohen et al 1990)
A shared neurobiology?: Hypotheses 1. Dopamine and reward 2. GABA dysfunction
MECHANISMS: DOPAMINE
Young men who reported high rates of hypomanic symptoms (Bipolar Phenotype) show blunted subjective responses to alcohol: Significantly lower intoxication effects from alcohol Higher expectation of positive effect of alcohol Similar low level response to alcohol found in those at high risk of developing alcohol dependence (Volavka et al 1996; Schuckit and Smith 1996) Yip et al Neuropsychopharmacology 2012
Casey et al Biological Psych 2013
Blunted dopamine release recently found in patients with schizophrenia and substance dependence after an amphetamine challenge Thompson et al Molecular Psychiatry 2013
Key Question Are those at risk of developing bipolar disorder also at high risk for addictions due to a blunted dopamine response to reward?
MECHANISMS: GABA
High rates of co-morbid GAD in mood disorders Patients with mood disorders have 14 x greater risk of generalised anxiety disorder: MDD: 6x Bipolar 1: 9x Bipolar 2: 5x Grant et al Psychological Medicine 2005
GABA-A receptor availability reduced in anxiety disorders GAD: Tiihonen et al 1997 GAD PTSD: Bremner et al Am J Psychiatry 2000 Panic: Malizia et al Arch Gen Psych 1998
Key Question Are patients with mood disorders self medicating with alcohol, cannabis and nicotine to compensate for a deficit in the GABA system?
TREATMENT: MOOD STABILISERS
How to treat pharmacologically? Lithium May not be effective in bipolar variants such as dysphoric, mixed, or rapid cycling, which are overrepresented in bipolar alcoholic patients. Lithium carbonate was ineffective in decreasing alcohol consumption in a large multicenter trial of depressed alcoholics (Dorus et al JAMA 1989)
24 week trial in Bipolar 1 patients & alcohol dependence All received treatment as usual : Li, detox if necessary, psychosocial interventions for SUD Valproate group had Less heavy drinking ; related to valproate plasma levels; improved GGT in Valproate group No difference in improvement of symptoms of mania or depression between groups Salloum et al. Am J Psych 2005
Most patients did not stabilize (31 vs 118) difficult trial to do / condition Alcohol, cocaine, cannabis dependence or abuse. BPD responders more likely to be no longer abusing drugs No difference in primary outcome : relapse to new mood episode Kemp et al., J Clin Psychiatry 2009 70(1) 113-121
Open label study of effect of 300mg lamotrigine on mood and cocaine use Improvements in: Depression and mania symptoms (HAMD, YMRS scores) Cocaine craving Dollars spent per week on cocaine Sherwood Brown et al J Affect Disorders 2006
TREATMENT: ANTIPSYCHOTICS
Heavy drinking CGI Randomised to lithium or valproate, then randomised to placebo or quetiapine (n=362, 42% completed). No significant change in heavy drinking or Clinical Global Impressions at 12 weeks.
Mania Depression Improvements in cocaine craving with both drugs Changes in mood not significantly associated with cocaine use Risperidone: 3.1 + 1.2mg/d Quetiapine: 303.6 + 150.7mg/d No placebo group
Challenges in assessing treatment effects Small number of studies overall e.g. No controlled trials of nicotine cessation for smokers with bipolar disorder available Most studies available are case studies or open label trials studying small numbers of patients with relatively short follow-up Very few well powered RCT s investigating treatment effects in co-morbid patients
Summary 1 Rates of alcohol and drug dependence much higher in bipolar disorder and also elevated in MDD BP2 and manic symptoms are risk factors for developing drug and alcohol abuse and dependence Co-morbidity impacts on clinical outcomes: increased risk of suicide, slower recovery and higher rates of admissions
Summary 2 Co-morbidity may be mediated by the dopamine-reward system or by impaired GABA function Mood stabilisers and antipsychotics may be effective in treating co-morbid addictions although evidence base is poor
Clinical implications 1 Look carefully for a history of co-morbid drug and alcohol dependence in patients with mood disorders (particularly BD) and vice versa Educating patients that they are at increased risk for substance dependence and the role that drug and alcohol use has in worsening outcomes in bipolar disorder is important
Clinical implications 2 Treat mood episodes as recommended in guidelines e.g. NICE, BAP however assess contribution of substance misuse to hypomania or mania in BD and consider if medically assisted withdrawal is required Review pharmacotherapy for bipolar disorder particularly if only on lithium, and consider adding sodium valproate.
Acknowlegments Allan Young (Centre for Affective Disorders, Kings College London) Anne Lingford Hughes (Centre for Neuropsychopharmacology, Imperial College London) David Nutt (Centre for Neuropsychopharmacology, Imperial College London)
BRITISH ASSOCIATION FOR PSYCHOPHARMACOLOGY 40 th Anniversary Summer Meeting 20 23 July 2014 Cambridge Online CPD Resource Schizophrenia Substance misuse including comorbidity Bipolar disorder Perinatal disorders ADHD focussing on adults Depression Anxiety disorders Sleep Old Age Child and Adolescent (coming soon) www.bap.org.uk
THANK YOU Dr. Paul Stokes Centre for Affective Disorders, Department of Psychological Medicine Institute of Psychiatry at King's College London Main Building, 4th floor, Room M4.01.01, De Crespigny Park London SE5 8AF Tel: +44-(0)20 Click to edit 7848 Master 5088 subtitle style e-mail: paul.r.stokes@kcl.ac.uk