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Mood Disorders
Shamim Nejad, MDMedical Director, Psycho‐Oncology ServicesSwedish Cancer InstituteSwedish Medical CenterSeattle, [email protected]
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Disclosures
“Neither I nor my spouse/partner has a relevant financial relationship with a commercial interest
to disclose.”
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Epidemiology
• Lifetime prevalence of major depressive disorder is estimated to be 13.2% to 16.6%
• Lifetime prevalence of bipolar mood disorder is estimated to be 4.4%
• Lifetime prevalence of MDD with AUD is 40.3% and with SUD is 17.2%
• Lifetime prevalence of BMD with SUD is 47.3% (BMD I is 60.3%)
National Epidemiologic Survey on Alcohol and Related Conditions (Conway et al., 2006)
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Diagnostic Dilemma
• DSM criteria indicate:– Mood disorder is primary if
it is not due to the effects of alcohol or drugs.
– Mood disorder symptoms should have been present prior to the patient’s substance problem and/or should persist during abstinent periods.
– All other occurrences of mood disorder symptoms, according to DSM, are likely “substance induced.”
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DSM Criteria
Independent Mood Disorder• Mood symptoms preceded the
onset of substance use• Mood symptoms persist for a
substantial period of time after cessation of acute withdrawal and severe intoxication
• Mood symptoms substantially in excess of what would be expected given the type or amount of the substance used or the duration of use
• Other evidence of an independent mood disorder
Substance‐Induced Mood Disorder• Prominent and persistent
disturbance in mood• Mood symptoms develop
during substance intoxication or withdrawal
• Mood symptoms are in excess of those usually associated with the intoxication or withdrawal syndrome
• Sufficiently severe to warrant independent clinical attention
• Not better accounted for by an independent mood disorder
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Relationships Between Co‐Occurring Mood Symptoms and SUDs
Relationship Mechanism Clinical ImplicationsSubstance use causes mood symptoms Use, intoxication, withdrawal or
neuropsychiatric sequelae of chronic useSUD is chronologically primary; mood symptoms resolve with abstinence or reduced substance use; treatment focused on substance use
Substance use causes mood symptomswhich worsen over time
Loss in multiple spheres lead to demoralization and depression; physiologic effects from chronic use lead to vulnerability to mood symptoms
Mood symptoms follow SUD but persist after abstinence; will need to treat both mood and SUD’s.
Mood symptoms lead to substance use Using substances to relieve symptoms of mood symptoms ‐ ‘self‐medication’
Mood symptoms are primary or emerge during abstinence, preceding relapse; pure ‘self‐medication’ is rare
Substance use is associated with increased disinhibition and impulsivity from hypomania/mania
Disinhibition/impulsivity Substance use is secondary to mood symptoms; pure ‘self‐medication’ is rare
Mood symptoms cause substance use which then worsens over time
Exposure to substances during episode of mood disorder induces vulnerability to SUD
Substance use is secondary but persists after mood disorder is treated; treatboth conditions
Independent disorders Both mood disorders and SUD are present in general population with increased comorbidity
Each disorder persists during remission of the other; treat both disorders
Adapted from Nunes and Weiss. Co‐Occurring Addictive and Mood Disorders. The ASAM Principles of Addiction Medicine.
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Effects of Independent and Substance Induced Depression on Outcomes
• Prospective cohort of 250 patients admitted to an urban community psychiatric IPU
• PRISM used to evaluate independent and substance‐induced major depression, alcohol, cocaine and heroin dependence, and other psychiatric disorders.
• Patients evaluated at baseline, 6, 12, and 18 months. Outcomes for each substance:
– (i) time (weeks) from hospital discharge to first use – (ii) time from discharge to onset of sustained (≥26 weeks) remission from
dependence– (iii) time from onset of sustained remission to relapse.
• Substance‐induced major depression significantly predicted post‐discharge use of alcohol, cocaine and heroin (hazard ratios 4.7, 5.3 and 6.5, respectively).
• Among patients achieving stable remissions from dependence, independent major depression predicted relapse to alcohol and cocaine dependence (hazard ratios 2.3 and 2.7, respectively).
Samet S, Fenton MC, Nunes E, Greenstein E, Aharonovich E, Hasin D. Effects of independent and substance‐induced major depressive disorder on remission and relapse of alcohol, cocaine and heroin dependence.Addiction. 2013;108(1):115‐123.
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Management of Depression and SUD
Greenfield SF, et al.. Archives of General Psychiatry. 1998; 55:259–65.
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Management of Depression and SUD
• 14 placebo‐controlled trials of antidepressant medications– DSM diagnosed patients with depression– Alcohol, cocaine, opioids
• Hamilton Depression Scale (Ham‐D)– ES=0.38 (95% CI: 0.18‐0.58)– Heterogeneity significant (p<0.02)
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Management of Depression and SUD
(Nunes and Levin, 2004)
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Management of Depression and SUD
• 14 placebo‐controlled trials of antidepressant medications– DSM diagnosed patients with depression– Alcohol, cocaine, opioids
• Hamilton Depression Scale (Ham‐D)– ES=0.38 (95% CI: 0.18‐0.58)– Heterogeneity significant (p<0.02)
• Self‐reported substance use outcome– HamD ES > 0.5: Substance use ES=0.56– HamD ES < 0.5: Substance use ES was around 0
• Remission or abstinence rates were low
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Associations where antidepressant medications was effective versus…not so much?
Medication Effective• Low placebo response• Diagnosis of depression
during abstinence• No structured
psychotherapy given• Tricyclic or other
noradrenergic medications used
Medication Similar to Placebo• High placebo response• Diagnosis during active
substance use• Manual guided
psychotherapy utilized• Serotonin re‐uptake
inhibitor
(Nunes and Levin, 2004)
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Sertraline and Naltrexone for AUD• 170 depressed alcohol‐dependent patients were randomly assigned to
receive 14 weeks of treatment with sertraline (200 mg/day [N=40]), naltrexone (100 mg/day [N=49]), the combination of sertraline plus naltrexone (N=42), or double placebo (N=39) while receiving weekly cognitive‐behavioral therapy.
Pettinati et al., Am J Psychiatry 2010; 167:668–675
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Sertraline and Naltrexone for AUD• 170 depressed alcohol‐dependent patients were randomly assigned to
receive 14 weeks of treatment with sertraline (200 mg/day [N=40]), naltrexone (100 mg/day [N=49]), the combination of sertraline plus naltrexone (N=42), or double placebo (N=39) while receiving weekly cognitive‐behavioral therapy.
Pettinati et al., Am J Psychiatry 2010; 167:668–675
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Management of Depression and SUD
• When to consider pharmacotherapy:– Prior positive responses to antidepressants– Moderate to severe symptom burden:
• PHQ‐9 scores > 10‐14: consider antidepressants• PHQ‐9 scores > 15‐19: antidepressants strongly encouraged• PHQ‐9 scores > 20‐27: antidepressants usually a priority
– Past history of severe depression (hospitalizations, suicidality, protracted disability)
– Significant disturbance of sleep or appetite, or agitation– Co‐morbid condition that may benefit from antidepressants (e.g., chronic
pain)– Relevance of maintenance pharmacotherapy: prior history of recurrences
and/or severity– Patient preference
• Shared decision‐making
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• Serotonin Reuptake Inhibitors (SSRIs): – Fluoxetine, paroxetine, sertraline, citalopram, escitalopram
• Serotonin‐Norepinephrine Reuptake Inhibitors (SNRIs):– Venlafaxine, duloxetine, desvenlafaxine, levomilnacipran*
• Norepinephrine‐Dopamine Reuptake Inhibitor (NDRI):– Bupropion
• Miscellaneous Agents– Mirtazapine– Vilazodone* and vortioxetine*
• Tricyclics (TCAs)– E.g., nortriptyline, amitriptyline, imipramine, clomipramine
* Brand name only
Management of Depression and SUD
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Selecting an antidepressant• Generic SSRIs, SNRIs, bupropion or mirtazapine are
reasonable first line agents.• No evidence for superiority of one agent or class for ‘usual’ outpatient depression.
Clinical considerations• Prior good response/tolerability re‐try same agent• Depression with anxiety and/or irritability SSRI• Severe depression and/or chronic pain SNRI• Prominent weight loss, insomnia mirtazapine• Problems with antidepressant sexual dysfunction bupropion or mirtazapine• Motivated for smoking cessation bupropion• Prior intermittent missed doses fluoxetine
Management of Depression and SUD
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The following agents are relatively less favorable first line agentswhen concerns exist about:
• Cytochrome P450 2D6 inhibition of metabolism of co‐prescribed substrates (e.g., codeine, tamoxifen, TCAs, propranolol):
X fluoxetine, paroxetine, duloxetine, bupropion• Weight gain: Xmirtazapine, paroxetine• Drowsiness: Xmirtazapine, paroxetine, trazodone• Hypotension: X trazodone• Hypertension: X SNRIs• Seizure risk: X bupropion• QTc prolongation: X citalopram, escitalopram• Abrupt discontinuation‐emergent reactions: X paroxetine, SNRIs
Management of Depression and SUD
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Generic name Trade name Manic Mixed Maintenance Depressed
Valproate Depakote x xCarbamezapine ER x xLamotrigine Lamictal
Lithium x x xAripiprazole Abilify x x xZiprasidone Geodon x x xRisperdone Risperdal x xAsenapine Saphris x xQuetiapine Seroquel x x xQuetiapine XR Seroquel XR x xChlorpromazine Thorazine xOlanzapine Zyprexa x x xOlanzapine fluoxetinecomb
Symbyax x
Management of BMD and SUD
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• Lithium– Only mood stabilizer shown to reduce suicide rate– Rate of completed suicide ~15%– Effective in long‐term prophylaxis of both mania and depressive episodes in 70+% of BMD, I patients
– Factors predicting positive response to lithium• Prior long‐term response or family member with good response • Classic pure mania• Family history of BMD• Obsessive features• Mania is followed by depression
Baldessarini R. CNS Spectr 2006;11:465‐71.
Management of BMD and SUD
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• Lithium (cont.)– Side effects
• Weight gain• Increased thirst, increased urination, water retention• Nausea, diarrhea• Tremor• Cognitive dulling (mental sluggishness)• Dermatologic conditions• Hypothyroidism• Birth defects
– Need to follow serum level– Get baseline creatinine and TSH– Lithium‐ start with 300mg BID
• Check level in a week• Titrate up by 300‐600mg at a time• Target level between 0.5‐1.0 meq/L
Management of BMD and SUD
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Other AEDs• Valproate
– Obtain baseline LFTs and CBC with differential– Valproate‐ start with 250mg BID – Check level in a week– Titrate up by 250‐500mg at a time– Target level is between 50‐100 mcg/mL
• Carbamazepine– Effect as a second line agent for mania prophylaxis– Effective for therapy of depression in about 25% of patients – Indicated for rapid cyclers, mixed patients. – More complicated to use because of many drug‐drug interactions
• Lamotrigine– Indication similar to other AEDs
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Other AEDs
• Lamotrigine– Obtain baseline LFTs– Start at 25mg X 2 weeks then
titrate to 25mg BID X 2 weeks then increase by 25mg increments weekly to target dose of at least 100mg BID
– Initial titration should not be faster due to risk of Stevens Johnsons Syndrome/toxic epidermal necrolysis
– Caution with recent or concurrent use of valproate
– If >3 days of doses missed consecutively then need to restart titration from beginning
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Gabapentin
• A 12‐week, double‐blind, placebo‐controlled, randomized dose‐ranging trial of 150 men and women older than 18 years with current alcohol dependence, conducted from 2004 through 2010 at a single‐site, outpatient clinical research facility adjoining a general medical hospital.
• Intervention was using oral gabapentin (dosages of 0 [placebo], 900 mg, or 1800 mg/d) and concomitant manual‐guided counseling.
• Looking at outcome measure rates of complete abstinence and no heavy drinking(coprimary) and changes in mood, sleep, and craving (secondary) over the 12‐week study.
Mason BJ, et al. JAMA Intern Med. 2014;174(1):70‐77.
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Gabapentin
• A 12‐week, double‐blind, placebo‐controlled, randomized dose‐ranging trial of 150 men and women older than 18 years with current alcohol dependence, conducted from 2004 through 2010 at a single‐site, outpatient clinical research facility adjoining a general medical hospital.
• Intervention was using oral gabapentin (dosages of 0 [placebo], 900 mg, or 1800 mg/d) and concomitant manual‐guided counseling.
• Looking at outcome measure rates of complete abstinence and no heavy drinking(coprimary) and changes in mood, sleep, and craving (secondary) over the 12‐week study.
Mason BJ, et al. JAMA Intern Med. 2014;174(1):70‐77.
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Gabapentin
Mason BJ, et al. JAMA Intern Med. 2014;174(1):70‐77.
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Gabapentin
Mason BJ, et al. JAMA Intern Med. 2014;174(1):70‐77.
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Dopamine Antagonists
• Second generation medications:– Risperidone
• Initiated at a dose of 1 to 2 mg once daily or in two divided doses• The usual target dose is 4 to 8 mg/day• Common side effects include hyperprolactinemia, akathisia, sedation, dyspepsia,
nausea, and weight gain
– Aripiprizole• Initiated at dose of 2.5 to 5mg once daily• The usual target dose is 10‐20mg taken once per day• Common side effects include akathisia, headache, nausea, vomiting, constipation,
insomnia
– Quetiapine• Initiated at a dose of 50 to 100 mg once daily or in two divided doses• The usual target dose is 200 to 800 mg taken at bedtime or in two divided doses• Common side effects include headache, dry mouth, constipation, weight gain,
sedation, dizziness, and orthostatic hypotension
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Management of Mood Disorders and SUD
• Behavioral approaches– Integrated group therapy– Cognitive‐behavioral therapy– Motivational enhancement therapy– Contingency management– Mindfulness based strategies
Weiss RD, J Subst Abuse Treat 2004; 27:307‐312.Schmitz J et al. Addict Disord Treat 2002; 1:17‐24.Devido JJ & Weiss RD, Curr Psychiatry Rep. 2012; 14(6): 610–618
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Recent Studies
• Analyzed 2280 adult MDD outpatients using data from STAR*D trial• Compared entry and post‐SSRI treatment QOL, functioning, and
depressive symptoms severity scores between 121 MDD + AUD with 2159 MDD‐no‐AUD subjects
Danovitc I, et al., J Addict Med 2017
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Recent Studies
• The MDD + AUD subjects did not experience worse functioning or worse QOL at entry or exit compared with MDD‐no‐AUD. Functioning and QOL significantly improved in both groups after SSRI treatment using citalopram, with no significant differences between groups.
• The large majority of MDD subjects, regardless of AUD comorbidity, experienced severely impaired scores in functioning and QOL at entry. There were significant improvements in these percentages after treatment; however, a substantial proportion of subjects (ranging from approximately 36% to 55%) still experienced severely impaired scores. There were no statistically significant differences between the 2 groups in proportions of subjects with severely impaired scores after treatment.
• The MDD + AUD and MDD‐no‐AUD subjects were equally likely to achieve remission after SSRI treatment with citalopram.
Danovitc I, et al., J Addict Med 2017
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Recent Studies
• Study involving cocaine‐dependent volunteers randomized to receive sertraline or placebo (N=126) following completion of >2 week drug‐free residential, and recevied weekly cognitive behavioral therapy and three‐times weekly supervised urine tox screening
• Outcome measures:– Relapse (2 consecutive cocaine positive or missing urines)
following residential– Moderators evaluated: treatment, sex, age, race,
depression measures, baseline cocaine urine result, and alcohol dependence diagnosis
Bashiri M, et al., Am J Addict 2017
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Recent Studies
Bashiri M, et al., Am J Addict 2017
• Abstinence rate with sertraline was nearly double that of placebo (34% and 18%)
• Regardless of treatment arm at risk patients were:– Older– Male– Lower HAM‐D scores– Baseline negative cocaine‐negative urines
• Older patients or those with current AUD had higher relapse risk than those without AUD– Treating older or AUD patients with SRT however reduced
cocaine relapse more than placebo
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Summary
• ‘Real’ patients don’t necessarily fit existing studies well• Obtain as detailed history as possible:
– Diagnosis of mood disorder with period of abstinence?– Ensure adequate treatment of mood disorder in those with ‘independent’ disorders
– Ensure asking about and treating craving in all patients, not just those with substance induced disorders
• May need to think of approaching treatment by stage patient may be in: peri‐detox (< 2 weeks), post‐detox (2‐12 weeks), and recovery stages (>12 weeks)
