D R . P A O L A R O S C AH E A D - D E P T . F O R T H E T R E A T M E N T O F

S U B S T A N C E A B U S ED E C E M B E R 1 7 , 2 0 1 2

Manic episodes and drug abuse – diagnosis and

treatment

BIPOLAR DISORDERS AND DRUG ABUSE

Bi-polar spectrum disorders and addiction often co-occur They are reciprocal risk factors Subjects falling in the bipolar spectrum have increased risk

for substance abuse and move towards addiction Frequently misdiagnosed especially in milder forms The use of opioid agonists in heroin addicts with bipolar

disorder has proved to be mood stabilizing and with combined mood stabilizing drugs it reaches best therapeutic effects

Maremmani I,Perugi G,Pacini M,Akiskal HS, J Affect Dis, 2006, 93(1-3):1-12.

Cocaine Abuse and Bipolar Spectrum

Specific relationship between bi-polar disorder and stimulant abuse

It has been assumed that cocaine use is intended to optimize hyperthymia, hypomania, cyclothymia.

It is frequently co-morbid with heroin addiction A study on 1090 heroin addicts in treatment between 1994-

2005, aged 29+-6 , 76% males showed a link between current cocaine abuse and double pathology, with special relevance to the bipolar spectrum, and psychotic disorders

Possible model linking bipolarity and cocaine Sub-threshold bi-polarity seems to predispose to heroin

addiction

Cocaine Abuse and Bipolar Spectrum

Craving for the suppressed hypomania could lead to cocaine abuse

Unmasking of frank bipolar disorder- mixed states, severe mania, and psychotic states

Further research needed

Maremmani I, Pacini M, Perugi G et al, J Affect Dis,2008;106(1-2):55-61.

SUD AND YOUTH ONSET BIPOLAR DISORDER

Co-morbid bipolar disorder and cannabis use is well known among adults

Youth-onset bi-polar disorder confers higher risk of SUD compared with adults

Bipolar disorder precede SUD in 55-83% of cases Opportunity for prevention: screening for SUD in

bipolar youth since the age of 10 Education and family intervention Preventive intervention has been found successful Goldstein BI, Bukstein OG, J Clin Psych, 2010; 71(3):348-58.

ADOLESCENT SUD AND BD

Study conducted on 211 offspring aged 12> with one BD parent

Lifetime SUD in24% offspring Cannabis use the most common Peak hazard of SUD 14-20 years of age Male sex, previous mood disorder, parental history of SUD

contributed to the risk of SUD in the offspring SUD predicted increased risk of psychosis The estimated hazard of a major psychosis in SUD youth

was 3 fold Duffy A, Horrocks J, Milin R et al, J Affect Dis,2012;142(1-

3):57-64.

Clinical outcomes in BD patients with cannabis use

The study compared clinical outcomes and neuro-cognitive functions of BD I patients with and without cannabis use

RETROSPECTIVE STUDY OF A LARGE COHORT-200 PATIENTS

The Cannabis group had more males, and a higher proportion of psychosis

Interestingly they showed better neuro-cognitive performance but poorer prognosis

Braga RG,Burdick KE,Derosse P et al, Psychiatry Res,2012;200(2-3):242-245.

Alcohol and Cannabis use and age of onset of BD

Cannabis use coincided with previous manic or hypo-manic episodes while alcohol with previous depressive episodes

Cannabis use is also associated with the development of manic symptoms and lifetime cannabis use is associated with 5 fold increase in BD.

Patients with alcohol use had a significant later onset of BD and were similar to non-users.

Family history of affective or psychotic disorders was higher in cannabis users

Alcohol and Cannabis use and age of onset of BD

Alcohol users had lower rates of other substances abuse than cannabis users

In cannabis users the use of cannabis generally preceded the onset of BD while in alcohol users the opposite was true.

Early onset of BD is associated with higher risk for cannabis use.

There seems to exist a common genetic pathway for cannabis use and BD.

Lagerberg TV,Sundet K, Aminoff SR et al, 2001; EurArch Psych Clin Neurosci;261(6):397-405.

CANMAT Task Force Recommendations for mood disorders and comorbid substance use

Bipolar disorders are frequently associated with SUDs.

Therapeutic efficacy may differ due to the presence of SUD THE NEED TO PROVIDE GUIDANCE TO CLINICIANS

First choice recommendations were possible only for alcohol,cannabis, and cocaine with bipolar disorder

Psychotherapies were considered an essential component ofthe overall treatment of comorbid SUD and Bipolar Disorder

Beaulieu S, Saury S, Sareen J et al, 2012, Am J ClinPsych;24(1):38-51.

Michael’s Case: Introduction

11

22-year-old man, in good general physical health Presents with a 7-10 day history of decreased need for sleep

(5 hours), restlessness, and difficulty concentrating In office, found to be somewhat agitated, impatient, rude

(unusual for him) No current medications Drinks alcohol socially; occasional THC use Usually gets along well with others, has no history of

impulsivity and has a steady circle of friends. 2 years ago had an episode of depression that lasted for 3

months, with no apparent precipitating event Family history: alcoholic father with history of depression,

impulsivity, grandiosity, and aggression

Scientific Committee. 2010.

What supplemental information would you ask for at this stage?

12

How bad is your sleep? How low has your mood become? Any suicidal ideations? How bad is your concentration/attention? Is your mood variable throughout the day?

Investigate both the depression and the mania Substance abuse – has patient’s THC consumption

increased? Assess functionality Evaluate if they can maintain a relationship Look at environmental stressors Check thyroid

Das AK et al. JAMA. 2005;293(8):956-963.Ebmeier KP. Practitioner. 2010;254(1729):19-22, 12.Scientific Committee. 2010.Yatham LN et al. Bipolar Disord. 2005;7 Suppl 3:5-69.

Diagnostic Challenges

13

Psychotic symptoms are common in bipolar

disorder

58% by clinical evaluation

90% by self-report

More common in mania than in depression

APA. Am J Psychiatry. 2002;159(4 Suppl):1-50.Zarate CA. J Clin Psychiatry. 2000;61 Suppl 8:52-61; discussion 62-53.

Misdiagnosis of Bipolar Disorder

14Hirschfeld RM et al. J Clin Psychiatry. 2003;64(2):161-174.

• Patients were incorrectly diagnosed with:

– Unipolar depression 60%– Anxiety disorders 26%– Schizophrenia 18%– Borderline or antisocial PD 17%– Alcohol abuse/dependence 14%

69%Misdiagnosed

15

Medical Comorbidities of Bipolar Disorder

Parikh SV, et al. Can J Psychiatry. 2010;55(3):33-40.Weiss RD, et al. J Clin Psychiatry. 2005;66(6):730-735; quiz 808-739.

31.9%

0 10 20 30 40 50 60 70

ADHD (n = 1000)Anxiety disorders (n = 1000)

Smoking (n = 1000)Past alcohol abuse (n = 2154)

Prevalence (%)

9.5%

31.2%

32.2%

Current alcohol abuse (n = 2154) 11.8%

Past drug abuse (n = 2154) 21.7%

Current drug abuse (n = 2154) 7.3%

16

• Neuroendocrine abnormalities• Affect on corticotropin-releasing hormone (CRH), cortisol levels, and

glucocorticoid receptor (GR) function

• Cardiovascular disease• Patients display an increase in cardiovascular risk factors (smoking,

diabetes, hypertension, dyslipidemia, and obesity)

• Obesity• 31-36% overweight; 26-34% obese

• Asthma, COPD, emphysema• smoking is prevalent among bipolar patients

• Compromised immune response• Dendritic cells aberrancies and decrease in lymphocytes

• Seizure disorders• Migraine headaches

Medical Comorbidities of Bipolar Disorder

Abeer et al. Egypt J Immunol. 2006;13(1):79-85.Knijff EM et al. Biol Psychiatry. 2006;59(4):317-326.Mula M et al. Expert Rev Neurother. 2010;10(1):13-23.Murray DP et al. Curr Psychiatry Rep. 2009;11(6):475-480.Watson S et al. Br J Psychiatry. 2004;184:496-502.

Obstacles to Management and Treatment

17

• Diagnostic confusion– Patients more likely to seek treatment for depressive than manic

symptoms

• Frequent comorbid substance abuse• Patient denial, fear of stigma, impaired insight• Clinician’s reluctance to use stigmatizing diagnosis• Inconsistent adherence with treatment recommendations• Previous treatment misadventures

Hirschfeld RMA, et al. J Clin Psychiatry. 2001;62 Suppl 14:5-9.Manning JS. Prim Care Companion J Clin Psychiatry. 2002;4(4):142-150.Shah NN, et al. Psychiatr Q. 2004;75(2):183-196.Young RC, et al. Br J Psychiatry. 1978;133:429-435.

PHARMACOLOGICAL TREATMENT

Double pathology including Bipolar Disorder and SUD should be treated with atypical anti-psychotics in the acute manic phase

It is suggested to add a mood-stabilizing agent’ which is also effective in preventing craving for substance abuse.

19

Agents RecoAAAAAmmended for Acute Mania

First-lineTreatment

Lithium, divalproex, olanzapine, risperidone, quetiapine, quetiapine XR, aripiprazole, ziprasidone, lithium or divalproex + risperidone, lithium or divalproex + quetiapine, lithium or divalproex + olanzapine, lithium or divalproex + aripiprazole

Second-lineTreatment

Carbamazepine, electroconvulsive therapy, lithium + divalproex, asenapine*, lithium or divalproex + asenapine, paliperidone mono-therapy

Third-lineTreatment

Haloperidol, chlorpromazine, lithium or divalproex + haloperidol, lithium + carbamazepine, clozapine, oxcarbazepine, tamoxifen

Not Recommended Mono-therapy with gabapentin, topiramate, lamotrigine, verapamil, tiagabine, risperidone + carbamazepine, olanzapine + carbamazepine

Yatham LN et al. Bipolar Disord. 2009;11(3):225-255.

Treatment Algorithm for Acute Mania

20

Start a 1st line agent for mania

Appropriately dose for 2 weeks as an initial trial period

Monitor response

Continue therapy

Adjust dose

Consider switching

Add another agent

Yatham LN et al. Bipolar Disord. 2009;11(3):225-255.

Alphabetical List of Medications by Generic Name

21

Atypical antipsychotics

aripiprazole (Abilify)asenapine (Saphris) clozapine (Clozaril)olanzapine (Zyprexa)paliperidone (Invega)quetiapine (Seroquel)risperidone (Risperdal)ziprasidone (Zeldox)

Generic name (Trade name)

What Additional Issues Should be Considered?

22

Akathisia Inner restlessness associated with an urge to move Risk factors: use of typical vs atypical antipsychotic agents,

rapid dose escalation, higher doses, switching Made worse by increased dose of antipsychotic

Agitation Unpleasant state of extreme arousal, increased tension, and

irritability Made better by increased dose of antipsychotic

Activation Stimulation of neural and symptomatic response

Anxiety Both a psychological and physiological state Characterized by an unpleasant feeling; typically tension,

uneasiness, fear, or worry

Day RK. J Affect Dis. 1999;55(2-3):89-98.Dressler D et al. J Neurol. 2005;252(11):1299-1306.

Taylor D et al. In: The Maudsley Prescribing Guidelines. 2007.

Significance of Weight Gain

23

“…Obesity has become an equal, if not greater, contributor to the burden of

disease than smoking.”Jia H, et al. Am J Prev Med. 2010;38(2):138-44.

Jia H et al. Am J Prev Med. 2010;38(2):138-144.Taylor VH et al. J Affect Disord. 2008;109(1-2):127-131.

Weight change in treatment-naive patients with a mood disorderCanadian

PopulationPatients’Baseline

Patients2 years

Normal (BMI 18< 25)

54.30% 42.40% 30.30%

Overweight(BMI 25 -30)

29.3% 34.90% 41.00%

Obese(BMI < 30)

16.4% 22.70% 28.80%

Metabolic Risk of Atypical Antipsychotics

24

Medication Diabetes Risk Dyslipidemia

Aripiprazole Low No effect

Olanzapine Increased effect Increased effect

Quetiapine Low** Possibly increased

Risperidone Intermediate Intermediate

Ziprasidone* Low Low

Fagiolini A et al. Curr Psychiatry Rep. 2007;9(6):521-528.Newcomer JW. Am J Manag Care. 2007;13(7 Suppl):S170-177.

Yatham LN et al. Bipolar Disord. 2009;11(3):225-255.

** Data suggest that quetiapine, like other atypical antipsychotics such as olanzapine, can cause clinically meaningful increases in insulin resistance, which may lead to new or exacerbated cases of type 2 diabetes.

Extrapyramidal Side Effects

Pseudoparkinsonism

Dystonic reactionsTardive dyskinesia

Taylor D et al.In: The Maudsley Prescribing Guidelines. 2007.

Akathisia

Extrapyramidalside effects

25

Side Effect Profiles

26

EPS Hyperlipidemia Weight Gain

QTc Prolongation

Sexual Dysfunction Sedation

Aripiprazole

Olanzapine

Quetiapine

Risperidone

Ziprasidone*

Harrigan EP et al. J Clin Psychopharmacol. 2004;24(1):62-69.Keck PE et al. J Clin Psychiatry. 2006;67(4):626-637.

Kim B et al. J Affect Disord. 2008;105(1-3):45-52.Miller D et al. J Clin Psychiatry. 2001;62(12):975-980.

Olfson M, et al. Am J Psychiatry. 2006;163(10):1821-1825.Yatham LN et al. Bipolar Disord. 2009;11(3):225-255.

Neutral - Low risk Moderate risk High riskEPS: extrapyramidal side effects

Prolactin-Related Adverse Effects

27Henderson DC et al. J Clin Psychiatry. 2008;69 Suppl 1:32-44.

*

*

28

Evolution of Antipsychotic Medications

Miyamoto S et al. Mol Psychiatry. 2005;10(1):79-104.Shapiro DA et al. Neuropsychopharmacology. 2003;28(8):1400-1411.

First-GenerationAntipsychotics

Dopamine Antagonists

D2 antagonism(High receptor affinity)

Second-Generation Antipsychotics

Dopamine/Serotonin Antagonists

D2 antagonism(Variable receptor affinity)

5-HT2A antagonism(High receptor affinity relative to D2

receptor affinity)

Third-Generation Antipsychotics

Dopamine Partial Agonists

High affinity for D2 receptors

Lower intrinsic activity vs dopamine

5-HT1A partial agonism(Low receptor affinity relative to D2 receptor

affinity)5-HT2A antagonism

(Moderate receptor affinity relative to D2receptor affinity)

chlorpromazinehaloperidol

clozapinerisperidoneolanzapinepaliperidonequetiapineziprasidone

aripiprazole