Treatment Issues In Drug-Dependent Women With Comorbid

Depression

Rajita Sinha, Ph.D.Department Of Psychiatry

Yale University School Of Medicine

Disclosure Statement

I have no significant or other relationship with the manufacturer of any product.

Prevalence of Co-occurring Depression and Drug Use Disorders

Each Disorder Alone

Depression Co-morbidity

Depression 7% – 14% -Opiates 1.5% 54%

Alcohol 10 - 17% 38% - 50%

Cocaine 2 - 3 % 32%

Nicotine 20% 35 - 48%

Depression and Drug Dependence - Sex Differences

Rates of drug dependence are 2:1 for men vs women.

On the other hand, women have higher rates of major depression than men.

Women with depression and anxiety disorders are at a higher risk of developing drug dependence than women without these psychiatric disorders.

Self-Medication Hypothesis—Drug Use to Self-Medication Hypothesis—Drug Use to Cope with Emotional Distress:Cope with Emotional Distress:

Emotional Distress as a Trigger (more common in women)

Drug UseTolerance to drug

THE CYCLE OF DRUG ABUSE

Chasing the HighAvoid Negative

Mood“Craving”

Self-medication; High/

Stimulating Effect

Coming Down – (Crash)/sedative Depressant

Effects;Withdrawal-Related Distress

Depression Alters Rewarding Depression Alters Rewarding Effects of DextroamphetamineEffects of Dextroamphetamine

Source: Tremblay, BSc, Naranjo, C.A., Cardenas, L., Herrmann, N. and Busto, U.E. (2002). Probing Brain Reward System Function in Major Depressive Disorder. Archives of General Psychiatry, 59; p.412

Sex Differences in Effects of Trauma Exposure

Early life stress, particularly childhood sexual abuse, is more common in women than men.

Childhood abuse increases risk of psychiatric illness in women, more so than men.

While rates of trauma are similar for men and women, women are 2-3 times more likely to develop PTSD as compared to men.

Higher rates of anxiety disorders in women may also play a role in their higher risk of depression.

Clinical Symptoms of Depression

MDD Symptoms:

Sad/depressed mood for a 2-week periodLoss of interest in natural rewardsSleep/eating problemsAttention/concentration problemsIrritability/restlessness Loss of energyWorthlessness feelings

Drug Related Mood Symptoms:

Irritability/restlessnessDepressed moodEating/Sleep difficultiesHigh drug cravingLoss of interest in natural rewardsAttention/concentration problemsproblems

Altered Neurobiology in Depression and During Drug Withdrawal

Adapted from Markou, A., Kosten, T., & Koob, G. (1998). Neuropsychopharmacology; 18(3), p.141.

Depression and Withdrawal from a Variety of Drugs of Abuse Are Depression and Withdrawal from a Variety of Drugs of Abuse Are Associated with Altered Function in Several Neurotransmitter SystemsAssociated with Altered Function in Several Neurotransmitter Systems

5-HT5-HT NENE AchAch DADA GABAGABA CRFCRF NPYNPY SSSS OpioidsOpioids

DepressionDepression

Drug withdrawalDrug withdrawal

PsychostimulantsPsychostimulants

OpiatesOpiates

EthanolEthanol

NicotineNicotine

BenzodiazapinesBenzodiazapines

or

Depression – Drug Dependence Link in Women

We have hypothesized that in women, presence of psychiatric disorders and the motivation to cope with distress through drugs increases the risk of developing drug addiction.

This increased risk may be associated with changes in stress circuits possibly linked to pre-existing psychopathology that results in an altered subjective response to drugs of abuse.

These changes in brain stress circuits continue to play a role in mediating the association between emotional distress and drug relapse in women.

Source: Sinha R, Rounsaville BJ (2002). J of Clinical Psychiatry, 63, 616-627

Depression Scores Predicts of Drug Abstinence Status (N=827)

Variable OR 95% CI p-value

Depression Scores at Treatment Entry

(BDI)

0.965 0.949 – 0.982

0.0001

Controlling for other variables that significantly predict abstinence:

•Length of Stay•Age•Race•Insurance Status•Frequency of Drug Use at Admission• Alcohol use

SOURCE: Sinha, R., Dodge R (under review). Depression Symptoms Predicts Drug Abstinence Outcome. Psychiatric Services

Social Burden/Support Factors Affecting Drug Abusing Women

Substance abusing women as compared to substance abusing men are:

More likely to live with a drug abusing conjugal partner. More likely to be introduced to drugs by a male partner.More likely to have the sole responsibility of children/minors. More likely to face the negative effects of the social stigma attached to substance abuse.

Sex Differences in Stress Responses

Sex differences in the HPA response to stress has been noted in numerous animal studies. In humans, women show a greater subjective response to stress but lower physiological and HPA response as compared to men. These responses vary by phase of the menstrual cycle and a greater stress response in the luteal phase of the cycle has been reported. Abnormalities in the stress response have been associated with PTSD, depression and early trauma, illnesses that are more common in women.

Laboratory Model of Stress and Stress-Induced Drug Craving

Using a guided imagery based method of stress induction, we’ve found that brief exposure to personal stress and to drug cues when compared to neutral relaxing imagery in drug dependent individuals resulted in:

Increases in cocaine craving and anxiety,Increases in heart rate and blood pressure,Increases in hypothalamic pituitary adrenal axis measures such as cortisol, ACTH and prolactin levels.Increases peripheral catecholamine responses.

Published previously Sinha et al., Psychopharmacology, 1999; 2000; 2003.

Craving Scale, Change Score from B (N=54)

Time Point (min.)

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-5 0 +5 +15 +30 +45 +60

0

1

2

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4 Stress conditionDrug Cue conditionNeutral condition

Main Effect Condition: F(2, 901) = 82.3, Adj. p < 0.0001 [ DC > S > N] Time point: F(5, 901) = 29.7, Adj. p < 0.0001

Anxiety Scale, Change Score from B (N=54)

Time Point (min.)

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0

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-5 0 +5 +15 +30 +45 +60

Stress conditionDrug Cue conditionNeutral condition

Main Effect Condition: F(2, 901) = 48.5, Adj. p < 0.0001 [ S > DC > N ] Time point: F(5, 901) = 20.2, Adj. p < 0.0001

Main Effects Condition: F(2, 828) = 20.4, Adj. p < 0.0001 [ S > DC > N ] Time Point : F(5, 828) = 7.9, Adj. p < 0.0001

Cortisol Plasma Levels, % Change from Baseline (N=52)

Time Point (min.)

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-30%

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0%

-5 0 +15 +30 +45 +60 +75

Stress conditionDrug Cue conditionNeutral condition

Norepinephrine Plasma Levels, % Change from B (N=42)

Time Point (min.)

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-10%

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-5 0 +15 +30 +45 +60 +75

Stress conditionDrug Cue conditionNeutral condition

Main Effect of Condition: F(2, 663) = 4.9, p < 0.01 [ S > N & DC > N]

Relapse Rates after Inpatient Treatment

Follow-up rates were 92%, i.e. 49 of 54 subjects successfully completed the 90-day follow-up interview.

34 or 65% of subjects had relapsed to cocaine use after inpatient cocaine treatment.

No sex differences in rates of relapse were observed.

e) Cortisol Plasma Levels: No Relapse

Time Point (min.)

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-30%

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-5 0 +15 +30 +45 +60 +75

f) Cortisol Plasma Levels: Relapse

Time Point (min.)

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-30%

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-5 0 +15 +30 +45 +60 +75

Relapse Group X Condition: F{2,726} =7.5, p<.0006Relapse Group X Condition: F{2,726} =7.5, p<.0006

No Relapse: D > S (p<.05); D > N (p<.001)No Relapse: D > S (p<.05); D > N (p<.001) Relapse: S > D (p<.0001); S > N (p<.0001)Relapse: S > D (p<.0001); S > N (p<.0001)

Stress:Stress: Drug Cues: Drug Cues: Neutral: Neutral:

a) Norepinephrine Plasma Levels: No Relapse

Time Point (min.)

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-15%

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0%

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-5 0 +15 +30 +45 +60 +75

b) Norepinephrine Plasma Levels: Relapse

Time Point (min.)

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-15%

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0%

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25%

-5 0 +15 +30 +45 +60 +75

Relapse Group X Imagery Condition: F {2,595}=5.6, p<.004Relapse Group X Imagery Condition: F {2,595}=5.6, p<.004

No Relapse: D > S (p<.02), D>N (p<.06)No Relapse: D > S (p<.02), D>N (p<.06) Relapse: S > D (p<.02); S > N (p<.002)Relapse: S > D (p<.02); S > N (p<.002)

Stress:Stress: Drug Cues: Drug Cues: Neutral: Neutral:

c) Epinephrine Plasma Levels: No Relapse

Time Point (min.)

Me

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-5 0 +15 +30 +45 +60 +75

-15%

-5%

5%

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35%

45%

55%

65%

d) Epinephrine Plasma Levels: Relapse

Time Point (min.)

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-5 0 +15 +30 +45 +60 +75

-15%

-5%

5%

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25%

35%

45%

55%

65%

No Relapse: No Differences between conditionsNo Relapse: No Differences between conditions Relapse: S > N (p<.001; S > D (p<.0001)Relapse: S > N (p<.001; S > D (p<.0001)

Relapse Group X Condition: F{2,551}=10.4, p<.0001Relapse Group X Condition: F{2,551}=10.4, p<.0001

Stress:Stress: Drug Cues: Drug Cues: Neutral: Neutral:

Sex Differences in Association Between Stress Response and

Cocaine Relapse

In contrast to men, women showed a significant positive association between stress response, as measured by cortisol and NE and time to cocaine relapse.

Furthermore, women who relapsed had greater cortisol and NE reactivity as compared to women who did not relapse and to men.

N (relapse)

Hazard Ratio

Sex Risk Factor

Sex x Risk Factor

Stress

Cortisol Reactivity 45 (28) 2.93* 1.01 5.08*

NE Reactivity 36 (23) 0.64 1.20 5.08*

EPI Reactivity 33 (20) 0.92 1.29 0.46

Drug Cues

Cortisol Reactivity 46 (28) 1.56 0.95 11.5*

NE Reactivity 38 (24) 0.69 0.66 19.5*

EPI Reactivity 34 (20) 1.08 0.89 0.92

* p<0.05

Sex Differences in Association Between Stress and Drug Cue Responses and Time to Cocaine Relapse

Pharmacological Treatment Issues

Evidence suggests that SSRIs and TCAs are of benefit in improving mood symptoms in drug dependent individuals with primary depression (data from cocaine, opiate, and alcohol dependent samples).

Women are significantly underrepresented in these studies, so gender-specific efficacy has been difficult to obtain.

It would be important to directly assess whether depressive symptoms and stress-associated responses are altered/normalized with SSRIs or TCAs in drug dependent women.

Psychosocial Treatment Issues

Cognitive Behavioral Approaches have shown efficacy in addressing mood related symptoms in drug dependent individuals:

Mood Management Training: Includes specific sessions to address dysphoric mood and negative affect. Seeking Safety: A new cognitive behavioral treatment for women with PTSD. It may be particularly useful for women with comorbid depression and PTSD/anxiety symptoms.Dialectical behavior Therapy (DBT) for Substance Abuse: Shown to be effective for substance abusing women with borderline personality disorder, majority of who have MDD.

Mood Management Modules

Cognitive Behavioral sessions that target mood and negative affect and their influence on drug use behaviors (Hall et al., 1994). It includes the following interventions:

Daily monitoring of mood, negative thoughts, and drug use behaviors.Relationship between mood, negative thoughts, and drug use behaviors are discussed (functional chain analysis). Develop ways to increase pleasant non-drug related activities.Relaxation training, communication, and assertiveness training.Coaching on applying skills to high-risk situations.

Seeking Safety (Najavits et al. 1998)

Cognitive behavioral group psychotherapy for 24 sessions. Safety is the highest priority. In addition coping skills to address the following themes are taught:

Asking for help

Setting boundaries

Self - nurturing skills

Fighting triggers

HIV risk

DBT for Substance Abuse (Linehan et al. 1998)

Cognitive behavioral approach that focuses on emotion dysregulation as a construct that influences drug use behaviors (Linehan et al., 1998). Interventions include:

Daily monitoring of emotions, other triggers, craving, and drug use behaviors.Behavior analysis of feelings, thoughts, urges, and actions. Focus on acceptance and change related skills. Specific skills training on mindfulness, distress tolerance, interpersonal effectiveness, and emotion regulation. Specific emphasis on skills coaching for skills generalizability to day-to-day life situations.

Future Directions

Pharmacological treatment studies addressing co-morbid disorders in drug dependence need to recruit adequate numbers of women to address gender-based hypotheses.

Clinical research on mechanisms underlying specific addiction treatments should address gender factors linking depression and drug abuse.

Gender related treatment differences in addiction have been found but we do not understand the underlying mechanisms for these differences.

Acknowledgements

Collaborators:

Robert Malison, MD

Ned Cooney, PhD

George Anderson, PhD

Mary Jeanne Kreek, MD (Rockefeller University)

Paul Maciejewski, Ph.D.

Carolyn Mazure, Ph.D.

Bruce Rounsaville, M.D.

Thomas Kosten, M.D.Thomas Kosten, M.D.

Acknowledgements

This research was supported by the NIH Office of Research on Women's Health and the National Institute on Drug Abuse.

Support was also provided by the following NIH grants: R01-DA11077, P50-DA16556 and M01-RR00125 to Yale, and P60-DA05130 to the Laboratory on the Biology of Addictive Diseases at Rockefeller University.