Treatment Issues In Drug-Dependent Women With Comorbid Depression Rajita Sinha, Ph.D. Department Of Psychiatry Yale University School Of Medicine

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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 Cope with Emotional Distress: Emotional Distress as a Trigger (more common in women) Drug Use Tolerance to drug THE CYCLE OF DRUG ABUSE Chasing the High Avoid Negative Mood “Craving” Self-medication; High/ Stimulating Effect Coming Down – (Crash)/sedative Depressant Effects; Withdrawal-Related Distress

Depression Alters Rewarding Effects of Dextroamphetamine Figure 2. Degree of rewarding effects experienced by participants as measured by the mean peak minus baseline Addiction Research Center Inventory (ARCI) Rewarding Effects Composite score vs severity of major depressive disorder. The P value represents the interaction between severity and drug. The age- and sex-adjusted mean (95% confidence interval) for the dextroamphetamine effect compared with placebo was 156.40 (94.64-218.16) in the severe group, 46.22 (-11.84 to 104.28) in the moderate group, and 55.70 (11.33-100.07) in the control group. The mean Hamilton Rating Scale for Depression (HAM-D) scores for the groups are 1.33 for control-dextroamphetamine, 0.28 for control-placebo, 19.73 for moderate-dextroamphetamine, 18.60 for moderate-placebo, 28.46 for severe-dextroamphetamine, and 27.25 for severe-placebo. Error bars represent SD. 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 period Loss of interest in natural rewards Sleep/eating problems Attention/concentration problems Irritability/restlessness Loss of energy Worthlessness feelings Drug Related Mood Symptoms: Irritability/restlessness Depressed mood Eating/Sleep difficulties High drug craving Loss of interest in natural rewards Attention/concentration problems

Altered Neurobiology in Depression and During Drug Withdrawal Depression and Withdrawal from a Variety of Drugs of Abuse Are Associated with Altered Function in Several Neurotransmitter Systems 5-HT NE Ach DA GABA CRF NPY SS Opioids Depression Drug withdrawal Psychostimulants Opiates Ethanol Nicotine Benzodiazapines or Adapted from Markou, A., Kosten, T., & Koob, G. (1998). Neuropsychopharmacology; 18(3), p.141.

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.

Time point: F(5, 901) = 29.7, Adj. p < 0.0001 Steve Tiffany’s comment: look at content of the scripts and code for affect? For stress and drug cues. 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

Main Effect Condition: F(2, 901) = 48. 5, Adj. p < 0 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

Time Point : F(5, 828) = 7.9, Adj. p < 0.0001 Feedback: given the diurnal drop, do a log co-sine function to represent significant effect in the direction of the effect; i.e. stress with greater response than DC which was greater than neutral. 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

Main Effect of Condition: F(2, 663) = 4. 9, p < 0 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.

Relapse Group X Condition: F{2,726} =7.5, p<.0006 Stress: Drug Cues: Neutral: No Relapse: D > S (p<.05); D > N (p<.001) Relapse: S > D (p<.0001); S > N (p<.0001) Relapse Group X Condition: F{2,726} =7.5, p<.0006

Relapse Group X Imagery Condition: F {2,595}=5.6, p<.004 Stress: Drug Cues: Neutral: No Relapse: D > S (p<.02), D>N (p<.06) Relapse: S > D (p<.02); S > N (p<.002) Relapse Group X Imagery Condition: F {2,595}=5.6, p<.004

Relapse Group X Condition: F{2,551}=10.4, p<.0001 Stress: Drug Cues: Neutral: No Relapse: No Differences between conditions Relapse: S > N (p<.001; S > D (p<.0001) Relapse Group X Condition: F{2,551}=10.4, p<.0001

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.

Sex Differences in Association Between Stress and Drug Cue Responses and Time to Cocaine Relapse 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 EPI Reactivity 33 (20) 0.92 1.29 0.46 Drug Cues 46 (28) 1.56 0.95 11.5* 38 (24) 0.69 0.66 19.5* 34 (20) 1.08 0.89 * p<0.05

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 Paul Maciejewski, Ph.D. Carolyn Mazure, Ph.D. Bruce Rounsaville, M.D. Thomas Kosten, M.D. Collaborators: Robert Malison, MD Ned Cooney, PhD George Anderson, PhD Mary Jeanne Kreek, MD (Rockefeller University)

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.