Carlos A. Zarate, Jr., M.D

Transcription

1 Performing valid analysis in sex differences and treatment response in depression vs. Multi-modal imaging and psychiatric stress testing: A strategy for translational psychopharmacology in mood disorders Carlos A. Zarate, Jr., M.D Experimental Therapeutics, Mood and Anxiety Disorders Program, Intramural Research Program National Institute of Mental Health

2 Complex behaviors require analysis of multiple possible interactions Biological differences women and men Compared to men, women have higher rates of comorbid depression and anxiety disorders The lifetime odds ration of having 3 comorbid disorders was 1.24 for women vs. men Atypical depression, anxious depression, and somatic depression is more common in women than in men Halbreich & Kahn J Affect Disord 2007

3 Very little has been reported on sex differences and treatment response to antidepressants. Why? Sex-linked genetic trait that has an influence of treatment response Dose? there is a large difference in the weights of males and females, on a mg/kg basis, there would be differences in dose. Pharmacokinetics? Differences in medicine absorption, distribution, metabolism, or excretion based on gender Drug interactions? women of child bearing potential are required contraception, oral contraceptives (3A4 substrate) could affect study medications Peri-menopause, menopause? Menstrual cycle

4 Sex and treatment response in depression It has been previous suggested that SSRI is under genetic control, and two polymorphisms in the serotonin transporter gene (SLC6A4) have been proposed as possible factors that explain the observed differences in clinical response Patients with the 5-HTTLPR s-allele had a non-significantly increased risk of SSRI nonresponse; odds ratio (OR) HTTLPR effects were strongest in female patients (OR 3.54) compared to males (OR 0.29) The overall effect of 5-HTTLPR on treatment outcome, if any, seems to be small and it is questionable whether this effect would be relevant in clinical practice Smits et al. Psychiatric Genetics 2008

5 STAR*D: Treatment outcomes to an SSRI by sex in major depressive disorder disorder Outcome Sex Adjusted a HRSD17 Remission Men N =1043 (36.3%) Women N =1833 (63.7%) Total N =2876 P value We need ~3000 depressed patients to show a 5% difference in sex!!! Young et al. J Psychiatric Res 2009

6 Towards an endophenotype strategy in mood disorders HD-EEG Melancholic vs. atypical N-back Specific cognitive Deficits (spatial memory) Anxious vs Non-anxious Fearful faces Slow Wave Activity Anterior Cingulate Activity BDNF MEG Response??

7 Ketamine Non-barbiturate, rapid-acting disassociate anesthetic at induction doses of 1-3 mg/kg Non-competitive NMDA receptor antagonist Psychotomimetic properties (5-20%) Abused as club drug Studied in: schizophrenia, cognition, alcoholism, chronic pain syndrome, and neuroprotection Peak plasma concentrations occur within 1 min following IV administration Elimination t1/2 = 2 hr; norket t1/2 = 4 hr Placebo Placebo Drug Free Period 2 weeks Ketamine 1 week Ketamine i.v. (0.5 mg/kg over 40 min) Ketamine Ratings: min: 0, 40, 80, 110, 230; Days: 1,2,3, 7

8 Robust, rapid & relatively sustained antidepressant effects of low dose ketamine, and response rates to ketamine in a double-blind placebo crossover trial in patients with treatment-resistant major depression Hamilton Depression Rating Scale 30 Infusion * ** ** *** *** *** 5 Infusion Day 1 Day 2 Day 3 Day 7 // Time (Minutes) Response: 50% decrease in HAMD from baseline 71% 62-65% 56% 58% 53% 53% 35% 35% 13% 40 m 80 m 110 m 230 m 1 d 3 d 2 d 7 d 8 wks Zarate et al. Arch Gen Psychiatry, 2006 Ketamine Placebo Venlafaxine Bupropion SSRI

9 Activation Studies Implicate Anterior Cingulate in Cognitive & Affective Processing Challenging the system or psychiatric stress testing Bush G, et al. Trends Cogn Sci 2000;4:

10 Experiment 1 (an affective task): rostral ACC activity is positively correlated with AD response to ketamine Experiment 2 (a cognitive task): rostral ACC activity is negatively correlated with AD response to ketamine Rostral ACC pretreatment activity (Emotion) +1 Rostral ACC pretreatment activity (Cognition) MADRS change score (%) L R r=0.68; p<0.05 x=5 - Antidepressant response (% change score) r = -0.80; p,0.01 r = Linear change in ACC activity Salvadore et al., Biol Psychiatry Salvadore et al., Neuropsychopharmacology advance online publication, March 10, 2010

11 High ACC activity in response to emotionally-salient stimuli (in red), but low ACC activity in response to increased cognitive demands (in yellow), predicts antidepressant response to ketamine Salvadore et al., Neuropsychopharmacology advance online publication, March 10, 2010

12 Conclusions Sex matters!!!! But so does age, genetics, trauma, comorbidity, imaging changes, etc. Sex in treatment response in depression has been little studied Neurobiological parameters may be valuable predictors of treatment response, possibly explaining more variation than common subdiagnostic classifications One approach to identifying biomarkers of response is to see which combination of factors explains (including sex) the greatest variance of response---personalized treatment

13 Mark O. Hatfield Clinical Research Center Intramural Research Program/NIMH Nancy DiazGranados Lobna Ibrahim Giacomo Salvadore R. Machado-Vieira Alan Mallinger Nancy Brutsche Wally Duncan Nadia Hejazi Libby Jolkovsky Yamila Carmona Madeline Gupta E Smith-Jackson Rezvan Ameli Sergio Bauza David Latov Jackie Baumann C. Wheeler-Castillo Brenda Phillips David Luckenbaugh Eva Kakoza 7SE staff, OT, VT, RT OP4 7SW sleep lab LMP (Du, Chen, Manji) Section on Neuroimaging Affective Pathophysiology Lab NCF staff Intramural research pgm Office of the Clinical Director/NIMH MEG CORE facility Anesthesia (Quezado, Kammerer) Tononi University Wisconsin NARSAD Patient and their families