Basic Physiology and Neurochemistry of Three Psychiatric Diseases, Including Drug Dependence

1. Basic Physiology and Neurochemistry of Three Psychiatric Diseases, Including Drug Dependence Carlton Erickson, Ph.D. Director, Addiction Science Research and Education Center University of Texas at Austin, USA APIA-Singapore, 2004

2. Brain Disorders That Co-occur with Dependence • ProbablyProbably Not • • PTSD • Alzheimer’s • • ADHD • Parkinson’s • • ASP/Conduct • Tourette’s • • Eating Disorders • • Aggression Compare today: • • Mood disorders • depression • • Schizophrenia? • OCD

3. Common Abbreviations • BZ - benzodiazepine (tranquilizer) • CD - chemical dependence • DA - dopamine • DAT - dopamine transporter • GAD - generalized anxiety disorder • MAO(I) - monamine oxidase (inhibitor) • MFB - medial forebrain bundle MH - mental health • NT - neurotransmitter • OCD - obsessive-compulsive disorder • SRI - serotonin reuptake inhibitor • TCA - tricyclic antidepressant • WNL - within normal limits

4. Research Validity Estimate (RVE) (A Thoughtful Appraisal of High-Quality Scientific Research) High RVE • many large, well-controlled studies • replicable results • much peer-reviewed, published literature Low RVE • few replicable studies • highly speculative results • little peer-reviewed, published literature 100 - 0

5. Neurophysiology 101 (….made simple)

7. Drug Receptors 70

8. Major Chemical Messengers of the “Mind” • • Acetylcholine (ACh) • • Dopamine (DA) • • Serotonin (SER) • • Gamma aminobutyric acid (GABA) • • Endorphins (END) • • Glutamate (GLU)

9. Neurophysiology and Function • Neurotransmitters (NTs): • • allow nerve cells to talk to one another and to other tissues. • • function can be disrupted by disease and by drugs. • • allow normal behaviors, emotions, and cognition, when WNL.

10. Neurophysiology and Function (cont) • Receptors: • • are the “binding sites” for NT in the brain. • • when activated, cause nerve cells to be excited or inhibited. • • can be dysfunctional in brain disease states.

11. NT Receptor Subtypes • • ACh: nicotinic and muscarinic • • DA: 5 different subtypes • • SER: 16 different subtypes • • GABA: 3 different subtypes • • END: 5 different opiate Rs • • GLU: 16 different subtypes 80

12. Neurochemistry and Brain Areas • • Depression - (SER, NE, DA) in limbic system • • OCD - (SER) in orbitofrontal cortex, cingulate cortex, caudate nucleus • • CD - (DA, SER, END, GABA, GLU, ACh functional dysregulation) in mesolimbic dopamine system 60

13. Neurotransmitter (NT) involvement in brain illness is inferred from observed effects of therapeutic drugs on the illness, plus indirect NT measurements.

14. For example…. • • Anti-depressant drugs such as Prozac increase brain SER function in animal studies. • • It is inferred that decreased brain SER function is one of the causes of depression in humans. • • Indirect evidence supports this. 50

16. Brain Area Functions • • cerebral cortex* - intelligence, judgment, and inhibitory control • • prefrontal cortex* - planning and reasoning, decision-making • • hippocampus* - cognitive learning and memory • • amygdala* - emotional memory • * involved in the limbic system 70

17. Brain Area Functions (cont) • • basal ganglia* - reaction time, fine motor control • • nucleus accumbens* - compulsions, locomotor activity • • thalamus* - way station for incoming • sensory signals • • hypothalamus* - instinctive and appetitive systems • • brainstem - alerting, stimulus • filtering, sleep, autonomic control • * involved in the limbic system 70

18. Psychotherapy • • drug therapy is often necessary to access psychotherapy • • drug therapy sets baseline; psychotherapy fine-tunes • • psychotherapy can help get at the primary cause of the disorder, drugs cannot 40

19. Brain Disease #1 Mood Disorders (ex: Depression)

20. Major Depressive Disorders • • a.k.a. “affective” or “mood disorders” • • Types: mild, moderate, severe w/o • psychotic features, severe with • psychotic features, in partial remission, in full remission, chronic, with postpartum onset, with melancholic features, etc.

21. Clinical Features of Depression • • excess sadness in response to loss, failure, or disappointment • • dysphoria: loss of interest and anhedonia • • loss of appetite, sleep disorders, crying, fatigue, loss of ambition • • 7-15% commit suicide

22. Dysthymic Disorder • * a.k.a. “depressive neurosis” • • chronically depressed mood most of each day for +2 years • • prevalence is ~ 6% of population • • best treated with tricyclic antidepressants and psychotherapy

23. Therapy of Depression • First choice: SSRIs (e.g. Prozac) - new, few side effects (impotence?) • Second choice: new generation - e.g., Effexor, Remeron, Edronax • Third choice: tricyclics (e.g. desipramine) - many choices, very effective • (Main NT?) 70

24. Therapy of Depression (continued) • Fourth choice: MAO Inhibitors (e.g., Nardil) - major interaction with tyramine-containing foods • Fifth choice: Electroconvulsive shock - in patients who are drug-resistant or who are suicidal 70

25. Some “Off-Label” Uses of Antidepressants • • ADHD • Insomnia • • PTSD • Panic disorder • • Social phobia • Enuresis • • Chronic pain • Anxiety • • Smoking cessation • • Anorexia and bulimia • • Premenstrual dysphoric disorder 25

26. Brain Disease #2 Obsessive-Compulsive Disorder (OCD)

27. Clinical Features of OCD • • obsessions (thinking about things all the time, which causes anxiety or distress) and compulsions (doing things all the time, which tend to neutralize anxiety) • • OCD adults recognize symptoms as excessive or unreasonable

28. Treatment of OCD • • SSRIs - esp. fluoxetine (Prozac), fluvoxamine (Luvox), Zoloft (kids) • • clomipramine (Anafranil) - 4-10 week onset • • behavioral therapy is also useful in some patients 20

29. Brain Disease #3 Chemical Dependence (addiction)

30. Two Critical Definitions* • • abuse - intentional overuse in cases of celebration, anxiety, despair, self-medication, or ignorance. Tends to decline with adverse consequences. • (“a problem to solve”) • • dependence - impaired control over drug use, probably caused by a dysfunction of the medial forebrain bundle, “pleasure pathway” • (“a disease to conquer”) • * Based on the Diagnostic and Statistical Manual-IV (DSM-IV)

31. Neurotransmitters of “Addiction” • • Dopamine (DA) • • Serotonin (SER) • • Endorphins (END) • • Gamma-aminobutyric acid (GABA) • • Glutamate (GLU) • • Acetylcholine (ACh) • (emphasis on dysregulations)

33. A Brain Chemistry Disease! • • addicting drugs seem to “match” the transmitter system that is not normal • • this is not a will power or poor judgment disease (frontal cortex) • • impaired control is caused by brain chemistry malfunction • • abstinence is the first step in the total treatment process, but new studies on reducing drinking are available 70

34. Is Chemical Dependency a Mental Disorder?

35. Impaired Control Problems • • problems with controllingbehavior: Tourette’s pts, schizophrenics, manic pts, OCD pts, addicts • • are the following OCD or addiction? • - pathological gambling • - compulsive shopping • - hypersexual behavior • - overeating • • impulse control disorders?

36. Are Addictions an Obsessive-compulsive Disorder Subtype? • • drug dependence satisfies all DSM OCD criteria • • are all pts in recovery always abstinent of all drugs? • • “addiction, a compulsive disease” Volkow & Fowler, 2000 • • OCD pts and heroin addicts have impairment in prefrontal areas • Papageorgiou et al. 2003 60

37. Today’s Treatment • • 12 step programs (abstinence) • • inpatient/outpatient/aftercare (insurance?) • • new meds to enhance abstinence • • harm reduction, MM, methadone • • brief motivational counseling, CBT, MET, SO-involved therapy, vouchers, vaccines • (MM= Moderation Management, CBT= cognitive behavioral therapy, • MET= motivational enhancement therapy, SO = significant other) 60

38. Final Thoughts • • Brain diseases • - caused by disrupted neurochemistry • - have a significant genetic component • - environment plays a lesser role • - are best treated with pharmacotherapy • - but “talk therapy” is also powerful • and can increase quality of life

39. Remember the Best Academic Website in the World! www.utexas.edu/research/asrec