1. Psychopharmacology and Psychiatric Disorders Pharmacology basics Psychiatric disorders –Their etiologies –The molecular action of therapeutic drugs

2. Psychopharmacology The treatment of psychiatric disorders through drugs (better living through chemistry). The understanding of the biological origins of most psychiatric illnesses has been driven by the pharmacology.

3. Pharmacology Basics Drugs have several names: –Chemical name Ex. 7-chloro-1,3-dihydro-1-methyl-5- phenyl-2H-1,3-benzodiazepin-2-one –Generic name Ex. diazapam (non-capitalized) By type: -pam (benzodiazapine), -al (barbituate), -caine (local anesthetics) –Trade or brand name Ex. Valium (capitalized)

4. Pharmacology Basics Kinetics –Metabolism The breakdown of a drug, by liver or other means. Some metabolites are as or more active than the original drug. Some genetic variability in drug metabolism. (cytochrome enzymes, e.g. CYP450 1A2) –Elimination Removal of the drug by the kidneys.

5. Pharmacology Basics Kinetics –Half-life Time required to eliminate half of the maximum concentration of drug in the blood. Long half-lives require infrequent dosing, and blood levels remain relatively more constant. Short half-lives require frequent dosing, or time- release dosing. Blood levels vary significantly.

6. Pharmacology Basics

7. Drug actions –Alter availability of neurotransmitter Alter availability of precursor Alter enzymatic processes on precursor Alter neurotransmitter synthesis –Alter release of neurotransmitter –Block reuptake of neurotransmitter –Alter autoregulation

8. Pharmacology Basics Drug actions –Alter synaptic neurotransmitter Enhance or inhibit enzymatic activity which breaks down the neurotransmitter in the synapse. –Alter postsynaptic receptors Upregulation/Downregulation – more receptors synthesized/destroyed. Typically takes 2-3 weeks, hence therapeutic delays.

10. Psychiatric Disorders Diathesis-Stress model Widely held belief that psychological disorders are caused by the interaction of: 1.A genetic propensity or predisposition (diathesis) 2.Environmental triggers (stress)

11. Psychiatric Disorders All have some biological underpinnings Neurotransmitter anomalies Polygenetic –Multiple propensity and protection factors More infectious causes constantly being found –Some autoimmune involvement –Rubella, HSV1, etc. tied to schizophrenia –Streptococcus associated with some OCD cases –HIV known to cause cognitive impairments

12. Psychiatric Disorders 3 Major classes of disorders: –Anxiety disorders –Affective disorders –Schizophrenia often comorbid

13. Anxiety/Affective Disorders

14. They are often comorbid. They share some pharmacology. They both activate the SNS and HPA axis. Current interpretation is moving towards a shared etiology.

15. Anxiety Disorders Chronic fears that persist in the absence of any direct threat. Can include physiological responses to the imaginary fears. Most prevalent of psychiatric disorders. Most easily treated with therapy.

16. Anxiety Disorders Five major classes: –Generalized anxiety disorders No obvious cause –Phobic anxiety disorders Specific fear –Panic disorders Rapid onset of extreme fear and anxiety –Obsessive-compulsive disorders Recurring, uncontrollable thoughts or actions –Post-Traumatic Stress Disorder (PTSD)

17. Anxiety Disorders Symptoms identical to stress: –SNS activation, increased cortisol and adrenaline (“fight”). –Avoidance (“flight”). –Hypervigilance Produce a variety of physiological stress reactions: –Tachycardia, hypertension, nausea, sleep disturbances, etc. Amygdala HPA Senses Cortisol Epinephrine

18. Anxiety Disorders Stress response is mediated by the HPA axis (hypothalamus, pituitary, adrenal glands) Increased amygdala activation increases the stress response. Increasing hippocampus activation decreases it. AmygdalaHippocampus HPA Cortisol - + + Senses

19. Anxiety Disorders The cortex can cause or inhibit fears. Inhibition is learned. High density of GABA receptors in amygdala. 5-HT increases hippocampal suppression of HPA. AmygdalaHippocampus HPA Cortisol Therap y Fear s + - - * 5-HT ↑ GCRs * Excessive cortisol kills GCRs + Therapy = learned compensatory/ inhibitory process 5-HT Senses +

20. Anxiety Disorders Etiology –Because of the effective drugs, GABA A and serotonin are both implicated. Both inhibit anxious behaviors. –Amygdala (high concentration of GABA A receptors) seems to be involved, as would be expected for a “fear” response. –Anxious persons have too little inhibition. –Anxiolytics increase inhibition.

21. Anxiety Disorders Benzodiazapines bind to GABA receptors. Radioactive benzodiazapine uptake sites. NormalAnxious

22. Anxiety Disorders Pharmacology –GABA A agonists Benzodiazapines (Valium, Xanax, etc.) Increase Cl - flow thru GABA A receptors and immediately increase inhibition. Ataxia, muscle relaxation, sedation side effects. –Serotonin agonists Buspirone (Buspar) selectively blocks 5HT 1A receptors – anxiolytic w/o side effects. Up- or down-regulation – takes weeks.

23. Anxiety Disorders Pharmacology –GABA agonists diazepam (Valium) alprazolam (Xanax). lorazepam (Ativan) oxazepam (Serax) chlordiazepoxide (Librium) clorazepate (Tranxene) –SSRIs buspirone (Buspar) paroxetine (Paxil) –[CRH antagonists]

24. Anxiety Disorders Obsessive-Compulsive Disorder –Swedo (1989) identified a link between OCD and Sydenham’s chorea, a basal ganglia disorder that often follows streptococcal infections. –Certain streptococcal infections cause an autoimmune response which attacks the basal ganglia in susceptible patients. –PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections)

25. Affective Disorders

26. Depression (unipolar) –Reactive or endogenous –6% incidence, F = 2xM (non-western cultures higher) –MZ: 60%, DZ: 15% reared together or apart Mania (bipolar) –Bipolar I: manic-depressive –Bipolar II: hypomanic-depressive –1% incidence, F = M –MZ: 80%, DZ: 16%

27. Affective Disorders Course –Chronic Relation to stress –Brown (1993) found: 84% of patients seeking help for depression had a severe stressor in the last year compared to 32% of controls. –Early life stress is hypothesized to contribute to adult depression, but proof is difficult.

28. Affective Disorders Depression pharmacology –Iproniazid, 1 st commercial antidepressant was developed for TB, but improved patient moods. –Tested on mixed psychiatric patients, it was found effective against depression. –Iproniazid is a monoamine oxidase inhibitor – it keeps monoamine oxidase from breaking down monoamines.

29. Affective Disorders Etiology –Monoamine theory of affective disorders: Excess monoamines (D, NE, 5-HT) cause mania. Monoamine depletion causes depression. Many receptor types involved. Dopamine (tyrosine) Serotonin (tryptophan)

30. Affective Disorders

31. Monoamine oxidase inhibitors (MAOIs) –Inhibit monoamine oxidases, which normally break down monoamines, allowing more monoamine to remain in the synapse. –The postsynaptic neuron downregulates. –Dietary restrictions (“cheese effect”) required to prevent severe hypertension problems. Dietary monoamines build up and cause hypertension.

32. Affective Disorders Major classes of affective pharmacology –Monoamine oxidase inhibitors (MAOIs) –Tricyclic & tetracyclic antidepressants (TCAs) –Selective serotonin reuptake inhibitors (SSRIs) –Others

33. Affective Disorders Tricyclic antidepressants –Named for their 3 ringed structures (tetracyclic = 4 rings). –Nonspecifically blocks reuptake of serotonin and norepinephrine. –Since neurotransmitter cannot be reuptaken, more remains in the synapse. –Downregulation also occurs. –Safer than MAOIs.

34. Affective Disorders Selective serotonin reuptake inhibitors (SSRIs) –Only block serotonin reuptake. –Leaves more serotonin in synapse. –Various SSRIs affect different serotonin receptors (at least 16 known!). Selective norepinephrine reuptake inhibitors –NE and 5-HT have reciprocal control pathways. –Same idea, but only block NE reuptake. –Can be as effective as SSRIs.

35. Affective Disorders MAOIs –iproniazid (), phenelzine (Nardil) and tranylcypromine (Parnate). Tricyclics –amitriptyline (Elavil), imipramine (Tofranil), desipramine (Norpramin), doxepin (Sinequan), clomipramine (Anafranil), nortriptyline (Pamelor). Tetracyclic –maprotiline (Ludiomil) SSRIs –fluoxetine (Prozac), paroxetine (Paxil) and sertraline (Zoloft) Other –trazodone (Desyrel), nefazodone (Serzone), bupropion (Wellbutrin)

36. Bipolar Disorder 1. Mania (I) or hypomania (II) (key factor) –Loss of inhibition, cognition, rational thinking. 2. Major depression –No depressive episodes required for diagnosis! Often comorbid with psychotic features. Perhaps a different mechanism than normal depression – like negative schizophrenia symptoms.

37. Bipolar Disorder Pharmacology –Lithium No effect in 1/3 of the population. Action unknown –Agonizes 5-HT system –Possibly modulates inositol-type second messenger systems. Low therapeutic index, caution required. –(therapeutic index = lethal dose / effective dose)

38. Bipolar Disorder Pharmacology –Anticonvulsants Seizures have (temporary) antidepressive effects. Course of bipolar disorder mimics epilepsy. Sometimes work when lithium doesn’t. valproate (Depakote) carbamazapine (Tegretol) oxcarbazapine (Trileptal) topiramate (Topamax) risperidone (Risperidal)

39. Schizophrenia

40. “Split mind” - breakdown of integration between emotion, thought and action – “going mad.” Incidence –1% of general population No race, sex or cultural differences. –MZ: 48%, DZ: 17%, Family 10%, GP 1% Course –Symptoms appear in adolescence or early adulthood (somewhat later in females). –Chronic, with possible remissions.

41. Schizophrenia Subtypes include paranoid (most treatable), disorganized, catatonic and residual types. Two classes of symptoms: –Positive Symptoms Abnormal behaviors and thoughts – delusions, hallucinations, disorganization. –Negative Symptoms Lack of appropriate responses – reduced motivation, decreased affect, etc.

42. Physical changes noted –Abnormally small cortex –Abnormally large ventricles –Prefrontal cortex, amygdala abnormalities –Smaller hippocampus –No ongoing deterioration –Abnormalities seem to be in place before symptoms (i.e. seems to be a developmental disorder).

43. Schizophrenia Relation to maternal factors –Prenatal stresses increase risk. –Rh incompatibility (Hollister, Laing and Mednick (1996) Incompatible Rh factor increases risk in males. Late male birth order increases risk in males. –Maternal stress Quebec Ice Storm of 1998 -> brain differences (King, LaPlant, Joober (2005) Dutch Winter Famine (1944-1945) (Hoek, etc.) Chinese famine of 1959-1961 (St. Clair, et al, 2005)

44. Schizophrenia Relation to infections –Late winter babies have a higher incidence rate Assumed to be from autumn (2 nd trimester) infection –Brown, et al. prospectively collected blood serum samples from mothers during 1959-1967 and tracked their offspring. (2002) 2 nd semester in utero rubella and respiratory infections are significantly linked to schizophrenic offspring. (2004) found elevated 2 nd trimester IL-8 levels in mothers of those who later developed schizophrenia.

45. Schizophrenia Relation to stress –Several studies have found: 1.Exposure to severe stress is common before onset. 2.Symptom severity is proportional to stress severity. 3.Maternal stress exposure may be correlated. –Susceptibility seems to be strongly genetic, but environmental factors, especially stress, can trigger disorder in susceptible individuals.

46. Schizophrenia Pharmacology –1950 Dr. Henri Laborit used the new antihistamine, chlorpromazine (Thorazine), to prevent surgical shock, and found it lessened surgical anxiety. It was tried on various mental patients and was found to be effective with schizophrenics. –An American psychiatrist got interested in the traditional Indian snakeroot treatment and confirmed the anti-psychotic effects of reserpine, the active agent in snakeroot.

47. Schizophrenia Pharmacology –Chlorpromazine and reserpine Dissimilar chemical structures 2-3 week period before effective Comorbid Parkinson-like effects –Parkinson’s research, ca. 1960 Found depleted dopamine in striatum –Amphetamines & cocaine, which cause psychotic effects, both elevate dopamine levels.

48. Schizophrenia Dopamine (primary) theory of schizophrenia Positive symptoms –Increased dopamine in mesolimbic pathway (D 2 ) is responsible for positive symptoms. Phenothiazines (incl. chlorpromazine): Bind to and block both D 1 and D 2 receptors. Reserpine: Destroys monoamine vesicles. Seeman (1976) anti-psychotic effects proportional to dopamine receptor D 2 affinity. Butyrophenones (haloperidol) bind only to D 2.

50. Schizophrenia Negative symptoms –Decreased dopamine in mesocortical pathway causes negative symptoms (few D 2 receptors in PFC). –Structural pathologies thought to be responsible (also related to bipolar/autism). –BDNF, dysbindin, etc. abnormalities during development lead to oddly wired brains. –Cell bodies are smaller. –Nerve connections are not normal.

51. Schizophrenia Glutamate theory of schizophrenia –Phenylcyclidine (PCP), originally an anesthetic, is hallucinogenic, but affects glutamate, not dopamine, receptors. –This lead to a glutamate theory of schizophrenia, with diminished NMDA receptor activation. –NMDA-receptor knockout mouse experiments confirm schizophrenia-like symptoms including altered social interactions and repetitive movements. Both conventional and atypical antipsychotics restore normal behavior.

52. Schizophrenia Mesocortical D system in prefrontal cortex normally inhibits (via glutamate) the mesolimbic D system in brainstem. Deficient D in mesocortical system causes negative symptoms. Excess D release in the mesolimbic areas from under- inhibition cause the positive symptoms.

53. Schizophrenia Pharmacology –chlorpromazine (Thorazine, Ormazine, Largactil) –trifluoperazine (Stelazine) –pimozide (Orap) –flupenthixol (Fluanxol) –thioidazine (Mellaril) –mesoridazine (Serentil) –haloperidol (Haldol) –clozapine (Clozaril) –risperidone (Risperidal) –olanzapine (Zyprexa) –quetiapine (Seroquel) –ziprosidone (Geodon)