Psychopharmacology and Psychiatric Disorders Pharmacology basics Psychiatric disorders –Their etiologies –The molecular action of therapeutic drugs.
<ul><li><p>Psychopharmacology and Psychiatric Disorders</p><p>Pharmacology basicsPsychiatric disordersTheir etiologiesThe molecular action of therapeutic drugs</p></li><li><p>PsychopharmacologyThe 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.</p></li><li><p>Pharmacology BasicsDrugs have several names:Chemical nameEx. 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,3-benzodiazepin-2-oneGeneric nameEx. diazapam (non-capitalized)By type: -pam (benzodiazapine), -al (barbituate), -caine (local anesthetics)Trade or brand nameEx. Valium (capitalized)</p></li><li><p>Pharmacology BasicsKineticsMetabolismThe 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)EliminationRemoval of the drug by the kidneys.</p></li><li><p>Pharmacology BasicsKineticsHalf-lifeTime 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.</p></li><li><p>Pharmacology Basics</p></li><li><p>Pharmacology BasicsDrug actionsAlter availability of neurotransmitterAlter availability of precursorAlter enzymatic processes on precursorAlter neurotransmitter synthesisAlter release of neurotransmitterBlock reuptake of neurotransmitterAlter autoregulation</p></li><li><p>Pharmacology BasicsDrug actionsAlter synaptic neurotransmitterEnhance or inhibit enzymatic activity which breaks down the neurotransmitter in the synapse.Alter postsynaptic receptorsUpregulation/Downregulation more receptors synthesized/destroyed.Typically takes 2-3 weeks, hence therapeutic delays.</p></li><li><p>Psychiatric DisordersDiathesis-Stress modelWidely held belief that psychological disorders are caused by the interaction of:A genetic propensity or predisposition (diathesis)Environmental triggers (stress)</p></li><li><p>Psychiatric DisordersAll have some biological underpinningsNeurotransmitter anomaliesPolygeneticMultiple propensity and protection factorsMore infectious causes constantly being foundSome autoimmune involvementRubella, HSV1, etc. tied to schizophreniaStreptococcus associated with some OCD casesHIV known to cause cognitive impairments</p></li><li><p>Psychiatric Disorders3 Major classes of disorders:Anxiety disordersAffective disordersSchizophreniaoften comorbid</p></li><li><p>Anxiety/Affective Disorders</p></li><li><p>Anxiety/Affective DisordersThey are often comorbid.They share some pharmacology.They both activate the SNS and HPA axis.Current interpretation is moving towards a shared etiology.</p></li><li><p>Anxiety DisordersChronic 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.</p></li><li><p>Anxiety DisordersFive major classes:Generalized anxiety disordersNo obvious causePhobic anxiety disordersSpecific fearPanic disordersRapid onset of extreme fear and anxietyObsessive-compulsive disordersRecurring, uncontrollable thoughts or actionsPost-Traumatic Stress Disorder (PTSD)</p></li><li><p>Anxiety DisordersSymptoms identical to stress:SNS activation, increased cortisol and adrenaline (fight).Avoidance (flight).HypervigilanceProduce a variety of physiological stress reactions:Tachycardia, hypertension, nausea, sleep disturbances, etc.AmygdalaHPASensesCortisolEpinephrine</p></li><li><p>Anxiety DisordersStress response is mediated by the HPA axis (hypothalamus, pituitary, adrenal glands) Increased amygdala activation increases the stress response.Increasing hippocampus activation decreases it. AmygdalaHippocampusHPACortisol-++Senses</p></li><li><p>Anxiety DisordersThe cortex can cause or inhibit fears. Inhibition is learned.High density of GABA receptors in amygdala.5-HT increases hippocampal suppression of HPA.AmygdalaHippocampusHPACortisolTherapyFears+--* 5-HT GCRs* Excessive cortisol kills GCRs+Therapy = learned compensatory/ inhibitory process5-HTSenses+</p></li><li><p>Anxiety DisordersEtiologyBecause of the effective drugs, GABAA and serotonin are both implicated. Both inhibit anxious behaviors.Amygdala (high concentration of GABAA receptors) seems to be involved, as would be expected for a fear response.Anxious persons have too little inhibition.Anxiolytics increase inhibition.</p></li><li><p>Anxiety DisordersBenzodiazapines bind to GABA receptors.Radioactive benzodiazapine uptake sites.NormalAnxious</p></li><li><p>Anxiety DisordersPharmacologyGABAA agonistsBenzodiazapines (Valium, Xanax, etc.)Increase Cl- flow thru GABAA receptors and immediately increase inhibition.Ataxia, muscle relaxation, sedation side effects.Serotonin agonistsBuspirone (Buspar) selectively blocks 5HT1A receptors anxiolytic w/o side effects.Up- or down-regulation takes weeks.</p></li><li><p>Anxiety DisordersPharmacologyGABA agonistsdiazepam (Valium)alprazolam (Xanax). lorazepam (Ativan)oxazepam (Serax)chlordiazepoxide (Librium)clorazepate (Tranxene)SSRIsbuspirone (Buspar) paroxetine (Paxil)[CRH antagonists]</p></li><li><p>Anxiety DisordersObsessive-Compulsive DisorderSwedo (1989) identified a link between OCD and Sydenhams 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)</p></li><li><p>Affective Disorders</p></li><li><p>Affective DisordersDepression (unipolar)Reactive or endogenous6% incidence, F = 2xM (non-western cultures higher)MZ: 60%, DZ: 15% reared together or apartMania (bipolar)Bipolar I: manic-depressiveBipolar II: hypomanic-depressive1% incidence, F = MMZ: 80%, DZ: 16%</p></li><li><p>Affective DisordersCourseChronicRelation to stressBrown (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.</p></li><li><p>Affective DisordersDepression pharmacologyIproniazid, 1st 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.</p></li><li><p>Affective DisordersEtiologyMonoamine theory of affective disorders:Excess monoamines (D, NE, 5-HT) cause mania.Monoamine depletion causes depression.Many receptor types involved.Dopamine (tyrosine) Serotonin (tryptophan)</p></li><li><p>Affective Disorders</p></li><li><p>Affective DisordersMonoamine 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.</p></li><li><p>Affective DisordersMajor classes of affective pharmacologyMonoamine oxidase inhibitors (MAOIs)Tricyclic & tetracyclic antidepressants (TCAs)Selective serotonin reuptake inhibitors (SSRIs)Others</p></li><li><p>Affective DisordersTricyclic antidepressantsNamed 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.</p></li><li><p>Affective DisordersSelective 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 inhibitorsNE and 5-HT have reciprocal control pathways.Same idea, but only block NE reuptake.Can be as effective as SSRIs.</p></li><li><p>Affective DisordersMAOIsiproniazid (), phenelzine (Nardil) and tranylcypromine (Parnate). Tricyclics amitriptyline (Elavil), imipramine (Tofranil), desipramine (Norpramin), doxepin (Sinequan), clomipramine (Anafranil), nortriptyline (Pamelor). Tetracyclic maprotiline (Ludiomil)SSRIsfluoxetine (Prozac), paroxetine (Paxil) and sertraline (Zoloft)Othertrazodone (Desyrel), nefazodone (Serzone), bupropion (Wellbutrin)</p></li><li><p>Bipolar Disorder1. Mania (I) or hypomania (II) (key factor)Loss of inhibition, cognition, rational thinking.2. Major depressionNo depressive episodes required for diagnosis! Often comorbid with psychotic features.Perhaps a different mechanism than normal depression like negative schizophrenia symptoms.</p></li><li><p>Bipolar DisorderPharmacologyLithiumNo effect in 1/3 of the population.Action unknownAgonizes 5-HT systemPossibly modulates inositol-type second messenger systems.Low therapeutic index, caution required.(therapeutic index = lethal dose / effective dose)</p></li><li><p>Bipolar DisorderPharmacologyAnticonvulsantsSeizures have (temporary) antidepressive effects.Course of bipolar disorder mimics epilepsy.Sometimes work when lithium doesnt.valproate (Depakote)carbamazapine (Tegretol)oxcarbazapine (Trileptal)topiramate (Topamax)risperidone (Risperidal)</p></li><li><p>Schizophrenia</p></li><li><p>SchizophreniaSplit mind - breakdown of integration between emotion, thought and action going mad. Incidence1% of general populationNo race, sex or cultural differences.MZ: 48%, DZ: 17%, Family 10%, GP 1%CourseSymptoms appear in adolescence or early adulthood (somewhat later in females).Chronic, with possible remissions.</p></li><li><p>SchizophreniaSubtypes include paranoid (most treatable), disorganized, catatonic and residual types.Two classes of symptoms:Positive SymptomsAbnormal behaviors and thoughts delusions, hallucinations, disorganization.Negative SymptomsLack of appropriate responses reduced motivation, decreased affect, etc.</p></li><li><p>Physical changes notedAbnormally small cortexAbnormally large ventriclesPrefrontal cortex, amygdala abnormalitiesSmaller hippocampusNo ongoing deteriorationAbnormalities seem to be in place before symptoms (i.e. seems to be a developmental disorder).</p></li><li><p>SchizophreniaRelation to maternal factorsPrenatal 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 stressQuebec 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)</p></li><li><p>SchizophreniaRelation to infectionsLate winter babies have a higher incidence rateAssumed to be from autumn (2nd trimester) infectionBrown, et al. prospectively collected blood serum samples from mothers during 1959-1967 and tracked their offspring.(2002) 2nd semester in utero rubella and respiratory infections are significantly linked to schizophrenic offspring.(2004) found elevated 2nd trimester IL-8 levels in mothers of those who later developed schizophrenia.</p></li><li><p>SchizophreniaRelation to stressSeveral studies have found:Exposure to severe stress is common before onset.Symptom severity is proportional to stress severity.Maternal stress exposure may be correlated.</p><p>Susceptibility seems to be strongly genetic, but environmental factors, especially stress, can trigger disorder in susceptible individuals.</p></li><li><p>SchizophreniaPharmacology1950 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.</p></li><li><p>SchizophreniaPharmacologyChlorpromazine and reserpine Dissimilar chemical structures2-3 week period before effectiveComorbid Parkinson-like effectsParkinsons research, ca. 1960Found depleted dopamine in striatumAmphetamines & cocaine, which cause psychotic effects, both elevate dopamine levels.</p></li><li><p>SchizophreniaDopamine (primary) theory of schizophreniaPositive symptomsIncreased dopamine in mesolimbic pathway (D2) is responsible for positive symptoms. Phenothiazines (incl. chlorpromazine): Bind to and block both D1 and D2 receptors.Reserpine: Destroys monoamine vesicles.Seeman (1976) anti-psychotic effects proportional to dopamine receptor D2 affinity.Butyrophenones (haloperidol) bind only to D2.</p></li><li><p>SchizophreniaNegative symptomsDecreased dopamine in mesocortical pathway causes negative symptoms (few D2 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.</p></li><li><p>SchizophreniaGlutamate theory of schizophreniaPhenylcyclidine (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.</p></li><li><p>SchizophreniaMesocortical 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.</p></li><li><p>SchizophreniaPharmacologychlorpromazine (Thorazine, Ormazine, Largactil)trifluoperazine (Stelazine)pimozide (Orap)flupenthixol (Fluanxol)thioidazine (Mellaril)mesoridazine (Serentil)haloperidol (Haldol)</p><p>clozapine (Clozaril)risperidone (Risperidal)olanzapine (Zyprexa)quetiapine (Seroquel)ziprosidone (Geodon)</p></li></ul>