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Pharmacology: Antipsychotic Drugs (Bannon) SCHIZOPHRENIA: Epidemiology: Affect 1% of the population worldwide 30% of all homeless people 30% of all hospitalizations Disease Characteristics: Psychotic Symptoms (Positive/Cognitive Symptoms): emerge in late teens o Loss of reality o Delusions and hallucinations (usually auditory) o Disordered thinking and memory Prodromal Signs (Negative Symptoms): poorer prognosis associated with prominent negative symptoms o Social isolation and withdrawal o Poverty of speech o Odd behavior/ideas o Blunted affect o Lack of motivation Biological Findings: especially associated with negative symptoms Decreased blood flow in frontal lobe and caudate during working memory tasks Reduced hippocampal and medial temporal lobe volume Enlarged ventricles Genetic Predisposition: 15% incidence in first degree relatives (compared to 1% incidence in the general population) 17% concordance in DZ twins; ~50% concordance in MZ twins Complex polygenic disorder (as evidenced by high frequency and partial penetrance) Dopamine Hypothesis: Evidence for the Involvement of DA: 1. Dopamine agonists can induce/exacerbate psychosis 2. Clinically effective APDs block DA receptors 3. DA receptor expression increased in schizophrenia (has since been proven UNTRUE) Dopamine Receptors: G-protein coupled receptors o D1 Family: includes D1 and D5 (less prominent) Location: D1: striatum and neocortex* D5: hippocampus and hypothalamus Second Messengers (Gq): Increase cAMP Increase PIP2 hydrolysis (PKC activation and Ca++ mobilization) o D2 Family: D2, D3 and D4 (latter 2 less prominent) Location: D2: striatum, substantia nigra and pituitary gland* D3: olfactory tubercle, nucleus accumbens, hypothalamus D4: frontal cortex, medulla, midbrain Second Messengers (Gi): Decrease cAMP Increase K+ currents Decrease voltage-gated Ca++ currents Dopamine Pathways: single source divergent systems o Nigrostriatal DA: modulates movement and learned habits; 80% of total DA o Mesolimbic DA: modulates motivation, goal-directed thinking, affect and reward o Mesocortical DA modulates cognition o Hypothalamic DA: hormone regulation o Area postrema: located outside the BBB; mediates emesis (very sensitive to DA drugs) Dopamine Pathways and their Relation to Psychotic Symptoms: o Mesolimbic/Mesocortical DA: overactive possibly related to positive Sx o Mesocortical DA: hypofunction possibly related to negative Sx (DA blockade not helpful for these) o Nigrostriatal DA: highest DA content and related to extrapyramidal (motor) SEs and tardive dyskinesia o Tuberoinfundibular/Hypothalamic DA: related to endocrine effects ANTIPSYCHOTIC DRUGS: D2R Blockade and Clinical Efficacy: strong correlation between blockage for these R and efficacy Original D2 Blocking Agents (ie. Chlorpromazine): not a real high affinity for D2 receptors and therefore needed very high doses to achieve desired effects (lots of SE) Newer D2 Blocking Agents with Higher Affinity (ie. Spiroperidol): although higher affinity, do not have improved efficacy over earlier agents; however, will have different SE profiles Commonality in APDs Relevant to Antipsychotic Effects: Possibilities: o 5HT2A: typical APDs occupy most striatal D2 receptors while atypical APDs occupy a lower proportion of D2 R and more 5HT2A; however, role for 5HT2A receptors in psychosis not clear o D4 in cortex: but not all block here (ie. quetiapine) o Fast dissociation relative to R binding allows better modulation of function (ie. high Kd at D2): but then atypical APDs should look lie low-affinity typical APDs (not the case) Another issue: blockade of receptors is immediate but effects are delayed BOTTOM LINE: o Antipsychotic MOA(s) still not really understood o However, D2 DA receptor blockade is a commonality to all agents Pharmacokinetics of APDs: Absorption: most are READILY but INCOMPLETELY absorbed o Highly lipid soluble and protein bound o Long clinical duration relative to plasma half life Administration: parenteral forms (IM depot injections) available (especially older APDs); often used when compliance is an issue Metabolism: significant FIRST PASS metabolism by P450; conjugation for urinary excretion Adverse Effects of APDs: Relatively high therapeutic index: pretty safe in overdose Autonomic Effects: o Muscarinic Block: dry mouth, urinary retention, constipation o Alpha Adrenergic Blockade (α1): orthostatic hypotension, impotence Cardiovascular Effects: o Phenothiazines (chlorpromazine and others): ↑HR, abnormal ECG o Atypical APDs (esp. ziprasidone): significant risk of QT prolongation o Overall: ~2x increased risk of sudden cardiac death with both typical and atypical (dose-dependent) Endocrine Effects: o Hyperprolactinemia: manifest as amenorrhea, galactorrhea, infertility, impotence Due to decreased action of DA (normally suppresses prolactin release from anterior pituitary) Metabolic Effects: o Atypical APDs (esp. clozapine and olanzapine): weight gain leading to insulin resistance and diabetes Possible cause: H1 and 5HT blockade Extrapyramidal Effects: o Seen in proportion to D2R affinity (drugs with higher affinity for this receptor cause more EP effects) o Some effects are short term and limiting, while others are long-term and irreversible Adverse Neurological Effects of APDs (Extrapyramidal Effects): Early Adverse Effects: o Acute Dystonic Reaction: of face or back (1-5 days after starting medication); NOT seizures or hysteria o Akathisia: uncontrollable restlessness (5-60 days after starting medication); NOT agitation o Parkinsonism: looks like idiopathic PD (5-30 days after starting medication) Treatment of Acute Dystonic Reaction/Akathisia/Parkinsonism: Reduce dose of APD Anti-muscarinics/anti-histaminics (bring system back into balance by reducing ACh) o Neuroleptic Malignant Syndrome: very rare sensitivity to DA blockade by all types of APDs When: first few weeks of taking medication OR after increasing dose Manifestations: Hypothalamic DA block leads to very high dangerous fever Basal ganglia DA block leads to parkinsonism Others symptoms include autonomic instability and muscle breakdown Treatment: Bromocriptine (DA agonist) and dantrolene - Late Adverse Effects: o Tardive Dyskinesia: occurs months to years after starting medication Most important side effect of APDs (20-40% of patients chronically treated with typical will develop TD) Advanced cases are difficult to reverse (early recognition is important) Masked by increasing APD dose and worsens upon drug withdrawal Special Adverse Effects with Clozapine: Seizures (1-4% of patients) Agranulocytosis (1-2% of patients) o Potentially fatal o Develops between weeks 6-18 and reversible if caught early o Therefore, need to do weekly blood counts for the first 6 months and every 3 weeks after that Studies of APD Efficacy: CATIE Study: o Basics: first generation perphenazine vs. second generation olanzapine, quetiapine, risperidone and ziprasidone o Phase I: ¾ of patients switched mediations because of adverse side effects Olanzapine showed a modest advantage in terms of duration of treatment and symptom relief (but substantial weight-related SEs) Other atypicals (second generation) showed no advantage over perhpenazie o Phase II: Patients who stopped APDs due to SEs/no response (and who refused to take clozapine) given one of the 4 atypicals mentioned above Patients continued on olanzapine and risperidone significantly longer Patients who stopped APDs because of inadequate symptom relief were given clozapine, olanzapine, risperidone or quetiapine Clozapine significantly more effective and patients stayed on it longer o Issues with the Study: Subject selection limitation (most patients had no EPS/TD and those that had TD were assigned to second generation APDs only) Therefore, study deals with side effects and efficacy but does not really address the issue of tardive dyskinesia CUtLASS Study: o Basics: Clinicians and patients UNBLINDED and initiated drug changes (better mimicked the clinical situation BUT less control of variables) Assessed by a blind rater after 1 year on the medications o Overall Results: Typicals and atypicals equivalent in quality of life, efficacy and side effects Clozapine between in managing symptoms than other second generation drugs in treatment resistance patients (overall quality of life also somewhat better) TEOSS Study: o Basics: Study of young patients on APDs (8-19 years old) Looked at olanzapine, risperidone or molindone PLUS benztropine (anticholinergic) o Overall Results: Roughly equivalent efficacy Side effects differed: Weight gain (olanzapine>risperidone>molindone) Increase in cholesterol and other metabolic disturbances (olanzapine- this arm of the trial was terminated) Determining the DOC for your Patient: Cost: newer atypicals 10-100x more costly than generics Adverse Side Effects: profile of typical vs. atypical; short term vs. long term use Compliance: depot injections or drug changes Treatment-resistance Important Examples of APDs: Chlorpromazine (and other phenothiazines): o Receptor Affinities: α1=5HT2A>D2=D4=H1>D1=M o Pros: Generic and inexpensive o Cons: Many adverse autonomic effects (dirty drug- action at many different receptors) Some risk of EPS and TD (action at D2 receptors) Haloperidol: o Receptor Affinities: D2>α1>D4>5HT2A>D1>>H1>>M o Pros: Generic and inexpesive Parenteral form available (depot injection) Less autonomic effects (does not have a high affinity for these receptors) o Cons: Strong D2 block means higher risk of EPS and TD Risperidone: o Receptor Affinities: 5HT2A>D2=α1>D4>H1>D1>>M o Pros: Generic and inexpensive Depot preparation available Borderline atypical and therefore LESS 5HT-related weight gain compared to other atypicals More tolerable than most others APDs (maybe) o Cons: Borderline atypical and therefore MORE DA-related side effects (hyperprolactinemia, EPS) Olanzapine: o Receptor Affinities: 5HT2A=M>H1>D4>D2>α1>D1 o Pros: More tolerable than other APDs (clozapine-like structure without risk for agranulocytosis or seizures) May be somewhat more effective than other APDs (subtle) Less risk of EPS and TD (less action at D2) o Cons: Expensive (no generic) Several metabolic adverse effects including weight gain and diabetes (more action at 5HT2A) Clozapine: o Receptor Affinities: 5HT2A>D4=α1=M=H1>D2>D1 o Pros: Clearly the most efficacious drug available for refractory cases Less risk for EPS and TD (less action at D2) o Cons: Expensive (no generic) Risk for weight gain and diabetes (more action at 5HT2A) More serious side effects of agranulocytosis and seizures Traditional Use of APDs: Schizophrenia: primary indication Schizoaffective Disorder: o Characteristics of schizophrenia PLUS affective disorders (depression, BPD) o Treat with APD plus antidepressants, lithium or valproate Neuroleptoanesthesia: o Droperidol (short-acting and highly sedating) + fentanyl Pre-Surgical Use: o Older APDs (with H1 blockade) used due to strong anti-emetic effects (via CTZ and GI), sedation and relief of pruritis (itching) Other Uses of APDs: Depression and Bipolar Disorder: some justification for the use of APDs in treatment o Atypical APDs: FDA-approved for acute mania and mixed episodes of BPD o Risperidone/Lithium Combination: FDA-approved for maintenance in refractory BPD o - - Atypical APD + Antidepressants: tested for drug-refractory depression (fluoxetine/olanzapine tested first); mixed results depending on the drug combination used Agitation in Alzheimer’s Disease and Dementias: o Rationale: calming, sedative, antipsychotic effects o Black Box Warning: both typical and atypical APDs increase death due to CV accidents and infections in patients with AD/dementia (therefore, really need to be careful/limit use in this population) Control of Aggressive Behavior in Pediatrics: o Risperidone: FDA-approved for use in autistic children over the age of 5 with aggression or selfinjurious behavior o Quetiapine and Aripiprazole: FDA-approved for children over the age of 10 with BPD o General Issues: Use especially high in Medicaid children (poor)- especially off label use for ADHD (cheaper than the drugs for ADHD) Off-label use in privately insured children aged 2-5 has also doubled