Pharmacotherapy With Anti Psychotic Medications

1. Pharmacotherapy With Anti Psychotic Medications Danesh A. Alam, M.D. Fellow, Psychopharmacology and Research Psychiatric Clinical Research Center University of Illinois at Chicago

2. Rauwolfia Serpentina:The First Herbal Antipsychotic • The first antipsychotic, Rauwolfia Serpentina, was prescribed by physicians in ancient India over two millennia ago. • The ancient Ayurvedic pharmacopoeia describes the use of R. Serpentina in the treatment of “insanity” (oonmaad in Sanskrit). “onmaad” is a description of psychosis by the Ayurvedic physician Chakra (circa 1000 BC) as an “abnormal condition of the mind, wisdom, perception, knowledge, memory, character, creativity, conduct, and behavior.”

3. Rauwolfia Serpentina:The First Herbal Antipsychotic • In 1931, Sen and Bose described the tranquilizing and antihypertensive effects of R. Serpentina root extracts. (Rauwolfia Serpentina: a new Indian drug for insanityand high BP. Indian Medical World 1931:11:194-201). • In 1952, reserpine was isolated from Rauwolfia extracts. • Arvid Carlsson (Sweden) discovered the central nervous system neurotransmitter properties of dopamine while studying the mechanism of action of reserpine. Reserpine works by depleting cells of dopamine, thus, reducing brain dopaminergic activity.

4. Anti Psychotic Drugs • Chlorpromazine, 1952 • Developed as an anti-autonomic agent • ~20 anti-psychotic drugs available (US) • 1st generation or typical i.e.- chlorpromazine, haloperidol, fluphenazine etc. vs. 2nd generation or atypical i.e.- risperidone, olanzapine, quetiapine etc.

5. Schizophrenia Schizoaffective disorder Mood Disorder with psychosis Dementia with psychosis Delirium Delusional disorder Psychosis secondary to a non-psychiatric medical disorder Developmental disability with psychosis and/or aggression Tourette’s disorder, Huntingdon’s chorea, intractable hiccups Acute Mania Augmentation in Major Depression and Bipolar disorder AntipsychoticsCommon Indications

6. Schizophrenia: Symptom domains • Positive symptoms • Hallucinations • Delusions • Negative symptoms (deficit syndrome) • Primary • Secondary • Dysphoria • Neuroleptic-induced deficit syndrome (NIDS) • Cognitive symptoms • Dissociated thinking • Disorganization of thoughts • Attentional impairments

7. Antipsychotics: Mechanism of Action • Dopamine hypothesis • Increased release • Increased sensitivity of postsynaptic receptors • Dopamine receptor subtypes • Serotonin • Norepinephrine • Gamma-aminobutyric acid (GABA) • Glutamate • N-methyl-D-aspartate (NMDA) • Phencyclidine (PCP) • Peptides • Neurotensin • Cholecytoskin (CCK) • Somatostatin (SOM)

8. Dopamine Receptors • Plethora of DA receptors exist • 5 pharmacological subtypes: • D1, D2, D3, D4 and D5 • D2 Receptor: Most extensively studied • Stimulated by agonists for treatment of Parkinson's • Blocked by antagonists for treatment of Schizophrenia

9. Dopamine Pathways (4) NIGROSTRIATAL DOPAMINE - projects from substantia nigra to basal ganglia - controls movements MESOLIMBIC DOPAMINE -projects from midbrain ventral tegmental area to nucleus accumbens- delusions, hallucinations, pleasurable sensations MESOCORTICAL DOPAMINE -projects from midbrain ventral tegmental area, sends axons to limbic cortex - mediates (+) and (-) symptoms TUBEROINFUNDIBULAR DOPAMINE -projects from hypothalamus to anterior pituitary gland - controls prolactin secretion

10. 2nd Generation or Novel Antipsychotics • Clozapine (Clozaril) • Risperidone (Risperdal) • Olanzapine (Zyprexa) • Quetiapine (Seroquel) • Ziprasidone (Geodon)

11. 2nd Generation/Novel/Atypical? Profile • Diminished extrapyramidal side effects (EPS) • Minimized risk for tardive dyskinesia (TD) • No hyperprolactinemia • Beneficial for treatment of refractory patients • Improved negative symptoms • Improved cognitive/mood symptoms

12. The Role of Clozapine AdvantagesDisadvantages Treatment of refractory patientsAgranulocytosis Negative symptomsSeizures Minimal risk of EPS or TD (?)Weight gain No prolactin increaseOrthostasis Tachycardia Sedation Sialorrhea Constipation

13. Refractory Psychosis • Change anti-psychotic after adequate dosage trial • Consider noncompliance and depot injections • Antipsychotic combinations • e.g., addition of neuroleptic • Adjunctive medications

14. Long-Acting (or Depot) Antipsychotics • Esters synthesized from the hydroxyl group of active base and long-chain fatty acids • Dissolved in sesame oil vehicle • Ester is hydrolyzed by plasma esterases after injection and slow release into systemic circulation • Css achieved in about 3 months • Terminal elimination half-life: 3 weeks

15. Depot Antipsychotics: Potential Advantages • May benefit treatment-refractory patients on oral preparations • May decrease noncompliance • Bioavailability approaches 100% • Lower and more predictable plasma drug levels with clinically equivalent doses of oral preparations • Longer duration of action

16. Transition from Oral to Depot Antipsychotics • Oral supplement during the vulnerable period • Use a high (or loading) depot dose initially • Increased frequency of injections early in course of depot therapy

17. Antipsychotic Combinations I Proposed Rationale: • Extensive unpublished clinical experience? (difficult to examine without bias) • Differences in pharmacological action between typicals and atypicals? (poor understanding of required neurochemical action) • Extensive published evidence? (no controlled trials to date. Most published studies examine addition of typical to clozapine)

18. Antipsychotic Combinations II Temporary Situations: • “Lead-In”combinations - typicals supposedly having more rapid action during acute emergency) • “Top-Up”combinations - addition of typical to overcome acute exacerbation • “Switch-Over”combinations - when switching between antipsychotics

19. Adjunctive Treatment • Anticholinergics • Benzodiazepines (anxiety, akasthisia) • Carbamazepine (effective in acute episode; long term studies not done) • Lithium (excitement, overactivity, euphoria) • Valproic acid (psychosis?) • Propranolol (akasthisia, psychosis)

20. Adverse Effects of Antipsychotics Major Points • Atypical antipsychotics represent a significant departure from the conventional neuroleptics • These agents can also adversely affect several systems • The most critical to consider are the neurological, hematological, cardiovascular, and endocrine • Other problems occur due to their cholinergic or sexual adverse effects • Drug interactions can also occur

21. Adverse Effects of Antipsychotics Neurological • Acute EPS • Dose-related EPS • Primary vs. secondary negative symptoms • Neuroleptic malignant syndrome • Tardive dyskinesia (other tardive syndromes) • Seizures (e.g., clozapine) • Sedation, headache, withdrawal syndrome

22. Adverse Effects of Antipsychotics Low EPS Risk of Atypical Antipsychotics • Preferential DA blockade in meso-cortico-limbic pathway • 5HT2 ‚ 5HT1c, or 5HT3 blockade • High 5HT2/DA2 blockade ratio • Low D2 occupancy • Rapid release of bound antipsychotic from receptor due to loose binding (clozapine and quetiapine) • Anticholinergic effects • Antihistaminergic effects

23. Adverse Effects of Antipsychotics Acute EPS Maximum Minimum NEUROLEPTICS RISPERIDONE OLANZAPINECLOZAPINE (DOSE-RELATED ZIPRASIDONE QUETIAPINE

24. Adverse Effects of Antipsychotics Hematological • Neuroleptics • Clozapine-induced agranulocytosis • Management Stop agent Reverse isolation; supportive measures GCSF (cytokines, filgastrim) • Rechallenging strategies

25. Adverse Effects of Antipsychotics Cardiovascular • Related to both alpha adrenergic and muscarinic effects • Hypotension • Tachycardia • Arrhythmogenic potential possible with all antipsychotics • QTC interval • QTC prolongation • QTC dispersion • Torsade de Pointes

26. Adverse Effects of Antipsychotics Anticholinergic • Most common with: • Clozapine • Olanzapine • Quetiapine • Low-potency neuroleptics

27. Adverse Effects of Antipsychotics Neuroendocrine • Inconsistent effects on hormone-related activity • Pituitary (prolactin, menstrual dysfunction) • Thyroid • Antagonism of DA receptors in the pituitary can result in increased prolactin levels, possibly causing: • Lactation/breast engorgement • Gynecomastia • Sexual dysfunction (decrease in sexual interest reversed by bromocriptine)? • Anxiety and mood disturbance?

28. Adverse Effects of AntipsychoticsSexual Adverse Effects • anti-Serotonin (5HT2) • anti-dopamine (impaired erection, inhibited orgasms) • anti-norepinephrine (reduced intensity of orgasm) • anti-cholinergic (impaired erection) • anti-histamine (loss of libido, impaired erection)

29. Adverse Effects of Antipsychotics Sexual Adverse Effects: Management • Dosage reduction, avoidance of antimuscarinic agents • Switching to another agent • Various drugs may be helpful (e.g., sildenafil, yohimbine (NE), cyproheptadine (5HT2 antagonist)

30. Adverse Effects of Antipsychotics Weight Gain: General Issues • Recognized problem since chlorpromazine • More common with atypicals • Altered metabolism vs. satiety vs. activity • Diabetes mellitus associated with typicals and atypicals • More problems managing DM • New-onset cases of DM; • Ketoacidosis • Long-term weight-associated concerns • Elevated triglycerides and cholesterol • Heart disease and hypertension

31. Adverse Effects of Antipsychotics Mean weight gain after 10 weeks (kgs) Allison DB et al. Am.J.Psychiat;156;1686-1696, 1999

32. Adverse Effects of Antipsychotics Weight Gain: Mechanism • Increased calorie consumption • Decreased calorie use (less activity, sedation) • Mechanism of weight gain is unknown • Genetic contribution • Dopamine blockade (e.g. amantadine) • Noradrenergic blockade (e.g., amphetamines) • Serotonin blockade (e.g., fenfluramine; 5HT2c, 2a, 1a ) • Histamine blockade (e.g., antihistamines) • Glucose and insulin dysregulation

33. Adverse Effects of Antipsychotics Weight Gain: Treatment Options • Dietary changes • Patient education about causes • Strategies to reduce food intake • Exercise • Screening for related health problems • Diabetes • Hypertension • Serum cholesterol

34. Adverse Effects of Antipsychotics Ocular • Retinitis pigmentosa (e.g., thioridazine) • Cataracts (e.g., quetiapine?)

35. Adverse Effects of Antipsychotics Ocular Assessments in Quetiapine Trials • Cataracts in chronic dog studies • No cataracts seen in two 1-year monkey studies • Lens changes in a long-term clinical trial were comparable to control group (haloperidol) • Across all controlled clinical trials, the proportions of patients with lens changes were similar in quetiapine, haloperidol , and placebo groups • Periodic ocular examinations are recommended

36. Summary of Antipsychotic Treatment • Fewer adverse effects with atypicals • greatly reduces adverse effects burden • clozapine is an exception • Major decrease in risk of EPS and TD • Prolactin increase and other risks are lower • Weight gain is a problem • varies across atypical class

37. Trivia • Antipsychotic that cause less weight gain: molindone & ziprasidone • droperidol- only approved for IV use in anaesthesia • Pimozide approved for use in Tourettes only • Clozapine- reduces suicide in schizophrenia • All antipsychotics lower the seizure threshold, 2nd generation <1% • Other meds that cause ac. Dystonia, akathesia, parkinsonian sideeffects and NMS- prochorperazine (compazine), metoclopramide, promethazine (Phenergan).