Pharmacotherapy With Anti Psychotic Medications Danesh A. Alam, M.D. Fellow, Psychopharmacology and...
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Transcript of Pharmacotherapy With Anti Psychotic Medications Danesh A. Alam, M.D. Fellow, Psychopharmacology and...
Pharmacotherapy With Anti Pharmacotherapy With Anti Psychotic MedicationsPsychotic Medications
Danesh A. Alam, M.D.Danesh A. Alam, M.D.Fellow, Psychopharmacology and ResearchFellow, Psychopharmacology and Research
Psychiatric Clinical Research CenterPsychiatric Clinical Research CenterUniversity of Illinois at ChicagoUniversity of Illinois at Chicago
Rauwolfia Serpentina:Rauwolfia Serpentina: The First Herbal AntipsychoticThe 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.”
Rauwolfia Serpentina:Rauwolfia Serpentina: The First Herbal AntipsychoticThe 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 insanity and 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.
Anti Psychotic DrugsAnti 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.
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
AntipsychoticsAntipsychoticsCommon IndicationsCommon Indications
Positive symptoms• Hallucinations• Delusions
Negative symptoms (deficit syndrome)• Primary• Secondary
DysphoriaNeuroleptic-induced deficit syndrome (NIDS)
Cognitive symptoms• Dissociated thinking• Disorganization of thoughts• Attentional impairments
Schizophrenia: Symptom domainsSchizophrenia: Symptom domains
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)
Antipsychotics: Mechanism of ActionAntipsychotics: Mechanism of Action
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
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
22ndnd Generation or Novel Antipsychotics Generation or Novel Antipsychotics
Clozapine (Clozaril)
Risperidone (Risperdal)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Ziprasidone (Geodon)
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
2nd Generation/Novel/Atypical? 2nd Generation/Novel/Atypical? ProfileProfile
Advantages Disadvantages
Treatment of refractory patients Agranulocytosis
Negative symptoms Seizures
Minimal risk of EPS or TD (?) Weight gain
No prolactin increase Orthostasis
Tachycardia
Sedation
Sialorrhea
Constipation
The Role of ClozapineThe Role of Clozapine
Refractory PsychosisRefractory Psychosis
Change anti-psychotic after adequate dosage trial
Consider noncompliance and depot injections
Antipsychotic combinationse.g., addition of neuroleptic
Adjunctive medications
Long-Acting (or Depot) AntipsychoticsLong-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
Depot Antipsychotics: Potential Depot Antipsychotics: Potential AdvantagesAdvantages
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
Transition from Oral to Depot Transition from Oral to Depot AntipsychoticsAntipsychotics
Oral supplement during the vulnerable period
Use a high (or loading) depot dose initially
Increased frequency of injections early in
course of depot therapy
Antipsychotic Combinations IAntipsychotic Combinations I Proposed Rationale: 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)
Antipsychotic Combinations IIAntipsychotic Combinations II Temporary Situations: 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
Adjunctive TreatmentAdjunctive 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)
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
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Major PointsMajor Points
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
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics NeurologicalNeurological
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
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Low EPS Risk of Atypical Low EPS Risk of Atypical
AntipsychoticsAntipsychotics
MaximumMaximum MinimumMinimum
Acute EPSAcute EPS
Adverse Effects of AntipsychoticsAdverse Effects of Antipsychotics
NEUROLEPTICS RISPERIDONE OLANZAPINE CLOZAPINE
(DOSE-RELATED ZIPRASIDONE
QUETIAPINE
Neuroleptics
Clozapine-induced agranulocytosis
• Management
Stop agent
Reverse isolation; supportive measures
GCSF (cytokines, filgastrim)
• Rechallenging strategies
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics HematologicalHematological
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
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics CardiovascularCardiovascular
Most common with:
Clozapine
Olanzapine
Quetiapine
Low-potency neuroleptics
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics AnticholinergicAnticholinergic
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?
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics NeuroendocrineNeuroendocrine
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)
Adverse Effects of AntipsychoticsAdverse Effects of Antipsychotics Sexual Adverse EffectsSexual Adverse Effects
Dosage reduction, avoidance of
antimuscarinic agents
Switching to another agent
Various drugs may be helpful
(e.g., sildenafil, yohimbine (NE),
cyproheptadine (5HT2 antagonist )
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Sexual Adverse Effects: ManagementSexual Adverse Effects: Management
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
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Weight Gain: General IssuesWeight Gain: General Issues
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Allison DB et al. Am.J.Psychiat;156;1686-1696, 1999
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Mean weight gain after 10 weeks (kgs)Mean weight gain after 10 weeks (kgs)
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
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Weight Gain: MechanismWeight Gain: Mechanism
Dietary changes
• Patient education about causes
• Strategies to reduce food intake
Exercise
Screening for related health problems
• Diabetes
• Hypertension
• Serum cholesterol
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Weight Gain: Treatment OptionsWeight Gain: Treatment Options
Retinitis pigmentosa (e.g., thioridazine)
Cataracts (e.g., quetiapine?)
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics OcularOcular
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
Adverse Effects of Antipsychotics Adverse Effects of Antipsychotics Ocular Assessments in Quetiapine TrialsOcular Assessments in Quetiapine Trials
Summary of Antipsychotic TreatmentSummary of Antipsychotic Treatment
Fewer adverse effects with atypicals – greatly reduces adverse effects burden– clozapine is an exception
Major decrease in risk of EPS and TDProlactin increase and other risks are lowerWeight gain is a problem – varies across atypical class
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).