Transcript medical student anti.. - University of Illinois at Chicago

Pharmacotherapy With Anti
Psychotic Medications
Danesh A. Alam, M.D.
Fellow, Psychopharmacology and Research
Psychiatric Clinical Research Center
University of Illinois at Chicago
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.”
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 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 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.
Antipsychotics
Common Indications
 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
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
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)
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
2nd Generation or Novel Antipsychotics
 Clozapine (Clozaril)
 Risperidone (Risperdal)
 Olanzapine (Zyprexa)
 Quetiapine (Seroquel)
 Ziprasidone (Geodon)
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
The Role of Clozapine
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
Refractory Psychosis
Change anti-psychotic after adequate dosage
trial
Consider noncompliance and depot injections
Antipsychotic combinations
e.g., addition of neuroleptic
Adjunctive medications
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
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
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
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)
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
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)
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
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
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
Adverse Effects of Antipsychotics
Acute EPS
Maximum
NEUROLEPTICS
Minimum
RISPERIDONE
OLANZAPINE
(DOSE-RELATED
CLOZAPINE
ZIPRASIDONE
QUETIAPINE
Adverse Effects of Antipsychotics
Hematological
 Neuroleptics
 Clozapine-induced agranulocytosis
•
Management
Stop agent
Reverse isolation; supportive measures
GCSF (cytokines, filgastrim)
•
Rechallenging strategies
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
Adverse Effects of Antipsychotics
Anticholinergic
Most common with:
 Clozapine
 Olanzapine
 Quetiapine
 Low-potency neuroleptics
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?
Adverse Effects of Antipsychotics
Sexual 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)
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 )
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
Adverse Effects of Antipsychotics
Mean weight gain after 10 weeks (kgs)
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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
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
Adverse Effects of Antipsychotics
Ocular
Retinitis pigmentosa (e.g., thioridazine)
Cataracts (e.g., quetiapine?)
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
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
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).