CHARLES P. SAMENOW, MD, MPH
INTRODUCTION TO PSYCHOPHARMACOLOGY
OBJECTIVES
• Identify major classes of somatic treatments for the major DSM-IV-TR Diagnoses• Describe basic mechanism of action of somatic
treatments• Explain how mechanism of action related to major
side effect profiles
ANTIDEPRESSANTS
TRICYCLIC ANTIDEPRESSANTS
• Block the re-uptake of three neurotransmitter systems:• Serotonin• Norepinephrine• Dopamine
• Utilized in:• Major Depressive Disorder• Dysthymia• Generalized Anxiety Disorder• Panic Disorder• Obsessive-Compulsive Disorder
TRICYCLIC ANTIDEPESSANTS
• Older “Dirtier” Medication:• 3-4 weeks for onset (sometimes even 4-6 weeks)• Can be lethal in overdose (cardiotoxic)• Have side effect profiles:• Anticholinergic: dry mouth, constipation, confusion, urinary
retention• Histaminic blockade: sedation and weight gain• Alpha-adrengergic blockade: orthostatic hypotention• Serotinergic: sexual side effect
MAOI
• Block Monoamine Oxidase in the wall of the gut, CNS and platelets leading to build up of Dopamine and Norepinephrine
• Utilized in:• Major Depressive Disorder• Atypical Depression• Anxiety Disorders
MAOI
• Inhibition of MAO in the gut leads to increased Tyramine absorption. Hence, patients must avoid Tyramine containing foods (fava beans, aged meats and cheeses, wines, sauerkraut, etc…)• Ingestion of Tyramine can lead to hypertensive crisis
• Require 3-4 weeks (sometimes 6-8 weeks)• Fatal in overdose• Cannot be combined with other serotinergic
acting drugs (Tricyclic’s, SSRI’s) due to risk of serotonin syndrome.• Overdose can be fatal
SSRI
• Blockade of serotonin reuptake from the synapse• Utilized in:• Major Depression• Dysthymia• OCD• Panic Disorder• PTSD• Social Phobia• Bulimia Nervosa• Depressed phase of Bipolar (only with a mood stabilizer)
SSRI
• Take 2-4 weeks for onset• Fewer side effects than older medications –
“Cleaner” and more easily tolerated• First line agents in pregnancy (although Class C)
• Major side effects:• Gastrointestinal (first few days)• Sexual Side Effects• Black Box Warning: Increased Suicidality in Adolescents• Treatment emergent mania in bipolar disorder• Discontinuation Syndrome
SNRI
• Blocks Re-uptake of Serotonin and Norepinephrine• Careful balance between two neurotransmitter
systems• Utilized in Depression, Anxiety and Pain
Syndromes• “Cleaner”/More Easily Tolerated• Major Side Effects:• Blood Pressure• Discontinuation Syndrome
MISCELLANEOUS
• Wellbutrin (Buproprion)• Inhibition of Norepinephrine Re-uptake• No sexual side effects• Also marketed as Zyban for smoking cessation• Contraindicated in eating disorders due to lowering
seizure threshold• Main side effect is anxiety
• Remeron (Mirtazapine)• Alpha-2 Antagonist (net effect -> increased
norepinephrine)• May cause sedation or increased weight gain• Often used in the elderly
SEDATIVES/ANXIOLYTICS
BENZODIAZAPINES
• Use is determined by ½ life:• Long (Diazepam, Chlorediazepoxide)• Medium (Alprazolam)• Short (Lorazepam)
• Utilized for panic and insomnia• Potentiation of GABA receptors by binding to
special binding site• Long-term use may lead to tolerance, withdrawal
and physiologic dependence• Side effects are sedation and amnesia
OTHERS
• Beta-Blockers – • Utilized for performance anxiety• Centrally acting/lipophilic propranolol
ANTIPSYCHOTICS
TYPICAL ANTIPSYCHOTICS
• High Potency (Haldol)• Primary action is blocking D2 receptors (antagonist)• High affinity for D2 = lower dose• Good control of positive symptoms• Major Side Effects:• EPS -dystonic reactions, prolactin, akasthesia, parkinsonism• Neuroleptic Malignant Syndrome –
• Mid/Low Potency (Thorazine)• Lower affinity for D2 = higher dose• Less EPS• More anticholinergic, alpha-adreinergic, and histiminic
side effects
Nigrostriatal pathwayNigrostriatal pathway (part of EP system)(part of EP system)
Mesocortical pathwayMesocortical pathwayHypoactivity:Hypoactivity:
negative, cognitive,negative, cognitive,and mood symptomsand mood symptoms
Tuberoinfundibular pathwayTuberoinfundibular pathway(inhibits prolactin release [D2])(inhibits prolactin release [D2])
HyperactivityHyperactivity::positive symptomspositive symptoms
(hallucinations,(hallucinations,delusions)delusions)
Mesolimbic pathwayMesolimbic pathway
DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA
Clinical profileClinical profile: Dopamine (D2) : Dopamine (D2) blockadeblockade
Mesolimbic Mesolimbic
MesocorticalMesocortical
NigrostriatalNigrostriatal
TuberoinfundibularTuberoinfundibular
EFFICACY: (+) SSX
INEFFICACY: (-) SSX, cognition, mood
SIDE EFFECTS: EPS
SIDE EFFECTS: HPL
D2
D2
D2
D2
SCHIZOPHRENIA (TREATMENT)
HIGH MEDIUM LOW
Fluphenazine Fluphenazine (D)(D)
TrifluoperazineTrifluoperazine
ThiothixineThiothixineHaloperidol Haloperidol (D)(D)
PerphenazinePerphenazineProchlorperazineProchlorperazineLoxapineLoxapineAcetophenazineAcetophenazineTriflupromazineTriflupromazineChlorprothixineChlorprothixineMesoridazineMesoridazine
ThioridazineThioridazineChlorpromazineChlorpromazine
EPS, HPL
Anti-H1: Sedation, wt gain
Anti-α-1: Orthostasis, reflex tachycardia
Anti-M1: Blurry vision, dry mouth, constipation, urinary retention, tachycardia, memory problems or delirium in susceptible patients
EPS, HPL
Anti-H1
Anti-α-1
Anti-M1
Seizure, arrythmias, retinitis, skin discoloration, photosens
EPS
• Dystonia – acute, involuntary muscle spasms often seen in ocular muscles and neck
• Parkinsonism – tremor, cogwheel rigidity, masked facies, and shuffling gait
• Akasthesia – a subjective sense of restlessness.
• Tardive Dyskinesia – long-term involuntary jerking of face, neck, trunk or extremities. May be permanent. http://www.youtube.com/watch?v=R0EbgpyztCA
ATYPICAL (SECOND GENERATION)
• Utilized in:• Acute Schizophrenia• Maintenance of Schizophrenia• Acute Mania• Maintenance of Bipolar• Treatment of Bipolar Depression
• Mechanism of Action: Blockade of D2 and 5HT-2A. Serotonin modulate dopamine, particularly in the nigrostriatal pathways. Hence, more Dopamine blockade in the mesolimbic as opposed to nigrostriatal pathways.
5HT DA release
DA
A. B.
C. D.
+/- DA release
DA5HT
ATYPICALS
• Often first line• Efficacy on positive and negative symptoms• NMS and EPS unlikely• Side Effects are based on receptor profile• Prolongation of QTc (Cardiovascular)• Metabolic Syndrome• Weight Gain• Glucose Intolerance• Increased Lipids and Triglycerides
MOOD STABILIZERS
LITHIUM
• Indicated for acute mania and maintenance bipolar• Specific evidence to support use in preventing
suicide• Blocks inositol-1-phosphatase• Narrow therapeutic range: dangerous in overdose• Side Effects:• Tremor• Renal Impairment• Thyroid Dysfunction• Cardiovascular
ANTICONVULSANTS
• Major Agents: Carbamazepine, Valproic Acid and Lamotrigene• May prevent kindling• Each agent has side effects that are outside
scope of this lecture
SUMMARY