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