Antidepressants & Neuroleptics

Lesson 20

Unipolar Depression

Major Depressive Disorder Extreme sadness & despair

extent & duration important Prevalence

females 9-26% males 5-12%

2:1 females ~

MAOIs Monoamine oxidase inhibitors

tranylcypromine (Parnate), phenelzine, (Nardil) NE, DA, 5-HT

Dietary restrictions (Cheese Effect) avoid foods containing tyramine metabolism amphetamine-like

risk of cerebral hemorrhages Many drug interactions Overdose risk ~

Nonselective Cyclic Antidepressants

Reuptake inhibitors DA, NE, & 5HT Tricyclic Antidepressants (TCA)

Imipramine, Desipramine Tetracyclic

Maprotiline Risk of many drug interactions (e.g.,

alcohol, neuroleptics, etc. ~

NSCA: Main Side Effects

Risk of overdose Mania or psychosis Sedation Anticholinergic syndrome

tremors, dry mouth, weakness, constipation, blurred vision, confusion

Impotence

Second GenerationAntidepressants

SSRIs Selective serotonin reuptake inhibitors

fluoxetine (Prozac, Sarafem) sertraline (Zoloft) paroxetine (Paxil) citalopram (Celexa) escitalopram (Lexapro) fluvoxamine (Luvox)

Fewer fx on NE & DA ~

SSRIs: Side Effects Fewer than TCAs

lower sympathetic arousal no anticholinergic fx

Serotonergic syndrome GI discomfort, anxiety, restlessness,

insomnia, etc. Sexual dysfunction Low risk of overdose Equally effective as TCAs ~

SSRIs: Pharmokinetics

All similar to fluoxetine (prozac) lipid soluble high protein binding

Half-life 2 - 3 days active metabolite 7 - 15 days

norfluoxetine ~

Other Selective Reuptake Inhibitors Norepinephrine Dopamine Reuptake

Inhibitor (NDRI) bupropion (Welbutrin) Also tx bipolar & Smoking cessation

(Zyban) Side fx

less sexual dysfuntion than SSRI Insomnia seizures - 150 mg/dose limit no subjective euphoria, abuse ~

Selective Serotonin Norepinephrine Reuptake Inhibitor (SNRI) venlafaxine (Effexor)

Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) 5HT2 –R: autoreceptor Anxiety disorders, bulimia

Noradrenergic/Specific Serotonergic Antidepressant (NaSSA) Mirtazapine (Remeron)~

Other Selective Reuptake Inhibitors

Schizophrenia

Disordered thoughts & bizarre behavior 1 percent of population equal among sexes

Progressive can only manage symptoms ~

Symptoms

Positive Symptoms Thought disorders Delusions Hallucinations

Negative Symptoms Poverty of speech Poverty of emotion Social withdrawal ~

Neuroleptic Drugs

Also called antipsychotics All Effective

No abuse liability Low overdose liability

Major side Effects: Motor impairments Agranulocytosis ~

Patient Populations: Mental Institutions

Thousandsof patients

400

300

200

100

1900 1930 1960 1975

600

500

YEAR

1956

First Generation Neuroleptics

Relieve only positive symptoms Chlorpromazine (Thorazine)

phenothiazines primarily blocks D1 & D2

Haloperidol (Haldol) butyrophenones primarily blocks D2

D2-R affinity and clinical potency ~

Strength of D2 binding

Therapeutic effects

Hi

LoChlorpromazine

Haloperidol

Spiroperidol

1st Generation: Pharmacokinetics

Administration Primarily p.o.; im for rapid effects

90-95% depot binding liver, lungs, adrenals, spleen

Long half-life Some metabolites active up to 3 mo.

No symptoms during this period compliance problems ~

Major Side Effects

Movement Effects (Extrapyramidal) Parkinsonism Akathisia Tardive Dyskinesia

Agranulocytosis white blood cells (WBC) Not frequent, but 50% mortality ~

Atypical Neuroleptics

Relieve negative & positive symptoms Lower M-PAT risk

tardive dyskinesia Atypical neuroleptics

affinity for D2-R 5HT antagonism ~

Clozapine Clozaril Agranulocytosis

Risperidone Risperdal agranulocytosis; M-PAT

Aripiprazole (Abilify) depression ~

Atypical Neuroleptics