Atypical Antipsychotic Dibenzo-oxepino pyrrole Metabolism: N-dealkylation follow by glucuronidation (Most recovered in urine and feces) Uses : Schizophrenia and Bipolar depression Side effect: Dementia in elderly Atypical Antipyschotic Piperidinyl benzisoxazole Metabolism: O- demethylation and carbony reduction Use: Schizophrenia Side effect: dementia in elderly

Atypical Antipsychotic Dihydrocarbostyril Administer: po and IM Partial agonist D2 and 5HT1A Antagonist at 5HT2A Side effect: Dementia in elderly Uses: Schizophrenia, Bipolar and Autistic disorders Atypical Antipsychotic Dihydroindolone D2 and 5HT2A antagonist Uses: Schizophrenia and Bipolar Side effect: dementia in elderly

Latuda (lurasidone HCI) Benzisothiazol D2 and 5-HT2A antagonist Marketed 2010

Clinical Depression is a mood disorder in which feelings of sadness, Loss, anger or frustration interfere with daily living Signs Expresses difficult sleeping or excessive sleeping Change in appetite Agitation, irritability Withdrawn Suicidal thoughts Common types Postpartum depression Premenstrual dysphoric disorder (one week before menstruation) Seasonal Affective Disorder (SAD) (Fall-Winter ends Spring-Summer)

Antidepressants (MAOI, Monoamine reuptake inhibitors and autoreceptor desensitizers and antagonist. Monamine oxidase inhibitors (MAOI) Nardil (Phenelzine sulfate) Irreversible inhibit MAO. What is the activity species? Parnate (Tranylcypromine sulfate) Amphetamine like activity

Monoamine Reuptake Inhibitors (Norepi and 5HT) SAR for Tricyclic Antidepressant (TCA) Two aromatic ring with a central ring Link to amine by 2 or 3 carbon atoms Tend to have high 5HT to NE reuptake blockage Monomethylated amine compounds are selective towards NE reuptake Anticholinergic effect for dimethylated amine It has both peripheral and central activity Overdose can be lethal Tofranil (Imipramine hydrochloride) Lead TCAs. It is closely related to antipsychotic phenothiazines Mainly effect serotonin, Norepi and dopamine through transporters. High serotonin to Norepi uptake ratio blockage (sertonin reuptake inhibitor (SERI). Weak D 2 postsynaptic antagonism Anticholinergic and sedative effects (blocking H 1 in brain) Metabolism oxidation at 2 follow by glucuronidation Imipramine (NSRI)

Elavil (Amitriptyline hydrochloride) Most anticholinergic and sedative effects of TCA (NSRI) Metabolism at 10 position (hydroxylation) and at 5 position followed by conjugation. N-demethylation occurs resulting in a metabolite with less anticholinergic and sedative effect but more stimulation. Its metabolite is a selective norepinephrine reuptake inhibitor, Aventyl (SNRI). Anafranil (Clomipramine hydrochloride) 50 times more potent imipramine Increase in CNS penetration Use obsessive-compulsive disorder, antianxiety and antidepressant Protonated form believe to appear beta arylamine (NSRI)

Adapin, Sinequan (Doxepin hydrochloride) Norepi and 5-HT reuptake blocker. The Z isomer is the more active. It is marketed as a mixture. Anticholinergic and sedative effects (NSRI) Cymbalta (S-(+)-Duloxetine) (NSRI)

Selective Norepinephrine reuptake inhibitors (SNRIs) Norpramin (Desipramine hydrochloride) Selective norepinephrine reuptake inhibitor (SNRI) Active metabolite of imipramine Decrease in anticholinergic and sedative effect Metabolism 2 –hydroxylation follow by gluc. Aventyl (Nortriptyline hydrochloride) Selective Norepinephrine reuptake inhibitor (SNRI) Active metabolite of amitriptyline. Metabolism: N-demethylation, 10- hydroxylation

Vivactil (Protriptyline hydrochloride) Relocation of double when compared with Aventyl (SNRI) Surmontil (Trimipramine Maleate) Marketed as a racemic Activity similar to Tofranil (SNRI)

Asendin (Amoxapine) Dibenzoxazpin Antidepressant/antipsychotic Active metabolite of loxapine D 2 receptor antagonism (SNRI) Vestra (Reboxetine) S,S, isomer is the active one (marketed enantiomeric mixture) Europe (SNRI)

Ludiomil (Maprotiline HCl) Tetracyclic compound Low anticholinergic effects CNS Stimulation Metabolism N- demethylation (active metabolite) (SNRI) Strattera ( R-Atomoxetine) Marketed as non-stimulant for ADD (2003) R-enantiomer (10 x more potent than S isomer) Similar to Prozac in structure. (SNRI) Metabolism N-demethylation another route p-hydroxylation Follow by gluc.

Nisoxetine Use as antidepressant In Europe (SNRI)

Prozac (Fluoxetine) Protonate it can for a pseudo ring. S isomer is more selective for SERT than Norepi transporter (NET) protein Movement of para substituent to orthro produce selective norepinephrine reuptake inhibitors. 2 or more weeks are required before antidepressant effect (desensitization of 5HT1A autoreceptor). Use for depression and anxiety (SSRI) Paxil (3S, 4R -Paroxetine) Contrained analogue of Prozac Very highly selective for SERT. (SSRI) Metabolism: formation of Catechol follow by gluc. Selective Serotonin Reuptake inhibitors (SSRIs) Structural differ than tricyclics in that tricyclic has been separate. Competitive inhibition of Sertonin transporter protein (SERT) Little anticholinergic activity by breaking ring structure

Zoloft (Sertraline) (1S, 4S) structure Stereochemistry is important for activity (SSRI) Metabolism: N-demethylation Luvox (Fluvoxamine) Nontricyclic SERT inhibitor E isomer Protonated folds back to form a pseudo ring Protected from light (convert Z-isomer) (SSRI)

Lexapro (S-Escitalopram) No advantage giving pure isomer Celexa is racemic mixture Metabolism: N-demethylation to active metabolite (SSRI)

Nontricyclic Nonselective Norepi and 5-HT reuptake inhibitors Effexor (Venlafaxine) Resemble open TCA Metabolism: O-demethylation (active metabolite) NSRI Selective Serotininergic Reuptake inhibitors and 5HT 2A Antagonists Desyrel (Trazodone) Metabolism: N-Dealkylation to m-chloropiperazine active metabolite

Serzone (Nefazodone) Structure similar to fluorobutyrophenone antipsychotics. Bind to SERT and active as 5HT 2A Antagonists. What metabolite is generated for both of the drugs? 5HT 1A Agonists and Partial Agonists BuSpar (Buspirone) Partial 5HT 1A agonist (decrease release of 5HT) (antianxiety) Postsynaptic receptors stimulation (anti-depressive)

Miscellaneous Antidepressant Wellbutrin (Bupropion) Complex mechanism involving dopamine transporter protein (DAT) and as well as norepi reuptake. What is the cyclic metabolite responsible for its activity? Remeron (Mirtazpine)  2 -antagonist/serotonin antagonist Metabolism: N-demethylation And hydroxylation of pyridine (8-position)

Other Treatments for Clinical Depression Lithium carbonate treat manic depression (mood stabilizer) Electroconvulsive therapy effect gold standard for treatment of major depression Herbal therapy (St. John Wort) works like SSRI

Structure of Key Neurotransmitters

Pristiq (desvenlafaxine) This a metabolite of which drug? Approved as antidepressant February of 2008 New Antidepressant Future class of Antidepressant called TRI