Antidepressants and Antipsycotics

Major Depressive Disorder (MDD)

• depressed mood most of the time for least 2 weeks and/or loss of interest or pleasure in most activites

• disturbance in sleep

• reduced appetite

• deficits in cognition and energy

• thoughts of guilt, hopelessness, worthlessness are common

4 Major Hypotheses of Depression Pathophysiology

1. catecholamine hypothesis

2. Monoamine hypothesis

3. Neurotropic hypothesis

4. other factors

Catecholamine hypothesis

• decrease in functional concentration of NE and dopamine

Monoamine hypothesis

• decrease in functional concentration of NE, dopamine, and serotonin

• There is supporting evidence

neurotropic hypothesis

• loss of neurotropic support (BDNF)

• BDNF is essential for neural development

• There is supporting evidence

Monoamine Oxidase Inhibitors

• First generation

• rarely used today due to high toxicity

• compounds resemble amphetamine

• MAO metabolizes NE, dopamine, and 5-HT to inactive products

• Inhibit MAO in neurons, increasing concentrations of specific NTs

• inhibit MAO in the liver

• Have drug-drug interactions with TCA

• can lead to serotonin syndrome

• Food-drug interactions

Tricyclic Antidepressants

• 1st generation

• still used today

• Inhibit re-uptake of NE and 5-HT into neurons

• can also inhibit muscarininc receptors, histamine receptors, and adrenergic receptors

• Primarily metabolized by CYP2D6

• Drug-drug interactions:elevated concentration of TCAs, additive anticholinergic drugs

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Chemically diverse group of compounds

• stereo-specific

• most commonly used antidepressants

• Inhibit the re-uptake of 5-HT into neurons, increasing concentrations of this NT

• do not affect other receptors

• Mostly metabolized by CYP2D6, then CYP2C19, and CYP3A4

• drug-drug interactions:can be highly plasma bound, can inhibit CYP2D6 activity

Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• inhibit both 5-HT and NE reuptake into neurons

• do not affect other receptors

• known as balanced inhibitors

• commonly used antidepressants

• metabolized by CYP2D6

• no significant drug-drug interactions

5-HT2 Receptors Antagonists

• activation of 5-HT2A receptors

• competitive antagonists of serotonin

• Trazadone, and nefazodone

• metabolized to pharmacologically active compounds

• Drug-drug interactions: inhibitors of CYP3A4 and are highly bound plasma proteins

Miscellaneous compounds (tetracyclic and unicyclic)

• 2nd generation

• Amoxapine: metabolized to hydroxamoxapine

• maprotilene is a NE reuptake inhibitor

• both of these effect reuptake of monoamines

• Mirtazapine: balnced anti-depressant, potent antihistamine

• Bupropion: mechanism of action is unknown, smoking deterrant, no known effect on serotonin system

Neuroleptics

• antipsycotic drugs to treat schizophrenia and BPD

• typical and atypical

Typical neuroleptics

• work by dopamine antagonism

• metabolized by CYP450

Atypical neuroleptics

• may involve dopamine receptors and/or serotonin receptors

• metabolized by CYP450

Dystonia

involuntary muscle contractions that cause repetitive or twisting movements

Tardive dyskinesias

caused by long-term use of neuroleptic drugs, which are used to treat psychiatric conditions. Causes repetitive, involuntary movements

Akithisia

a feeling of muscle quivering, restlessness, and inability to sit still

2nd generation Anti-psycotics

• complex

• block 5-HT2a receptor activity

• partial agonsits of 5-HT1, synergistic effects with 5-HT2a

• metabolized by CYP2D6, 1A2, or 3A4

• oxidation or methylation

• lipid soluble, High Vd

• execrated in urine

• mechanism of action is unknown