Psychopharmacology of Mood Disorders

Therapeutic agents

Mood stabilizing agents: lithium, anticonvulsants

Antidepressants: Tricyclic, SSRI’s, MAOI’s, novel antidepressants

Somatic therapies: electroconvulsive therapy (ECT), Transcutaneous magnetic stimulation (TMS)

Mood Stabilizing Agents

Lithium

Mechanism:

inhibition of inositol monophosphatase (secondarily modulates secondary messenger production via IP₃/DAG pathway)

modulation of neurotransmitter receptor actions via longterm efects on gene transcription and regulation of G protein actions,

inhibition of glycogen synthase Kinase (GSK) Þ not clear which of these actions is most important

Indications: Bipolar disorders, acute or chronic mania

Toxicity: increases the toxic effects of other psychotic drugs

Anticonvulsants

General Mechanism: modulate neurotransmission via alteration of GABA-ergic neurotransmission, modulate gene expression via GSK or Protein Kinase C; ultimate mechanism still unclear

Side effects:

Carbamazepine: Ý risk of agranulocytosis (acute ß of PMN’s) risk not as great as seen in clozapine

indications: bipolar disorder

Valproic acid: hepatotoxicity and polycystic ovary disease

Action: may modulate GABA transmission

Lamotrigine: Stevens-Johnson Syndrome (acute bullous form of erythema multiforme terminating in a fatal course), rash, nausea

GABApentin: ataxia (inability to coordinate voluntarymovement), hypotension

Antidepressants

Tricyclic antidepresants (TCA’s)

Mechanism: inhibit norepinephrine and serotonin reuptake via inhibition of Norepinephrine Transporter (NET) and SERT, Down regulation of b adrenergic/5-HT₂a receptors, alterations in signal transduction, modulation of gene transcription (esp. Brain Degredative Neurotrophic Factor (BDNF), trkB)

Side effects: anticholinergic (dry mouth, tachycardia, sweating), Anti a ₁-adrenergic (orthostatic hypotension), Antihistamine, Cardiotoxicity - lethal overdose (10 day supply can KILL you!!!)

Secondary amines: fewer side effects than tertiary amines, Norepinephrine (NE) reuptake inhibition

Tertiary amines: inhibit norepinephrine and Serotonin reuptake

Serotonin (5-HT) selective reuptake inhibitors (SSRI’s)

Mechanism:

inhibit reuptake of 5-HT
desensitization of autoreceptors (leads to greater 5-HT neurotransmission)
changes in gene transcription - leads to long term therapeutic effects (e.g. trkb, CREB, BDNF - causes neurodegeneration and elevated in depression, SSRI’s stop its production - justifies long-term therapy)

Side effects: Nausea, anxiety, insomnia, sexual dysfunction (anorgasmia, impotence), contraindicated with MAOI’s

Fluoxetine (Prozac): Serotonin syndrome - fatal drug interaction with MAOI’s because together serotonin is neither being broken down or taken up Þ sudden Ý in serotonin Þ fatality

Sertraline (Zoloft): less interference with P450 (therefore fewer drug interactions)

Paroxetine (Paxil): large degree of P450 inhibition

Citalopram (Celexa): most selective SSRI (whatever that means)

Fluvoxamine (Luvox): for obsessive-compulsive disorder (OCD)

Clomipramine (anafranil): serotonin selective, OCD

Indications: anxiety, depresion, obsessive-compulsive disorder, panic disorder

All SSRI’s have nearly EQUIVALENT therapeutic efficacies

Monoamine oxidase inhibitors (MAOI’s)

Mechanism: inhibits breakdown of monoamines (norepinephrine, dopamine, serotonin) by blocking monoamine oxidase (enzyme in outer membrane of mitochondria)

Drugs: Phenylzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan)

Side effects: Fatal interactions with foods rich in tyramine (cheese, yeast products (beer), fermened sausages, guac dip, fava beands, chianti wine ). Tyramine acts as ligand for adrenergic receptors Þ release of norepinephrine and epinephrine Þ hypertensive crises

Very safe compared to other drugs, can’t lethally overdose

Mixed action antidepresants

Mechanism:

enhance serotonin and/or norepinephrine neurotransmission acutely

induce compensatory alterations in norepinephrine and/or serotonin neurotransmission (b-adrenergic/5-HT_2A/5-HT_1A receptor down-regulation/desensitization)

induce

compensatory alterations in gene transcription (BDNF, CREB, trkB)

Side effects:

Venlafaxine (Effexor): 5-HT and norepinephrine reuptake inhibition; faster onset of action, fewer side effects than TCA’s

Nefazadone (Serzone): 5-HT reuptake inhibition and 5-HT_2A receptor blockade; sedating; less effective; good antipanic/antianxiety

Mirtazapine (Remeron) a ₂-adrenergic antagonist (enhances norepinephrine release); 5-HT_2A antagonist

Buproprione (Wellburint): norepinephrine and dA reuptake inhibitor; fewer sexual side-effects

Indications: those patients with sexual side effects taking SSRI’s

Somatic Therapies

(1) Electroconvulsive therapy (ECT) Gold standard for depression therapy

Mechanism: leads to acute enhancement of neurotransmission, alterations in receptor activities, gene transcription occurs quicker with ECT than medications

(2) Transcranial magnetic stimulation (TMS)

Mechanism: unclear, may be less effective than ECT