Julie Kennedy

Symptoms•Anhedonia- loss of interest in everyday activites

•Despondent mood•Altered sleep patterns•Changes in weight/appetite•Persistent feelings of guilt •Morbid thoughts•Agitation•Inability to concentrate•Loss of executive memory•Indecisiveness

•Depleted monoamine neurotransmitters: serotonin, norepinepherine, dopamine•Degeneration of neurons and synaptic connectivity•Decreased GABA levels•Imbalanced HPT (hypothalamic-pituitary-thyroid) axis•Increased cytokine levels

Physiological effects

Systems of diagnosisDSM-IV• Major depressive disorder: 2 weeks depressed mood or loss of interest accompanied by 4 additional symptoms

• Dysthymic disorder: 2 yrs depressed mood for more days than not

ICD-10• Mild to moderate depression: common symptoms + functional impairment

• Severe depression: physical symptoms

Treatments available

• Antidepressant drugs (SSRIs, TCAs, MAOIs)

• Counseling (Cognitive therapy, interpersonal psychotherapy, non-directive counseling, befriending, exercise, problem solving therapy)

• Natural supplements (St Johns Wort)• Electroconvulsive therapy (ECT)

Electric shock treatment• Anaesthetisia,

muscle relaxant administered to avoid self-injury

• Electrical current passed through brain to induce seizure

• Unknown method of action (thought to involve NTs)

• Mainly for drug resistant depressed patients

• 10% inpatients receive ECT

• 70% of all patients receiving ECT are women

• Older patients more common

• More common in Asia, S. America, Africa--may be used without anaesthesia & muscle relaxants

Targets of antidepressants

• Monoamine neurotransmitter receptors

• Monoamine reuptake transporters

• Glutamate receptors (NMDA, mGluRs)

• GABA receptors, transporters

Serotonin

Norepinepherine

Dopamine

GlutamateGABA

Monoamine Oxidase Inhibitors

• 1st antidepressants introduced (iproniazid, antitubercular agent)

• Inhibit degradation of catecholamine to aldehydes

• Mechanis of MAOI action not well understood

• More likely to have side effects

• Used more commonly for atypical depression

• Interaction with tyramine (cheese)--MAOIs enable its systemic circulation

Tricyclic antidepressants

• Three fused rings (6,7,6 carbons)

• Inhibit serotonin and norepinepherine reuptake

• Developed from antihistamines

• Common side effects: dry mouth, constipation, dizziness

Desipramie

Imipramine

Selective Serotonin Reuptake

Inhibitors

•Mode of action remains largely inconclusive•Direct-to-consumer marketing•Sales exceed $17 billion worldwide in 2003•Interference with MDMA, cocaine, TCAs•May intitially increase suicide risk

•Similar efficacy with Tricyclic’s, but lower side effects•Introduced in the 1980s-90s•Block serotonin uptake @ presynaptic 5-HT transporter•Act on 4-TM ion channel receptors and 7-TM GCPRs

Theories for 2-3 week delay in effectivness

• Quickly increase serotonin concentraion, which inhibits 5-HT firing, autorecptors become desensitized after prolonged SSRI exposure

• Feedback regulation at 5-HT receptors requiring chronic administration to sustain therapeutic sertonin levels

• Need for alterations in genetic ∂ and ß-adrenergic receptor expression

• Changes in nerve connectivity and neurotrophic factors

Common SSRIs • Fluoxetine (Prozac): best selling antidepressant, 1st SSRI to have real success

• Sertraline (Zoloft): 6th best-selling overall med. In the US in 2004 ( >$3 bill.)

• Paroxetine (Paxil)” short half-life, controlled release available

Serotonin-Norepinepherine

reuptake inhibitors• Even newer, less selective

• Faster onset• Venlafaxine (Effexor): 1993, generic 2006

• Duloxetine (Cymbalta): lower risk of relapse

• Common side effects: sweating, weightloss, nausea, diarrhea, constipation, vomiting, dry mouth

Norepinepherine reuptake inhibitors

• Introduced in 1970s to increase selectivity

• Reboxetine: most effective at improving social functioning

• Side effects: blurred vision, hypotension tremors, headache, urinary hesitancy

Dopamine agonists

• Bupropion (Wellbutrin): blocks reuptake of norepinepherine and dopamine, less risk of side effects, used as an aide to quit smoking(Dopamine)

Lithium

• Lithium bicarbonate (Li2CO3)

• Most commonly used for bipolar disorder

• Mode of action poorly understood, thought to reduce the action of the HPT system

• Dosed by augmentation (increasing until desired effects acheived)

Antidepressant Dis-continuation

Syndrome• Occurs within 3 days of cessation, only occurs after taking antidepressants for at lease 6 weeks

• Also occurs when switching antidepressants or switching to generic “equivalent” (may be up to 20% different)

• Flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, hyperarousal

• Generally resolves itself after 2 weeks

• Misleadingly termed “withdraw,” since antidepressant are not habit-forming

Future of anitdepressants

• Many aspects of both depression and action of antidepressants remain not well understood

• Much room for development: increased specificity, decreased side effects, decreased time for onset of action