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 diagnosis DSM-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 Glutamate GABA

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 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 (Li 2 CO 3 ) 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