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Depression as an Illness
Mood and physiological/biological changes Physiology: sleep EEG Neuroendocrine: Hypothalamus-pituitary-adrenal hormonal system Anatomic: Brain magnetic resonance imaging (MRI) Clear genetic component less pronounced than in schizophrenia, bipolar disorder. Multigenic, not Mendelian. Major depressive disorder is heterogeneous = several similar conditions with similar symptoms
Antidepressant Mechanisms
Three General Classes: 1. Amine uptake inhibitors 2. Monoamine oxidase inhibitors 3. Novel antidepressants
Result: rapid
Why do Antidepressants Take So Long to Work? Not just a simple deficit of 5-HT or NE
No consistent NE or 5-HT deficits found Amphetamines, cocaine increase 5-HT & NE, but are not antidepressants Monoamine Hypothesis of Depression (1950s - 1990s: RIP)
Antidepressants: Mechanisms
5-HT, Norepinephrine, (dopamine) Changes in 5-HT, NE, DA receptor stimulation, neuronal activity Changed neuronal sensitivity, growth factors (BNDF), gene expression, cell number & morphology
Minutes
2 - 6 Weeks
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CRF in Depression
CRF activity increased in depression CRF receptor type 1 antagonists reverse depression-like features in animal models
A Serotonergic Synapse
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Tertiary Amines: NE reuptake 5-HT reuptake blockade Secondary Amines: NE reuptake >> 5-HT reuptake blockade
NE
Moderate Very high Moderate High Very high Moderate
5HT
Moderate Very low Moderate Low Very low High
DA
0 0 0 0 0 0
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Drug
Anticholinergic
Sedation
++++ ++++ ++ ++ ++
Other Side Effects: Quinidine like antiarrhythmic Can cause cardiac conduction delay, heart block Serious risk of successful suicide by overdose Ingestion of a two week prescription may be fatal
All are approximately equally effective at appropriate doses (50 70% in most trials) May be more effective than SSRIs in severe depression Some individuals are more responsive to one agent than others: NE vs. 5-HT Selection is mostly on the basis of side effects
Fluoxetine (Prozac) 1988 Sertraline (Zoloft) 1992 Paroxetine (Paxil) 1993 Fluvoxamine (Luvox) 1994 Citalopram (Celexa)1998 Lexapro (Escitalopram) 2002
A Serotonergic Synapse
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Obsessive compulsive disorder (OCD) Post-Traumatic Stress Disorder (PTSD) Panic disorder Generalized anxiety disorder
And:
Eating disorders Premenstrual dysphoric disorder Social anxiety disorder
nervousness, insomnia, anxiety somnolence, loss of drive nausea, diarrhea sexual dysfunction weight loss or gain headaches Neuromuscular excitability (tremor/myoclonus) SSRI withdrawal syndrome with short half-lives headache, fatigue, insomnia, myalgias
Mostly very similar: Comparable efficacy, side effects Half-life: Long: Fluoxetine (Prozac) (3-11 days) - too long Moderate (~24hr): Sertraline, Paroxetine, Citalopram Long enough, but not too long Weak P450 interactions: Sertraline, Citalopram Individuals may have preferential response or side effects
F.I.N.I.S.H. Flu-like symptoms: fatigue, muscle aches, headache, diarrhea Insomnia: vivid or disturbing dreams Nausea Imbalance: gait instability, dizziness, lightheadedness, vertigo Sensory disturbance: paresthesia, electric shock sensation, visual disturbance Hyperarousal: anxiety, agitation Onset: 24-72 hours + Resolution: 1-14 days Incidence: ~ 20 - 40 % (who have been treated at least 6 weeks)
Venlafaxine (Effexor) Duloxetine (Cymbalta) Trazodone (Desyrel) Nefazodone (Serzone) Bupropion (Wellbutrin) Mirtazapine (Remeron)
SSRI-Plus: also have weak NE reuptake blockade (quite weak) May be more effective than other SSRIs? Side effects are essentially identical to other SSRIs except increased risk of hypertension Possible increased risk of liver damage (duloxetine)
Bupropion (Wellbutrin)
Mechanism of action: unique, not well understood Active metabolite: 4-hydroxybupropion (CYP2B6) Weak DA, NE uptake blocker Enhances Vesicular Monoamine Transporter-2 (VMAT2) = intraneuronal uptake of dopamine into synaptic vessicles Chronic nicotine may decrease numbers of VMAT2
? Related to bupropions action in smoking cessation
Novel mechanism: alpha2, 5HT-2, 5-HT3 antagonist Alpha2 blockade: probably contributes to therapeutic effect 5-HT2A antagonism: blocks sexual side effects 5-HT3 antagonism: may block some GI side effects
Mirtazapine Mechanism
Presynaptic alpha2 receptors mediate inhibition of NE release
1. Mirtazapine Takes the brakes off NE activity 2. Alpha1 receptors 5HT neuron activity 3. NE activity leads to 5-HT neuron firing
Mirtazepine (Remeron)
Side effects moderate Sedation: H1 histamine antagonism Weight gain Hypotension: Alpha1, 5-HT2 blockade Moderate anticholinergic activity. Little dopaminergic activity Agranulocytosis - rare but serious ? mechanism
Like Nefazodone, mechanism unclear - weak 5-HT reuptake blocker, 5HT2 partial agonist, alpha1 antagonist May have lower clinical efficacy than other agents Sedation prominent Often prescribed with SSRIs for sedative effect
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