antidepressants
TRANSCRIPT
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Drugs Used in Affective Disorders
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MOOD/MOOD DISORDER
• Sustained emotion
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INCIDENCE
• Higher in women than in men• Between ages 25 to 44
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Etiology of Depression
Biogenic Amine Hypothesis • Depression and mania are due to an alteration in neuronal
and synaptic catecholamine concentration at adrenergic receptor sites in the brain.
– Depression: deficiency of catecholamine, especially norepinephrine
– Mania: excess amines
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ETIOLOGY
• Biogenic amine theory• Dysregulation theory• Family history
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Range of emotions
• Euthymia• Hypomania• Euphoria• Mania• Dysthymia• Dysphoria• Depression
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Clinical features of major depression
One of the following must be present:– Depressed mood– Anhedonia (i.e., loss of interest or pleasure)
Plus four or more of the following:– Decreased or increased appetite– Unintentional weight loss or gain– Insomnia or hypersomnia– Psychomotor agitation or retardation– Fatigue or loss of energy– Feelings of worthlessness or excessive or inappropriate
guilt– Diminished ability to think or concentrate or
indecisiveness– Recurrent thoughts of death and/or suicidal ideation– Suicide attempt
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Treatment
• Psychotherapy• Pharmacotherapy• ECT
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Treatment phases for depression
Treatment phase Duration Goal
Acute 6 weeks Resolve symptoms
Continuation 6-9 months Prevent relapse
Maintenance 3-5 years of lifelong Prevent recurrence in high risk patients
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Drug selection/administration
• All drugs are equally effective• Half the lowest dose• 1-2 wks• 4-6wks• Try onother class
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Changing antidepressant
• 2 wks• 5 wks with fluoxetine
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Clinical manifestations of serotonin syndrome and serotonin withdrawal syndrome
Classification of dysfunction
Serotonin syndrome Serotonin withdrawal syndrome
Cognitive-behavorial dysfunction
Confusion HypomaniaAgitation
none
Autonomic nervous system dysfunction
Diarrhea DiaphoresisShivering Fever Changes in blood pressureNausea and vomitting
Flu-like symptomsDizzinessLight headednessChills Sleep disturbances
Neuromuscular dysfunction
Myoclonus HyperreflexiaTremor SeizureDeath
Lethargy Myalgia sensory disturbances (e.g., paresthesia)
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Selective 5-HT uptake inhibitors (SSRI)
• 1st line for depression• Actions similar in efficacy & time course to TCA • Acute toxicity is less than that of MAOI or TCA • Side-effects include nausea, insomnia & sexual
dysfunction. • dangerous 'serotonin reaction' – (hyperthermia, muscle rigidity, cardiovascular collapse)
can occur if given with MAOI. • Long half-lives
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SSRI
• Fluoxetine• Fluvoxamine• Nefazodone• Paroxetine• Sertraline• Trazodone• venlafaxine
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SSRIs
• Am bec of its stimulatory effect• Metabolize via cytochrome P450
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SSRI’s• Fluoxetine- bulimia– Most stimulatory– For depression with negative symptoms
• Paroxetine– Most sedating– Depression with anxiety and insomnia
• Sertraline– Less stimulatory and less sedating
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Tricyclic antidepressants (TCA) • TCA are chemically related to phenothiazine• 2nd line of choice • Inhibit reuptake of serotonin and norepinephrine• Important side-effects:
– sedation (H1-block), postural hypotension (α-adrenoceptor block), dry mouth, blurred vision, constipation (muscarinic block), occasionally mania and convulsions.
– Risk of ventricular dysrhythmias through potassium channel block.
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Cyclic Antidepressants• Tricyclic antidepressants—primary: amitriptyline
(Elavil), doxepin (Sinequan), imipramine (Tofranil)• Tricyclic antidepressants—secondary:
desipramine (Norpramin), nortriptyline (Aventyl), protriptyline (Vivactil)
• Tetracyclic antidepressants: amoxapine (Asendin), maprotiline (Ludiomil)
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Cyclic Antidepressants Mechanism of Action
• Block reuptake of neurotransmitters, causing accumulation at the nerve endings.
• It is thought that increasing concentrations of neurotransmitters will correct the abnormally low levels that lead to depression.
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Cyclic Antidepressants Mechanism of Action—Drug Effects
Blockade of norepinephrine:– antidepressant, tremors, tachycardia, additive
pressor effects with sympathomimetic drugs
Blockade of serotonin:– antidepressant, nausea, headache, anxiety,
sexual dysfunction
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Cyclic Antidepressants Therapeutic Uses
• Depression• Childhood enuresis (imipramine)• Obsessive-compulsive disorders
(clomipramine)• Adjunctive analgesics• Trigeminal neuralgia
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TCA– PM DOSAGE ALL- SEDATING ACTIVITY– 4-6 WKS- FULL RESPOSE– 1 WK ASSYMPTOMATIC RELIEF– ANTICHOLINERGIC SIDE EFFECTS
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Cyclic Antidepressants Side Effects
• Sedation• Impotence• Orthostatic hypotension• Older patients:– dizziness, postural hypotension, constipation,
delayed micturation, edema, muscle tremors
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TCA
• TCA USER• HEALTHY • NONSUICIDAL• REFRACTORY TO NEWER DRUGS
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Monoamine oxidase inhibitors (MAOI)
• Action is long lasting (weeks) due to irreversible inhibition of MAO A & B.– Moclobemide has a short duration of action
• 3rd line of choice • Main side-effects:
– postural hypotension (sympathetic block)– atropine-like effects (as with TCA); – weight gain – CNS stimulation – Serotonin syndrome– liver damage (rare). ISOCARBOXAZID
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Antidepressants: MAOIs Hypertensive Crisis and Tyramine
• Ingestion of foods and/or drinks with the amino acid TYRAMINE leads to hypertensive crisis, which may lead to cerebral hemorrhage, stroke, coma, or death
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Antidepressants: MAOIs Hypertensive Crisis and Tyramine
Avoid foods that contain tyramine!• Aged, mature cheeses (cheddar, blue, Swiss)• Smoked/pickled or aged meats, fish, poultry (herring,
sausage, corned beef, salami, pepperoni, paté)• Yeast extracts• Red wines (Chianti, burgundy, sherry, vermouth)• Italian broad beans (fava beans)
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MAOI
• ATYPICAL DEPRESSION• HYPERSOMNIA• AGITATION• ANXIETY
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Monoamine oxidase inhibitors (MAOI)
• Phenelezine,Tranylcypromine,• Isocarboxazid– Rarely clinical due to serotonin syndrome– hypertensive crisis- most common (tyramine-rich foods)– 3 -4 wks- do not discontinue– Insomnia effect – not at pm
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Side effects
• Othostatic hypotension• Weight gain• Edema• Sexual dysfunction• Hepatocellular damage-isocarboxacid
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MANIA
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Etiology
• Genetics• Neurotransmitter level• GABA level• Calcium• G proteins• Psychosocial and physical stressors
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Symptoms of mania
• Grandiose ideations or expansive self-esteem• Decreased need for sleep• Pressured speech• Racing thoughts or flight of ideas• Distractability• Psychomotor agitation• Engaging in dangerous, high-risk activities
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LITHIUM• Mechanism of Action–? –alters intracellular second messengers:
adenyl cyclase-cyclic AMP system and the G protein-coupled phosphoinositide systems (NE and serotonin)–alters ion channel function–alters metabolism of GABA
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LITHIUM• Adverse effects–Narrow therapeutic index –Therapeutic range: 0.5-1.5mEq/L–Minor S/E: tremors, polyuria,
GI distress, memory problems, acne, weight gain – Long-term S/E: hypothyroidism –Toxic levels: ataxia, tremors, confusion, coma, sinus
arrest, death
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LITHIUMBaseline
labsAdverse effects
Thyroid function
hypothyroidism
BUN/Crea Renal insufficiency
Electrolytes (esp.sodium)
Dec. Na
CBC leukocytosis
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• Alternative mood-stabilising drugs (e.g. carbamazepine, valproate, gabapentin,clonazepam)
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Summary
• ANTICHOLINERGIC-TCA• CHLOMIPRAMINE-OC• IMIPRAMINE –NOCTURNAL• MAOI- HYPERTENSIVE CRISIS• SEIZURE-SE OF BUPROPION