Antidepressants

Drugs Used in Affective Disorders

MOOD/MOOD DISORDER

• Sustained emotion

INCIDENCE

• Higher in women than in men• Between ages 25 to 44

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

ETIOLOGY

• Biogenic amine theory• Dysregulation theory• Family history

Range of emotions

• Euthymia• Hypomania• Euphoria• Mania• Dysthymia• Dysphoria• Depression

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

Treatment

• Psychotherapy• Pharmacotherapy• ECT

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

Drug selection/administration

• All drugs are equally effective• Half the lowest dose• 1-2 wks• 4-6wks• Try onother class

Changing antidepressant

• 2 wks• 5 wks with fluoxetine

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)

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

SSRI

• Fluoxetine• Fluvoxamine• Nefazodone• Paroxetine• Sertraline• Trazodone• venlafaxine

SSRIs

• Am bec of its stimulatory effect• Metabolize via cytochrome P450

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

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.

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)

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.

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

Cyclic Antidepressants Therapeutic Uses

• Depression• Childhood enuresis (imipramine)• Obsessive-compulsive disorders

(clomipramine)• Adjunctive analgesics• Trigeminal neuralgia

TCA– PM DOSAGE ALL- SEDATING ACTIVITY– 4-6 WKS- FULL RESPOSE– 1 WK ASSYMPTOMATIC RELIEF– ANTICHOLINERGIC SIDE EFFECTS

Cyclic Antidepressants Side Effects

• Sedation• Impotence• Orthostatic hypotension• Older patients:– dizziness, postural hypotension, constipation,

delayed micturation, edema, muscle tremors

TCA

• TCA USER• HEALTHY • NONSUICIDAL• REFRACTORY TO NEWER DRUGS

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

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

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)

MAOI

• ATYPICAL DEPRESSION• HYPERSOMNIA• AGITATION• ANXIETY

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

Side effects

• Othostatic hypotension• Weight gain• Edema• Sexual dysfunction• Hepatocellular damage-isocarboxacid

MANIA

Etiology

• Genetics• Neurotransmitter level• GABA level• Calcium• G proteins• Psychosocial and physical stressors

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

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

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

LITHIUMBaseline

labsAdverse effects

Thyroid function

hypothyroidism

BUN/Crea Renal insufficiency

Electrolytes (esp.sodium)

Dec. Na

CBC leukocytosis

• Alternative mood-stabilising drugs (e.g. carbamazepine, valproate, gabapentin,clonazepam)

Summary

• ANTICHOLINERGIC-TCA• CHLOMIPRAMINE-OC• IMIPRAMINE –NOCTURNAL• MAOI- HYPERTENSIVE CRISIS• SEIZURE-SE OF BUPROPION