Drugs for Affective Disorders

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jncates
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210827
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Drugs for Affective Disorders
Updated:
2013-04-01 23:36:38
Tags:
Pharmacology Affective Disorders Mania Depression Bipolar
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Description:
treatment of Affective disorders
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  1. Mania
    abnormally elevated, expansive or irritable mood

    • includes (3 of following):
    • inflated self esteem or grandiosity
    • decreased need for sleep
    • pressured speech
    • racing thoughts
    • distractibility
  2. Depression
    abnormal depressed mood or anhedonia

    • including (4 of the following):
    • appetite disturbance
    • sleep disturbance
    • activity disturbance
    • abnormal fatigue
    • abnormal self reproach or guilt
    • poor concentration or indecisiveness
    • recurrent thoughts of suicide

    not attributable to psychosis, physical illness, alcohol, medication, street drugs, bereavement

    there also cant be any manic episodes or hypomanic
  3. Affective disorders
    different types
    • Major Depressive Disorder
    • Manic episodes
    • Hypomanic episodes
    • Mixed episodes - features of both depression and mania
    • Bipolar I disorder - one or more manic or mixed manic episodes
    • Bipolar II disorder - one or more episodes of BOTH hypomania and depression
    • Cyclothymic disorder - 2 years of cycling mood with hypomanic and depressive
  4. Monoamine theory
    too much serotonin and NE leads to mania

    not enough serotonin and NE leads to depression
  5. Mechanisms of Antidepressant action
    • Reuptake inhibitors - increase extraneuronal levels of 5-HT and NE
    • Tricyclic antidepressants - block neuronal reuptake of NE and 5-HT
    • Selective Serotonin Reuptake Inhibitors - block reuptake of 5-HT
    • Selective NE Reuptake Inhibitors - block reuptake of NE

    • Monoamine Oxidase Inhibitors (MAOI's)
    • inhibition of MAO-A increases intraneuronal levels of NE and 5-HT
  6. Dysregulation hypothesis
    Depression results from dysregulated output of adrenergic/serotonergic transmission. Antidepressant Effect (delayed 2-4 weeks) is thought to arise from downregulation of β and a2 adrenergic and 5-HT receptors. This   restores normal homeostatic neuronal regulation
  7. Tricyclic Antidepressants
    • Imipramine (Tofranil)
    • Desipramine (Norpramin)
    • Amitriptyline (Elavil)
    • Nortriptyline (Pamelor)
  8. SSRI's
    • Fluoxetine (Prozac/Sarafem)
    • Sertraline (Zoloft)
    • Paroxetine (Paxil)
    • Citalopram (Celexa)
    • Escitalopram (Lexapro)
    • Fluvoxamine (Luvox)
  9. Other NE and 5-HT reuptake inhibitors
    • Bupropion (Wellbutrin) - NE and DA
    • Venlafaxine (Effexor) - 5-HT and NE
    • Duloxetine (Cymbalta) - 5-HT and NE
    • Mirtazapine (Remeron)
  10. SNRI's
    Atomoxetine (Srattera)
  11. Tertiary Amines vs Secondary Amines
    Imipramine and Amitriptyline are tertiary amines with 5-HT action more than NE

    Desipramine and Nortriptyline are secondary amines with NE action more than 5-HT
  12. Effects of antidepressants
    • Normal Subject
    • Perceived as unpleasant
    • Increased anxiety
    • sedation
    • clumsiness
    • difficulty thinking
    • poor judgement

    • Depressed Subject
    • Elevation of mood

    All antidepressants are equally effective and have the same delayed onset of therapeutic effects... therefore consider side effects for different ones
  13. Reuptake inhibitor major side effects
    • tertiary TCA's > Secondary TCA's > SSRI's
    • sedation
    • antimuscarinic
    • orthostatic hypotension
    • cardiovascular problems
    • weight gain

    • SSRI's > Secondary TCA's > Tertiary TCA's
    • agitation/insomnia
    • GI distress
    • Sexual Dysfunction
  14. Sedation causes for Reuptake inhibitors
    Due to H1 receptor blockade

    • tertiary TCA's high
    • secondary TCA's medium
    • SSRI's none

    • others
    • Bupropion none
    • Trazodone high

    • therefore give TCA's or Trazodone at night
    • give SSRI's or Bupropion in AM or early PM
  15. Antimuscarinic Side Effects for Reuptake inhibitors
    • 3 TCA's high
    • 2 TCA's medium
    • SSRI's low

    • Dry mouth
    • blurred vision
    • constipation
    • urinary retention
    • mydriasis
    • tachycardia
    • confusion

    • use TCA's with caution in patients with:
    • Angle Closure Glaucoma
    • BPH
    • Anticholinergics - Paralytic Ileus
    • Dementia / cognitive dysfunction
  16. Orthostatic Hypotension side effect in Reuptake inhibitors
    Due to a1 blockade

    • 3 TCA's high
    • 2 TCA's medium
    • SSRI's low

    serious problem in elderly
  17. Cardiovascular Effects as side effects in Reuptake inhibitors
    TCA's can increase the probability of Ventricular arrhythmias by inhibiting fast sodium channels... (QRS prolong)  also block potassium channels causing prolongation of QT interval

    • 3 TCA high
    • 2 TCA medium
    • SSRI none

    • TCA's with caution in patients with 
    • Dysrhythmia
    • Ischemic Heart Disease
  18. Weight Gain as SE of reuptake inhibitors
    • 3 TCA's high
    • 2 TCA's medium
    • SSRI's medium

    • Use TCA's in anorexic patients (HIV or cancer)
    • Use TCA's with caution in diabetics
  19. Agitation/Insomnia as SE of reuptake inhibitors
    prolong REM stage, less restfull sleep, activating, sleep may improve over time

    • SSRI's high
    • 2 TCAs low
    • 3 TCAs none/low
    • Bupropion high
    • Trazodone None

    Activating properties may be beneficial in some patients
  20. GI distress as SE of reuptake inhibitors
    diarrhea, remits after about 1 week 

    • SSRI's high
    • TCA's low

    • Take SSRIs with a meal to reduce GI irritation
    • TCA's lead to constipation
    • SSRI's lead to diarrhea
  21. Other Side Effects of reuptake inhibitors where TCA's=SSRIs
    • lower seizure threshold
    • use with caution in patients with history of seizures

    • Provoke switch in bipolar disorder
    • Any antidepressant can switch bipolar patient to mania
  22. Acute overdose symptoms with reuptake inhibitors and Acute MAO inhibitors
    • agitation
    • coma
    • depressed respiration
    • hyperthermia
    • hypotension
    • mydriasis
    • flushed skin
    • seizures
    • cardiac rhythm disturbances

    • Treatment:
    • gastric lavage with activated charcoal
    • DO NOT use physostigmine as it may aggravate conduction disturbances

    • Treatment of MAO inhibitor overdose
    • Maintain vitals and late toxic effects may occur
  23. Drug interactions of TCA's
    • inhibition of CYP450 isozymes
    • additive antimuscarinic activity
    • potentiate direct acting sympathomimetics
    • block indirect acting sympathomimetics (tyramine)
    • block antihypertensive effects of a2 agonists (Clonidine / Methyldopa)
  24. Serotonin Syndrome
    TCA's and SSRIs are incompatible with MAO inhibitors


    • Symptoms
    • hyperthermia
    • diaphoresis
    • myoclonus
    • hyperreflexia
    • autonomic instability
    • coma
    • death

    NO TREATMENT
  25. Reuptake inhibitors to use for OCD
    • Clomipramine - most effective
    • Fluvoxamine also approved
  26. Reuptake inhibitors used in Panic disorder
    • Paroxetine 
    • Sertraline
  27. Reuptake inhibitors to use in generalized and social anxiety disorder
    • Paroxetine 
    • Sertraline
  28. Reuptake inhibitors to use in ADHD
    Desipramine
  29. Reuptake inhibitors to use in Bulimia Nervosa
    • Fluoxetine
    • TCA's
  30. Reuptake inhibitors to use in PTSD
    • Sertraline
    • Paroxetine
  31. Reuptake inhibitors to use in chronic pain
    amitriptyline
  32. Reuptake inhibitors to use in Nocturnal Enuresis
    Imipramine
  33. Reuptake inhibitors to use in Migraine Prophylaxis
    • TCA's and SSRIs
    • Propranolol
    • Valproic Acid
    • CCB's
  34. Reuptake inhibitors to use in Premenstrual Dysphoric Disorder
    SSRI's
  35. Reuptake inhibitors to use in obesity
    fluoxetine
  36. Bupropion
    Dopamine and NE reuptake inhibitor

    • SE
    • psychosis
    • high incidence of seizures
    • low incidence of sexual dysfunction

    Also used for smoking cessation
  37. Duloxetine
    5-HT and NE reuptake inhibitor

    • SE
    • similar to 2 TCA's

    • Other uses
    • indicated for pain due to diabetic neuropathy and post herpetic pain (shingles)
  38. Venlafaxine
    5-HT > NE reuptake inhibitor

    • SE
    • similar to SSRIs except that it increases BP

    • Other Uses
    • Treatment of generalized and Social Anxiety disorder
  39. Atomoxetine
    NE reuptake inhibitor

    • hepatotoxicity
    • SE similar to 2 TCA's

    Treatment of ADD/ADHD
  40. Mirtazapine
    Blocks 5-HT2A/C 5-HT3A and a2 receptors

    • SE
    • weight gain, sedation
  41. How to select a reuptake inhibitor
    side effect profile and patient history

    Before initiation do a baseline ECG - TCA's only

    After monitor vegetative signs

    inadequate response... change drugs

    • if partial response.. augment with:
    • Lithium, active thyroid hormone, aripiprazole or olanzapine
  42. MAO inhibitors
    Phenelzine - irreversible

    Tranylcypromine - pseudoirreversible

    both inhibit MAO-A and MAO-B

    MAO-A increases NE and 5-HT takes 2-3 weeks to produce antidepressant effect

    MAO-B increases Dopamine
  43. MAO inhibitors Side Effects
    • CNS
    • Provoke switch to mania in bipolar
    • Sedation - phenelzine
    • Arousal - Tranylcypromine

    • Hepatotoxicity
    • Infrequent... more often phenelzine

    Orthostatic Hypotension

    DO NOT lower seizure threshold though
  44. MAO inhibitors Drug interactions
    direct and indirect acting sympathomimetic amines... TYRAMINE

    TCA's/SSRI's/Meperidine leads to serotonin syndrome
  45. Therapeutic Uses for MAO inhibitors
    • Major Depressive Disorder
    • equivalent to Reuptake inhibitors
    • Refractory patients
    • Atypical Depression
    • Patients with seizures

    Panic attacks with agoraphbia

    OCD
  46. Treatment of Bipolar Disorder
    USE LITHIUM
  47. Lithium
    Mechanism
    inhibition of IP3 Signaling

    inhibition of signaling via adenylyl cyclase... uncouples Gs Protein

    decreases NE by inhibiting release and stimulating reuptake

    Only way to clear lithium is through the kidneys... any loss of Na leads to increase in lithium
  48. Lithium Side Effects
    • Initial
    • GI: nausea, vomiting diarrhea
    • Anorexia
    • Polyuria/polydipsia - Na diuresis
    • Edema/ weight gain - increased aldosterone
    • Fine Tremor (intention)

    • Chronic
    • Goitrogenic hypothyroidism - uncouples TSH-R from Gs protein... treat T4

    Nephrogenic Diabetes Insipidus - Uncouples ADH receptor from Gs Protein.. treat Amiloride

    Leukocytosis

    Renal Tubular Necrosis
  49. Toxicity with Lithium
    • Mild - Flue like symptoms
    • Apathy, lethargy, nausea, muscle weakness, irritability

    • Moderate 
    • Course tremor, dysarthria, unsteady gait, somnolence, muscle twitches

    • Severe Toxicity
    • Seizures, coma, cardiovascular collapse, death
  50. Conditions increasing likelihood of Li toxicity
    • renal insufficiency
    • Na depletion
    • NSAIDS

    Caffeine increases Li clearance
  51. Drug interactions with Li
    • Na Depleting Diuretics (thiazides)
    • NSAIDS
    • Methylxanthines (caffeine/theophylline)
    • TCA - urinary retention
    • Phenothiazine antipsychotics - blocks vomiting
  52. Uses for Li
    • Bipolar Disorder
    • Major Depressive Disorder
    • Cyclothymia
    • Schizo-Affective Disorder
    • SIADH - with Demeclycycline
    • Chemo Induced Neutorpenia
    • Prophylaxis of Cluster headache
    • Premenstrual Dysphoric disorder
  53. Considerations with Li
    • Before initiation
    • creatinine
    • TSH
    • WBC with differential
    • Pregnancy Test

    • After Initiation
    • Monitor Li until stable
    • monitor baseline tests ever 6-12 months

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