Therapy of Major depression and manic-depressive Illness

  1. Major depression
    • • unipolar disorder (unidirectional mood swing) --> last a week
    • • lifetime risk 17% --> more in women than men (in seeking treatment)
    • • intense sadness and despair (pervasive, all-consuming, self-deprication, antodonia) 
    • • disruption of circadian rhythms (inc REM sleep --> changes in Stage 4 sleep) 
    • • suicidal behavior 10-15%
    • • good response to therapy with antidepressant drugs   (~70%)
    • • ECT (Electrical shock) for drug resistant cases
  2. Economic cost of depression
    +inc in cost (absenteeism, decrease productive capacity, in-out patient care)

    +pharmaceutical costs increased to 15%, but suicide-related costs decreased to 7%.
  3. Monoamine hypothesis of Major Depression
    • •Involves brain monoamines
    • –Norepinephrine(NE)
    • –Serotonin(5-HT)
    • –Dopamine (DA)?

    •Hypothesis says

    –Functional dec in amine-dependent synaptic transmission resulting in depression

    Drugs that enhance dopaminergic neurotransmission, like amphetamines and cocaine donot alleviate depression.

    Chronic use leads to psychosis (hallucinations, delusions, paranoia).
  4. Key to Monoamine Hypothesis of Depression
    •Drugs that deplete monoamines are depressant.

    •Most antidepressants enhance monoaminergic transmission at some point in the synaptic signaling process.

    • •The concentration of monoamines and their metabolites is reduced in the CSF of
    • depressed patients.

    •In various post-mortem studies, the most consistent finding is elevation in cortical 5-HT2 binding --> bc deplete seretonin lead to inc in receptor to make up for the depression.
  5. Problems with Monoamine hypothesis
    •Multiple problems with hypothesis

    • If it works then should see mood elevation
    • •However: therapeutic drugs cause

    – Change in amine activity within hours   but takes weeks to see clinical effects

    - A slow down-regulation of amine receptor
  6. Major classes of Antidepressant Drugs
    • Amine reuptake blocking drug 
    •  +Non-selective
    •       -Tricyclic, Second generation, 3rd generation
    •  + SSRI
    • MAO inhibitor 

    All current treatments are palliative. Treat symptoms, not the underlying disorder.

    If pharmacotherapy fails, electroshock therapy is an option.
  7. Electroconvulsive therapy = Trephination ???
    • •Shock (70-130 V) delivered unilaterally under general anesthesia and with muscle
    • relaxants --> induce seizure w/o motor output

    •Increases brain NE and 5-HT levels

    •6 to 10 sessions

    •Side effect: memory dysfunction, generally fully recovers

    • Note: pt experience full remission of depression w/in 3-4 days (unlike pharmacotherapy - 2-3 weeks)
    •        Relapse within 6 month need booster ECT or pharmacotherapy
    •        Good for pregnant women since monoamine is not good for the fetus 
    •        Swimming with dolphins is effective for mild to moderate depression
    •        Bright light therapy for seasonal (winter) depression.
    • •Mixed NE and 5-HT uptake inhibitors
    • at presynaptic terminal; some amount of DA uptake block.

    • •All TCAs have some affinity for
    • –H1 and muscarinic receptors
    • –a1 and a2 adrenoceptors

    •Dangerous in overdose due to cardiotoxicity

    • Similar
    • to phenothiazine antipsychotic drugs.
    • Normal people:  lethargy, clumsiness, dry mouth (antimuscurinic), blurred vision
    • dec REM and stage 4 sleep

    • Depressed patients: side effects as in normal people dec REM, stage 4, mood
    • elevating effect2-3 weeks
    • for effect
  10. TRICYCLIC ANTIDEPRESSANTS --- effects and manifestion
    •Drugs quite effective.

    –Cost effective

    –Decline in use not related to efficacy (suicide)

    • –Have low margin of safety in overdose, poor adverse reaction profiles and drug
    • interaction profiles.

    –Children and elderly particularly susceptible


    –M1, H1, a1, and Na+-channel  blockade

    • –Dry mouth, constipation, urinary retention, sinus tachycardia, blurred vision,
    • postural hypotension, sedation, sexual dysfunction.

    –Quinidine-like effects on cardiac conduction
    •Tricyclic Overdose

    • –Often
    • suicidal intent

    • –Extremely
    • hazardous


    • •Agitation,
    • delirium, neuromuscular   irritability,  convulsions, coma

    • •Respiratory
    • depression and circulatory collapse


    • •Cardiac
    • conduction defects and severe   arrhythmias
  12. TCAs:  Drug Interactions
    – Anticholinergics

    – Alcohol and CNS depressants

    – Local anesthetics +vasoconstrictors

    Sympathomimetic effects (vasoconstrictor) may be enhanced

    Use epinephrine cautiously

    Avoid levornordefrin
  13. Monoamine Oxidase Inhibitors
    –Tranylcypromine (Parnate)

    –Phenelzine (Nardil)

    –Irreversibly inhibit both MAO A and MAO B leading to increased levels of NE, 5-HT and DA.

    • –Use reserved for refractory or atypical depression or those associated with panic
    • disorder and/or phobias.

    • –Limited due high incidence of side effects, serious food/drug and drug/drug
    • interactions.
    •Monoamine oxidase A (MAO A)

        •Deaminates: 5-HT –NE –Tyramine Selective blocker:  clorgiline

    •Monoamine oxidase B (MAO B)

    •       •Breaksdown primarily DA
    •          Selectiveblocker:  selegiline
  15. MAOI Pharmacokinetics
    –Clinical effect persists after drug   discontinued and absent from blood --> source for interaction

    –Pharmacokinetic parameters no good for predicting doses

    • –Must assume effects last for 7 days (Tranylcypromine) to 2-3 weeks (Phenelzine)
    • after discontinuing drug
  16. MAOI Therapeutic Effects
    •Antidepressant effect (2-3 weeks)

    • dec REM sleep

    •Correction of sleep disorder in depressed patients
  17. MAOI Adverse Effects

    –CNS stimulation (with tranylcypromine)

    –CNS depression (with phenelzine)

    –Dry mouth

    –Weight gain

    –Postural hypotension

    –Sexual disturbances
  18. MAOI Adverse Effects
    –Deceptive absence of overt signs of MAO blockade

    • –Major change in capacity to handle endogenous and exogenous
    • amines
    •  ---> notes:  Exogenous catecholamines are removed primarily by uptake and COMT. So, MAOIs have a relatively small effect on potentiating direct-acting catecholamines. Much greater problems occur with indirectly-acting catecholaminergics (e.g., tyramine) escapes oxidative deamination in the liver, accumulates in terminals and releases catecholamines from the terminals.
  19. Drug interaction
    •Indirectly acting sympathomimetics (hypertensive crisis)

    •Opioid analgesics (esp. meperidine)

    •Alcohol and CNS depressants
  20. SSRIs
    • •Better tolerated than TCAs and MAOIs, with less severe side effects and have a wide margin of safety in overdose.
    • •Onset: 2-4 weeks (up to 12)

    Citalopram, fluoxetine, and sertraline are converted to their active metabolites which are potent and selective for serotonin --> long lasting and dont have to small divide the quantity
  21. SSRIs - Paxil®
    • •Used for
    •        –Depression
    •        –OCD
    •        –Social anxiety

    •# 9 in sales on the list of the top 200 drugs of 1999

    •# 15 in prescriptions on the list of the top 200 drugs of 1999

    •Generated sales in excess of $11.6 billion by 2012
  22. SSRIs: Adverse Effects
    •Anxiety, insomnia, increased appetite, tremors

    •GI symptoms



    • dec Libido, sexual dysfunction (#1 reason for pt non-compliance) 

    • •Contraindicated with MAOIs
    •   (Serotonin syndrome)
  23. Serotonin syndrome
    • •Interaction when serotonergic drugs are
    • taken together

    –example: SSRI & MAOI

    –Fever, agitation, hypertension, hyperthermia, rigidity, myoclonus

    –Can lead to seizure, coma, death

              •Always get complete list of drugs prior to starting therapy

              •Must have “washout” period between meds
  24. 2nd Generation nonselective monoamine
    reuptake blockers --- Trazodone (Desyrel)
    –1st non-lethal in overdose antidepressant

    • –Adverse effects: sedation (useful
    • in depressed patients with insomnia), hypotension (mild), priapism (rare), dry mouth, blurred vision, nausea, headache

    - Weak 5-HT reuptake inhibitor, 5-HT2R antagonist.
  25. 2nd Generation nonselective monoamine
    reuptake blockers ---- Buproprion (Wellbutrin,
    –Uses: depression, smoking cessation, ADHD

    • –Adverse effects: anxiety, insomnia, weight loss (incentive for pt), lowered seizure threshold
    • –Dosing: Start low, taper up

    • –Contraindications:
    •           •Seizure disorder, head injury, electrolyte imbalance, alcoholism (low seizure threshold)
  26. 3rd Generation nonselective monoamine
    reuptake blockers ---- Venlafaxine (Effexor)
    •Adverse effects

           –Drowsiness, nervousness, dizziness, sexual dysfunction, fatigue

           –­ BP, HR and cholesterol with higher doses

    •Drug interactions: MAOIs
  27. 3rd Generation nonselective monoamine
    reuptake blockers ---- Duloxetine
    • -Also used to treat: 
    • a) pain symptoms of diabetic neuropathy 
    • b) generalized anxiety disorder

    •Adverse effects & drug interactions as with venlafaxine
  28. pharmacotherapy vs ECT
    • delayed vs fast-acting 
    • nonresponder vs responder
  29. TCAs and MAOI use declined due to
    • lowmargin of safety in overdose,
    • poor adverse reaction profiles
    • drug interaction profiles
  30. SSRIs and newer non-selective reuptake inhibitors
    • similar effectiveness, better tolerated, sexual function adversely affected - common
    • cause of non-compliance
  31. Bipolar disorder
    An illness characterized by extreme changes in mood, behavior and energy levels (not unidirectional, bidirectional -- mood swing)

    Also called manic-depressive illness

    Affects ~1% of the U.S. population age 18 and over = epilepsy
  32. Bipolar's Clinical signs: Mania (the "high")
    •1.  Inflated self-esteem

    •2.  Severe insomnia

    •3.  Excessive talkativeness

    •4.  Racing thoughts

    •5.  Distractibility

    •6.  Activities done to excess

      (e.g. spending money)

    •7.  Pursuit of risky behaviors or activities
  33. Bipolar's clinical signs: depression (the "low")
    • •1.  Loss of interest in activities enjoyed
    • previously

    •2.  Changes in appetite resulting in weight gain or loss

    • •3.  Changes in sleep patterns resulting in
    • difficulty sleeping or oversleeping

    •4.  Agitation

    •5.  Loss of energy

    •6.  Trouble concentrating or thinking

    •7.  Repeated thoughts of suicide or death
  34. Therapy: LITHIUM SALTS
    •Primary use

    –Bipolar affective (manic-depressive) disorder

    •Decreases manic behavior

    •Modulates frequency and magnitude of mood swings

    •Decreases suicide risk

    •Usually used together with antidepressants or anticonvulsants (e.g. valproate)

    •Antipsychotic therapy may also be indicated
  35. Lithium: Pharmacokinetics
    • •Absorption
    • –Virtually complete   within 6-8 hrs

    –Peak plasma levels   in 30 min to 2 hrs


    –Total body water

    –Slow entry into intracellular compartment

    –No protein binding --> no drug intereaction

    •Metabolism None

    • •Excretion 
    • - Almost entirely in   urine
    • –Lithium clearance   about 20% of   creatinine
    • –Plasma T1/2 about 20 hrs

    • Any
    • decrease in renal function decreases Li+ excretion.

    Drugs that affect renal transport  mechanisms may affect Li+ excretion. E.g., thiazide diuretics and some NSAIDs (ibuprofen) decrease Li+ clearance.

  36. LITHIUM SALTS ---toxicity
    • Therapeutic range: 0.5 1.2 mEq/L
    • Therapeutic index: <5

    • Symptoms:Nausea, vomiting, diarrhea, tremor, confusion, arhythmias, convulsions --> can be masked by other drugs
    • Dehydration from the symptom could accumulate the drug --> more toxicity 


    –More common than those due to deliberate or accidental ingestion of drugs

    –Usually due to accumulation of lithium due to some change in patient status

    Generally requires monitoring of [Li+] in plasma --> according to weight (important because it might accumulate
  37. Lithium:  Adverse Effects
    • i Impaired verbal memory
    • i Tremor
    • i Sedation
    • i Ataxia
    • i Aphasia
    • i Thyroid enlargement (dysfunction rare)
    • i Polyuria ???
    • i Salivary gland dysfunction
    • i Arrhythmias
    • i Edema
    • i Leukocytosis

    Dentistry implications: Lithium causes dry mouth. Anticholinergics produce urinary retention, interferes with polyuria.

    Someething about steroid

    NSAIDS (e.g. ibuprofen) decrease renal Li+ clearance.
Card Set
Therapy of Major depression and manic-depressive Illness
System 4 Depression and Manic-Depressive Illness