Anti depressants

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  • High correlation particularly among kin Reserpine, a drug used in the treatment o hypertension and schizophrenia can cause depression because it depletes the vesicular storage of amine neurotransmitters (NE, 5-HT, DA). Depression could be relieved by isoniazid, a drug used in the treatment of tuberculosis. TCAs, MAOIs, SSRIs, and all the new drugs. ECT causes a massive release of NTs and is a very effective antidepressant.
  • Anti depressants

    1. 1. ANTIDEPRESSANTS www.freelivedoctor.com
    2. 2. Classification of Major Affective Disorders www.freelivedoctor.com
    3. 3. Episodal (reactive) Depression <ul><ul><ul><li>Adverse life events. </li></ul></ul></ul><ul><ul><ul><li>Physical illness. </li></ul></ul></ul><ul><ul><ul><li>Hormonal steroids. </li></ul></ul></ul><ul><ul><ul><li>Drugs. </li></ul></ul></ul><ul><ul><ul><li>Other psychiatric disorders. </li></ul></ul></ul>www.freelivedoctor.com
    4. 4. Reactive (episodal) Depression <ul><ul><li>More than 60% of all depressions. </li></ul></ul><ul><ul><li>Core depressive syndrome: feelings of misery, apathy, inadequacy, pessimism, anxiety, tension, guilt. </li></ul></ul><ul><ul><li>Bodily complaints </li></ul></ul><ul><ul><li>May respond spontaneously or to a variety of administrations. </li></ul></ul>www.freelivedoctor.com
    5. 5. Major Endogenous Depression <ul><li>Recurrent, Cyclic, Seasonal. </li></ul><ul><li>Degree of depression is not adequate for precipitating event. </li></ul><ul><li>Automaton (unresponsive). </li></ul>www.freelivedoctor.com
    6. 6. Major Endogenous Depression <ul><li>Core Symptoms : </li></ul><ul><li>Feeling of misery, apathy and pessimism. </li></ul><ul><li>Withdrawn. </li></ul><ul><li>Low self –esteem, feelings of guilt, inadequacy and ugliness. </li></ul><ul><li>Loss of interest in pleasurable activities. </li></ul><ul><li>Indecisiveness, loss of motivation. </li></ul><ul><li>Retardation of thought and action. Sleep disturbance and significant weight change (without dieting or changes in appetite). </li></ul><ul><li>Psychomotor agitation or retardation. </li></ul>www.freelivedoctor.com
    7. 7. Major Endogenous Depression <ul><li>Core Symptoms (con’t): </li></ul><ul><li>In severe cases, it is accompanied by hallucinations and delusions. </li></ul><ul><li>Recurrent suicidal ideation, a suicide attempt or a specific suicide plan. </li></ul>www.freelivedoctor.com
    8. 8. Mania <ul><li>Mania alone is rare (10%) and most frequently cycles with Major/endogenous depression (Manic-Depressive Disease, Bipolar Disorder). </li></ul>www.freelivedoctor.com
    9. 9. Mania <ul><li>Core Symptoms: </li></ul><ul><li>It is characterized by an elevated “high” mood. </li></ul><ul><li>Talkative, go on-and-on about the things they will do. </li></ul><ul><li>Increased self-esteem. </li></ul><ul><li>Auditory hallucinations. </li></ul><ul><li>Decrease need to sleep. </li></ul><ul><li>Lack judgement, indiscrete. </li></ul><ul><li>SuperME </li></ul>www.freelivedoctor.com
    10. 10. III. Biological Correlates of Depression <ul><li>1. Hypersecretion of cortisol. </li></ul><ul><li>2. Escape from dexamethasone suppression. </li></ul><ul><li>3. Blunted TSH response to TRH. </li></ul><ul><li>4. Blunted GH response to hypoglycemia. </li></ul><ul><li>5. Altered 24hr rhythm of prolactin secretion. </li></ul><ul><li>6. Decreased 5-HT metabolites in plasma. </li></ul><ul><li>7. Decreased REM latency. </li></ul>www.freelivedoctor.com
    11. 11. IV. Biological Basis for Depression <ul><li>1. Has a genetic component. </li></ul><ul><li>2. Depression can be drug-induced. </li></ul><ul><li>3. Depression can be drug-repressed. </li></ul><ul><li>4. Depression can be treated with drugs. </li></ul><ul><li>5. Depression can be treated with </li></ul><ul><li>Electroconvulsive Therapy (ECT). </li></ul>www.freelivedoctor.com
    12. 12. <ul><ul><ul><li>The precise cause of affective disorders remains elusive. </li></ul></ul></ul><ul><ul><ul><li>Evidence implicates alterations in the firing patterns of a subset of biogenic amines in the CNS, Norepinephrine (NE) and Serotonin (5-HT). </li></ul></ul></ul><ul><ul><ul><li> Activity of NE and 5 -HT systems ? . </li></ul></ul></ul>V. Biogenic Theory of Depression www.freelivedoctor.com
    13. 13. VI. NE System <ul><li>Almost all NE pathways in the brain originate from the cell bodies of neuronal cells in the locus coereleus in the midbrain, which send their axons diffusely to the cortex, cerebellum and limbic areas (hippocampus, amygdala, hypothalamus, thalamus). </li></ul><ul><ul><ul><li>Mood : -- higher functions performed by the cortex. </li></ul></ul></ul><ul><ul><ul><li>Cognitive function : -- function of cortex. </li></ul></ul></ul><ul><ul><ul><li>Drive and motivation : -- function of brainstem </li></ul></ul></ul><ul><ul><ul><li>Memory and emotion : -- function of the hippocampus and amygdala. </li></ul></ul></ul><ul><ul><ul><li>Endocrine response : -- function of hypothalamus . </li></ul></ul></ul><ul><li> and  receptors. </li></ul>www.freelivedoctor.com
    14. 14. VII. Serotonin System <ul><li>As with the NE system, serotonin neurons located in the pons and midbrain (in groups known as raphe nuclei) send their projections diffusely to the cortex, hippocampus, amygdala, hypothalamus, thalamus, etc. --same areas implicated in depression. This system is also involve in: </li></ul><ul><ul><ul><ul><li>Anxiety. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Sleep. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Sexual behavior. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Rhythms (Suprachiasmatic nucleus). </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Temperature regulation. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>CSF production. </li></ul></ul></ul></ul>www.freelivedoctor.com
    15. 15. Antidepressants <ul><li>TCAs </li></ul>MAOIs SSRIs TCAs TCAs TCAs TCAs SSRIs SSRIs SSRIs SSRIs MAOIs MAOIs MAOIs MAOIs MAOIs MAOIs Venflaxine Venflaxine Venflaxine MAOIs MAOIs maprotiline Amoxepine doxepin isocarboxazide Nortriptyline www.freelivedoctor.com
    16. 16. Antidepressants <ul><li>1. Tricyclic anti-depressants (TCAs). </li></ul><ul><li>Imipramine, desipramine, nortriptyline, </li></ul><ul><li>protryptyline, amytriptiline, doxepin. </li></ul><ul><li>2. Monoamine oxidase inhibitors (MAOIs). </li></ul><ul><li>Isocarboxacid, phenelzine, tranylcypromine. </li></ul><ul><li>3. Selective serotonin reuptake inhibitors (SSRIs) </li></ul><ul><li>Fluoxetine, sertraline, paroxetine, trazodone . </li></ul><ul><li>4. Atypical anti-depressants (Others) </li></ul><ul><li>New TCAs, amoxapine, bupropion, </li></ul><ul><li>alprazolam, maprotiline, nomifensine, mianserin. </li></ul>www.freelivedoctor.com
    17. 17. Mechanism of Action <ul><ul><ul><li>Inhibition of NE and 5-HT reuptake. </li></ul></ul></ul><ul><ul><ul><li>(TCAs, SSRIs, Newer TCAs). </li></ul></ul></ul><ul><ul><ul><li>2. Inhibition of MAO enzymes. </li></ul></ul></ul><ul><ul><ul><li>(MAOIs). </li></ul></ul></ul><ul><ul><ul><li>3. 5-HT 2A and 5-HT 2C antagonists. </li></ul></ul></ul><ul><ul><ul><li>(Nefazodone, trazodone, mirtazapine) </li></ul></ul></ul><ul><ul><ul><li>4. Alteration of NE output . </li></ul></ul></ul><ul><li>(Bupropion) </li></ul><ul><li>5. Stimulation of 5-HT 1A receptors . </li></ul><ul><li>( </li></ul><ul><li>6.  2–AR antagonists. </li></ul><ul><li>(mirtazapine) </li></ul>www.freelivedoctor.com
    18. 18. Tricyclic Antidepressants (TCAs) <ul><ul><ul><ul><li>amytriptiline </li></ul></ul></ul></ul><ul><ul><ul><ul><li>imipramine </li></ul></ul></ul></ul><ul><ul><ul><ul><li>desipramine </li></ul></ul></ul></ul><ul><ul><ul><ul><li>nortriptyline </li></ul></ul></ul></ul><ul><ul><ul><ul><li>protryptyline </li></ul></ul></ul></ul><ul><ul><ul><ul><li>doxepin. </li></ul></ul></ul></ul>www.freelivedoctor.com
    19. 19. Tricyclic Antidepressants (TCAs) <ul><li>Characteristic three ring nucleus. </li></ul><ul><li>Most are incompletely absorbed, all are metabolized in liver => High first pass effect: </li></ul><ul><ul><ul><li>1) Transformation of the tricyclic nucleus => hydroxylation => conjugation => glucoronides. </li></ul></ul></ul><ul><ul><ul><li>2) Alteration of aliphatic side chain => demethylation of the nitrogen => active metabolites. </li></ul></ul></ul><ul><li>High protein binding, high lipid solubility. </li></ul>www.freelivedoctor.com
    20. 20. Tricyclic Antidepressants (TCAs) <ul><ul><ul><li>/ CH 3 / H </li></ul></ul></ul><ul><li> N N </li></ul><ul><li> CH 3 CH 3 </li></ul><ul><li>tertiary amine secondary amine </li></ul><ul><ul><ul><li>3 o => 2 o </li></ul></ul></ul>www.freelivedoctor.com
    21. 21. Tricyclic Antidepressants (TCAs) <ul><li>3 ° Amines: Imipramine, Amitriptyline </li></ul><ul><li>    </li></ul><ul><li>2 ° Amines: Desipramine, Nortriptyline </li></ul><ul><li>Selectivity 2 o Amines -- NE > 5-HT </li></ul><ul><li>3 o Amines -- 5-HT > NE </li></ul>www.freelivedoctor.com
    22. 22. Tricyclic Antidepressants (TCAs) <ul><li>Mechanism of Action: </li></ul><ul><li>- Inhibition of NT reuptake. </li></ul><ul><li>- Immediate action = >  NE and 5-HT in synapse. </li></ul><ul><li>- After chronic treatment (2 - 4 weeks) = > </li></ul><ul><ul><ul><ul><ul><li>  NE-R and  5-HT 2 R. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li> NE release and turnover. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li> NE-stimulated cAMP in brain. </li></ul></ul></ul></ul></ul><ul><li> Sensitization of 5-HT receptors. </li></ul><ul><li>* Adaptive Responses * </li></ul><ul><li>- Takes up to 4 weeks for all TCA antidepressants to have an effect. </li></ul>www.freelivedoctor.com
    23. 23. Tricyclic Antidepressants (TCAs) <ul><li>Side Effects: </li></ul><ul><li>Atropine-like side effects: dry mouth, paradoxical excessive perspiration, constipation, blurred vision, mydriasis, metallic taste, urine retention => muscarinic blockade. </li></ul><ul><li>Orthostatic hypotension =>  1-AR and possibly  2-AR blockade. </li></ul><ul><li>Drowsiness, sedation and weight gain => Histamine-Receptor blockade. </li></ul>www.freelivedoctor.com
    24. 24. Tricyclic Antidepressants (TCAs) <ul><li>Side Effects (con’t): </li></ul><ul><li>Most serious side effect is cardiac toxicity => Palpitations, tachycardia, dizziness => excessive CNS stimulation =>  NE in Heart. </li></ul><ul><li>Sexual dysfunction, including loss of libido, impaired erection and ejaculation and anorgasmia </li></ul><ul><li>.  COMPLIANCE </li></ul>www.freelivedoctor.com
    25. 25. Tricyclic Antidepressants (TCAs) <ul><li>Other effects (con’t): </li></ul><ul><li>Metabolism is affected by: Smoking, Barbs, estrogens, neuroleptics and anticonvulsants. </li></ul><ul><li>Can lower seizure threshold. </li></ul><ul><li>All TCAs can cause: vagal block, postural hypotension, arrythmias, sinus tachycardia. </li></ul><ul><li>All potentiate CNS depressants (BZDs, Barbs, ETOH) => coma and death. </li></ul><ul><li>TCA administration in bipolar disorder may precipitate acute mania or rapid cycling. </li></ul><ul><li>Fatal in overdose (a 2 wk supply can kill anyone). </li></ul>www.freelivedoctor.com
    26. 26. X. MAO INHIBITORS <ul><ul><ul><ul><ul><li>Isocarboxacid </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Phenelzine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Tranylcypromine. </li></ul></ul></ul></ul></ul>www.freelivedoctor.com
    27. 27. X. MAO INHIBITORS <ul><li>Developed for the treatment of tuberculosis (iproniazid derivatives) - 1951. </li></ul><ul><li>These drugs are not widely used today, although a small number of patients appear to do better in MAOIs than TCAs or the newer drugs. </li></ul><ul><li>Are readily absorbed from GI tract and widely distributed throughout the body. </li></ul><ul><li>May have active metabolites, inactivated by acetylation. </li></ul><ul><li>Effects persist even after these drugs are no longer detectable in plasma (1-3 weeks). </li></ul>www.freelivedoctor.com
    28. 28. X. MAO INHIBITORS <ul><li>Mechanism of action: </li></ul><ul><li>Inhibit MAO enzymes (non-selective): </li></ul><ul><li>1) Irreversible MAO inhibitors </li></ul><ul><ul><li>Phenelzine and isocarboxazid => hydrazides. </li></ul></ul><ul><li>2) Reversible MAO Inhibitors. </li></ul><ul><ul><li>Tranylcypromine => non-hydrazide, </li></ul></ul><ul><ul><li>prolonged blockade, but reversible within 4hr. </li></ul></ul><ul><ul><li>Decrease metabolism of most biogenic amines (NE, 5HT, DA, tyramine, octopamine). </li></ul></ul>www.freelivedoctor.com
    29. 29. X. MAO INHIBITORS <ul><li>Mechanism of action (con’t): </li></ul><ul><li>Acute administration causes: </li></ul><ul><ul><li> NE and 5-HT in synaptic terminals in brain but  NE in PNS.  NE synthesis. </li></ul></ul><ul><ul><li>Acute euphoria </li></ul></ul><ul><ul><li>Suppressed REM sleep. </li></ul></ul><ul><li>Chronic administration causes: </li></ul><ul><ul><li> NE-stimulated cAMP in brain. </li></ul></ul><ul><ul><li>Down regulation of  receptors. </li></ul></ul><ul><ul><li>Down regulation of 5-HT 2 receptors. </li></ul></ul>www.freelivedoctor.com
    30. 30. X. MAO INHIBITORS <ul><ul><ul><li>MAO-A  NE, 5-HT, Tyramine </li></ul></ul></ul><ul><ul><ul><li>MAO-B  DA </li></ul></ul></ul><ul><li>Selective MAOIs : </li></ul><ul><ul><ul><li>Inhibitors MAO-A </li></ul></ul></ul><ul><ul><ul><ul><ul><li>Moclobemide, Clorgyline </li></ul></ul></ul></ul></ul><ul><ul><ul><li>Inhibitors of MAO-B. </li></ul></ul></ul><ul><ul><ul><ul><ul><li>Deprenyl, Selegiline </li></ul></ul></ul></ul></ul>www.freelivedoctor.com
    31. 31. X. MAO INHIBITORS <ul><li>Wine-and-Cheese Reaction </li></ul><ul><ul><li>- Fatal interaction with tyramine-containing foods (fermented foods in particular, such as wine and cheese). </li></ul></ul><ul><ul><li>-  MAO-A =>  Tyramine in the body =>  NE in circulation => induces hypertensive crisis => can lead to intracranial bleeding and other organ damage. </li></ul></ul>www.freelivedoctor.com
    32. 32. X. MAO INHIBITORS <ul><li>Negative drug interactions with: </li></ul><ul><li>Any drug metabolized by MAOs * including SSRIs, TCAs and meperidine, alcohol, CNS depressants, sympathomimetics, phenylephrine (O/C nasal decongestants), ampetamines, and other indirect-acting adrenergic drugs. </li></ul><ul><li>* Interaction with drugs metabolized by MAOs (e.g. Meperidine (opioid analgesics) => hyperpyrexia or “hyperexcitation syndrome” involving high fever, delirium and hypertension). </li></ul>www.freelivedoctor.com
    33. 33. X. MAO INHIBITORS <ul><li>Other side effects: </li></ul><ul><li>Hypotension </li></ul><ul><li>Hepatotoxicity. </li></ul><ul><li>Sedation. </li></ul>www.freelivedoctor.com
    34. 34. XI. SSRIs <ul><ul><ul><ul><ul><li>Fluoxetine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Sertraline </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Paroxetine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Fluvoxamine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>(Labeled for obsessive-compulsive disorder) </li></ul></ul></ul></ul></ul>www.freelivedoctor.com
    35. 35. XI. SSRIs <ul><li>Most widely prescribed drugs for depression. </li></ul><ul><li>They have few side effects and seem to be rather safe. More rational prescribing and better patient compliance. </li></ul><ul><li>Adverse effects include: nausea, decreased libido, decrease sexual function. </li></ul><ul><li>Low threat for overdose. Suicide may be considered in severe depression. </li></ul>www.freelivedoctor.com
    36. 36. XI. SSRIs <ul><li>Mechanism of action: </li></ul><ul><ul><ul><li>Specific serotonin uptake inhibitors increase 5-HT by inhibiting reuptake. </li></ul></ul></ul><ul><li>Current theory holds that: </li></ul><ul><ul><ul><li>Enhanced stimulation or responsiveness of postsynaptic 5-HT 1A receptors is particularly important in the action of antidepressants. </li></ul></ul></ul>www.freelivedoctor.com
    37. 37. XI. SSRIs <ul><li>Fluoxetine is the prototype. </li></ul><ul><li>Approximately 70% of depressed patients will respond to an SSRI therapy at the end of 6 weeks (4 to 6 weeks before effects are evident to patient). </li></ul><ul><li>T 1/2 of 16 – 24 hrs. except for fluoxetine’s metabolite norfluoxetine (T 1/2 = 8 days). </li></ul><ul><li>Fluoxetine and paroxetine inhibit liver enzymes, particularly P450-2D6. </li></ul><ul><li>Paroxetine and Sertraline have PK parameters similar to TCAs. </li></ul>www.freelivedoctor.com
    38. 38. XI. SSRIs <ul><li>Drug-drug interactions: </li></ul><ul><li>dangerous with other antidepressant drugs, MAOIs in particular. </li></ul><ul><li>” Serotonin Syndrome”: </li></ul><ul><ul><li>hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status and vital signs. </li></ul></ul><ul><li>Thus it is important to wait up to 6 weeks after medication is stopped, before starting with another drug. </li></ul>www.freelivedoctor.com
    39. 39. XII. Heterocyclics <ul><li>2nd Generation heterocyclics </li></ul><ul><ul><ul><ul><ul><li>amoxapine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>maprotiline </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>trazodone </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>bupropion </li></ul></ul></ul></ul></ul><ul><li>Third Generation heterocyclics </li></ul><ul><ul><ul><ul><ul><li>mirtazapine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>venlafaxine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>nefazodone </li></ul></ul></ul></ul></ul>www.freelivedoctor.com
    40. 40. XII. Heterocyclics <ul><li>The second and third generation antidepressants are by no means a homogeneous group. </li></ul><ul><li>As with the TCA's , they all have variable bioavailability. </li></ul><ul><li>High protein binding. </li></ul><ul><li>Some have active metabolites. </li></ul><ul><li>Trazodone and Venlafaxine have the shortest plasma half-lives, which mandates divided doses during the day. </li></ul><ul><li>Nefazodone and fluvoxamine cause inhibition of CYP3A4. </li></ul>www.freelivedoctor.com
    41. 41. XII. Heterocyclics <ul><li>Mechanism of Action: </li></ul><ul><ul><li>1) NT reuptake inhibition. </li></ul></ul><ul><ul><ul><li>maprotiline. </li></ul></ul></ul><ul><ul><li>2) 5-HT receptor antagonism (for 5-HT 2A or 2C receptors). </li></ul></ul><ul><ul><li>nefazodone, mirtazapine, and trazodone </li></ul></ul><ul><ul><li>3) Alteration of NE Output. </li></ul></ul><ul><ul><li>bupropion, amoxapine, and trazodone. </li></ul></ul>www.freelivedoctor.com
    42. 42. XII. Heterocyclics <ul><li>Amoxapine. Metabolite of Loxapine (an anti-psychotic) -- retains some antipsychotic activity and DA receptor antagonism => parkinson's-like symptoms. May be useful if psychosis is present. NE output. </li></ul><ul><li>Maprotiline. A tetracyclic drug, resembles desipramine with less sedative and antimuscarinic side effects. Evokes seizures at high doses. Blocks NT reuptake. </li></ul>www.freelivedoctor.com
    43. 43. XII. Heterocyclics <ul><li>Trazodone. Antagonist of 5-HT 2A or 2C receptors . Unpredictable efficacy. Highly sedative (hypnotic), but minimal antimuscarinic action. </li></ul><ul><li>Bupropion. Resembles amphetamine. Blocks DA reuptake (not important in depression). Causes CNS stimulation. Inhibits appetite. Aggravates psychosis. NE output. </li></ul>www.freelivedoctor.com
    44. 44. XII. Heterocyclics Third Generation <ul><li>Mirtazapine . A derivative of mianserin . Antagonist of 5-HT 2A or 5-HT 2C receptors. Also antagonizes  2 -adrenergic receptors, thus increasing NE and 5-HT release. Very sedating. </li></ul><ul><li>Venlafaxine. Short plasma half-live, thus needs to be given in divided doses. Potent inhibitor of 5-HT uptake and weaker at NE reuptake (at low concentrations it acts like an SSRI). </li></ul><ul><li>Nefazodone. Antagonist of 5-HT 2A or 5-HT 2C receptors. Moderately sedating. Potent inhibitor of CYP3A4, so cannot be given with cisapride </li></ul>www.freelivedoctor.com
    45. 45. XII. Atypical/Heterocyclic <ul><li>2nd Generation heterocyclics </li></ul><ul><ul><ul><ul><ul><li>Amoxapine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Maprotiline </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Trazodone </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Bupropion </li></ul></ul></ul></ul></ul><ul><li>Third Generation heterocyclics </li></ul><ul><ul><ul><ul><ul><li>Mirtazapine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Venlafaxine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Nefazodone </li></ul></ul></ul></ul></ul>Similar to TCAs 5-HT antagonists  2-AR antagonist SSRI-like  NE output www.freelivedoctor.com
    46. 46. Noradrenergic Control of Serotonergic Release NE 5-HT NE  2 -AR  1 -AR 1 2 3 Mianserin 5-HT1 5-HT2 5-HT3 Receptors www.freelivedoctor.com
    47. 47. XIV. Alternative Therapies <ul><li>No way of a priori knowing which therapy will be best for a patient. </li></ul><ul><ul><ul><li>Light Therapy </li></ul></ul></ul><ul><ul><ul><li>Psychological Treatment </li></ul></ul></ul><ul><ul><ul><li>ECT </li></ul></ul></ul><ul><ul><ul><li>St. John’s Wort </li></ul></ul></ul>www.freelivedoctor.com
    48. 48. www.freelivedoctor.com
    49. 49. www.freelivedoctor.com
    50. 50. www.freelivedoctor.com
    51. 51. XVI. Anti-Manic Drugs <ul><li>Lithium (Li + ) remains the drug of choice for the treatment and prophylaxis of mania. </li></ul><ul><li>Acute manic episodes are managed with lithium salts (carbonate or citrate) alone, or in combination with: </li></ul><ul><ul><ul><li>1) Antipsychotics (carbamazepine, similar in structure to TCAs but not effective in depression). </li></ul></ul></ul><ul><ul><ul><li>2) Valproic acid </li></ul></ul></ul><ul><ul><ul><li>3) Calcium-channel blockers (nifendipine, diltiazem, verapamil). </li></ul></ul></ul>www.freelivedoctor.com
    52. 52. XVI. Anti-Manic Drugs <ul><ul><li>Li + </li></ul></ul><ul><li>Small monovalent cation (between H + and Na + ). </li></ul><ul><li>Distributed in total body water, similar to sodium. </li></ul><ul><li>May partially inhibit Na + -K + ATPase. </li></ul><ul><li>Inhibits ADH => diuresis. </li></ul><ul><li>May decrease thyroid function. </li></ul><ul><li>Teratogenic (tricuspid valve malformation). </li></ul><ul><li>Excreted by kidney. </li></ul>www.freelivedoctor.com
    53. 53. XVI. Anti-Manic Drugs <ul><ul><li>Li + </li></ul></ul><ul><li>Not to be taken with thiazide diuretics (e.g. chlorthiazide). </li></ul><ul><ul><ul><li>Lithium clearance is reduced by 25%. </li></ul></ul></ul><ul><ul><ul><li>All neuroleptics (with the exception of clozapine), produce more severe extrapyramidal syndromes when combined with lithium. </li></ul></ul></ul>www.freelivedoctor.com
    54. 54. XVI. Anti-Manic Drugs <ul><li>Li + </li></ul><ul><li>Helps alleviate the depressive phase of bipolar illness. </li></ul><ul><li>Useful in refractory depression when added to SSRIs or TCAs, but not a good antidepressant alone . </li></ul>www.freelivedoctor.com
    55. 55. XVI. Anti-Manic Drugs <ul><li>Li + </li></ul><ul><li>Mechanism of action: </li></ul><ul><li>Does not alter receptor numbers but alters the coupling of the receptors with their second messengers by reducing coupling of G-proteins. </li></ul><ul><li>Regulation of  -AR and DAR. </li></ul><ul><li>Can reduce release of NTs (5-HT) and affinity of binding to receptor. </li></ul>www.freelivedoctor.com
    56. 56. XVI. Anti-Manic Drugs <ul><li>Li + </li></ul><ul><li>Mechanism of action (Con’t): </li></ul><ul><li>Inhibits breakdown of IP 2 to IP 1 (during PIP hydrolysis) => depletion of DAG and IP 3 and  [Ca 2 + ] in response to receptor activation (i.e. from 5-HT 2 R,  1 -AR, muscarinic receptors and others). </li></ul><ul><li>Alterations in adenylate cyclase and phospholipase C. </li></ul>www.freelivedoctor.com
    57. 57. XVI. Anti-Manic Drugs PIP PIP 2 G IP 3 IP 2 IP 1 Inositol PI X Li + PLC DAG Ca 2+ www.freelivedoctor.com
    58. 58. XVI. Anti-Manic Drugs <ul><li>Valproic Acid </li></ul><ul><li>A well known antiepileptic has been found to have antimanic effects. Shows efficacy equivalent as that of lithium during the early weeks of treatment and is being evaluated for maintenance treatment. Titrated well, the sedation can be controlled. Nausea being the only limiting factor in some patients. </li></ul><ul><li>May be used as first line treatment for mania, although it may not be as effective in maintenance treatment as lithium for some patients. </li></ul><ul><li>Mechanism of action: ??? </li></ul>www.freelivedoctor.com
    59. 59. XVI. Anti-Manic Drugs <ul><li>Carbamazepine </li></ul><ul><li>Effective as an antimania medication </li></ul><ul><li>Mechanism of action (Con’t): </li></ul><ul><li>May be due to decrease overexcitability of neurons (anticonvulsive effect). </li></ul>www.freelivedoctor.com
    60. 60. XVI. Anti-Manic Drugs <ul><li>Ca 2+ Channel blockers </li></ul><ul><ul><li>Nifedeipine </li></ul></ul><ul><ul><li>Verapamil </li></ul></ul><ul><li>Mechanism of action (Con’t): </li></ul><ul><li>NT Release? </li></ul>www.freelivedoctor.com

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