1. Drugs Used For Affective Disorders By Prof. Abdulqader Alhaider Prof. Abdulqader Alhaider

2. Definition of Affected Disorders Definition of Affected Disorders Either Depresion or mania Either Depresion or mania Incidence: Depression is a chronic and recurrent illness that can affect at least 20% of the population at some period in their lifetime. An estimated 35-40 million Americans living today will suffer from major Depressive Illness during their lives.

3. For each person directly suffering, three or four times that number of their relatives, employees, associates, and friends will also be adversely affected. Cost: 15-35 billions $/years in USA only. Cost: 15-35 billions $/years in USA only.

4. Symptoms of Depression The symptoms of Depressive Illness are highly recognizable, both to those affected and to those closest to them, once they are told what to look for. The symptoms of Depressive Illness are highly recognizable, both to those affected and to those closest to them, once they are told what to look for. Here is a checklist of symptoms of Depressive illness: Here is a checklist of symptoms of Depressive illness: –Loss of energy and interest. –Diminished ability to enjoy oneself. –Decreased -- or increased -- sleeping or appetite. –Difficulty in concentrating; indecisiveness; slowed or fuzzy thinking. –Exaggerated feelings of sadness, hopelessness, or anxiety. –Feelings of worthlessness. –Recurring thoughts about death and suicide. –If most of these symptoms last for two weeks or more, you probably have Depressive Illness. Sometimes depression alternates with "mania" and is called Manic-Depressive Illness (Bipolar).

5. Symptoms of Mania causes mood swings creating periods with the following symptoms: causes mood swings creating periods with the following symptoms: –A high energy level with decreased need for sleep. –Unwarranted or exaggerated belief in one's own ability. –Extreme irritability. –Rapid, unpredictable emotional change. –Impulsive, thoughtless activity, with a high risk of damaging consequences (i.e., stock speculations, sudden love affairs, etc.).

6. Affective DisordersSerotonin Affective DisordersSerotonin NE NE Mania Depression Mania Depression Rx Drugs that decrease NE Drugs that increase NE What is the evidence to support this theory ? What is the evidence to support this theory ? Amphetamine and mania while Clonidine and methyldopa produce depression. Figure 1:Biochemical Theory of Affective Disorders.

7. What are the features of drugs that are to be used for Rx of Depression? What are the features of drugs that are to be used for Rx of Depression?

8. Classification of Antidepressants Based on Site of Action (see Fig 29-2) A ) Drugs that Block the RE-uptake of NE and 5- HT ( e.g.:Most tricyclics) A ) Drugs that Block the RE-uptake of NE and 5- HT ( e.g.:Most tricyclics) B)Drugs that Selectively Block Re-Uptake of 5- HT (SSRIs) (Fluoxetine; Paroxetine; Sertraline; Citalopram) B)Drugs that Selectively Block Re-Uptake of 5- HT (SSRIs) (Fluoxetine; Paroxetine; Sertraline; Citalopram) C)Drugs that Block Presynaptic α 2 - adrenoceptors (e.g.: Mirtazapine, Mianserin). C)Drugs that Block Presynaptic α 2 - adrenoceptors (e.g.: Mirtazapine, Mianserin). D)Drugs that Inhibit MonoAminoOxidase (MAOIs, Phenelzine, Tranylcypraine, Moclobemide) D)Drugs that Inhibit MonoAminoOxidase (MAOIs, Phenelzine, Tranylcypraine, Moclobemide)

10. Mechanism of Action of Antidepressants Mechanism of Action of Antidepressants 1) Inhibition of reuptake of NE and or 5-HT ?? or increases the release of NE or 5-HT. ??? 2) Desensitization (down-regulation) of β- adrenoceptors (decrease c-AMP). (very important and related to clinical response). How do SSRIs desensitize β-adrenoceptors? Hint: Remember Raphe nuclei!!

11. Tricyclic Antidepressants (TCAs) Tricyclic Antidepressants (TCAs) e.g.: Imipramine; Amitriptyline ; Desipramine; Doxepin (see Table 1).

12. Pharmacological Actions of TCAs: Monoamineuptake (see Table 1) Monoamineuptake (see Table 1) Which one of them selectively blocks NE? Side effects of TCA (see table 2 ) Side effects of TCA (see table 2 ) Note: They are drugs with broad spectrum of pharmacological effects at many receptors (e.g. Histamine ; ACH therefore, they are also associated with many side effects) (see table 2). Note: They are drugs with broad spectrum of pharmacological effects at many receptors (e.g. Histamine ; ACH therefore, they are also associated with many side effects) (see table 2). –Sedation Why? –Cardiovascular effects (Tachycardia and hypotension) How? –Anticholinergic effects –Weight gain. –Seizure –Hypomania

13. Table 1: Effects of tricyclic antidepressants on Reuptake and 5-HT 2 5-HT2 antagonism Noradrenaline reuptake 5-HT reuptake Tricyclic antidepressants +?--+--++-+++++++ + + +?-++- Tricyclic antidepressants AmitriptylineClomipramineDesipramineDothiepinDoxepinImiprmineLofipramineNortriptyline Which one of the tricyclics is more selective on inhibiting reuptake of NE? Which one of the tricyclics is more selective on inhibiting reuptake of 5-HT?

14. Table 2: Side Effects of Tricyclic antidepressants Relative Side effects Reuptake inhibition Relative Side effects Reuptake inhibition 5-HT 5-HT NE NE Anti- Cholinnergic Hypotension Cardio- toxicity Sedation ++++++++/-+++++++++++++++/-+++++++++++++++++++++++++++++++++++++++++++++++++++++++++0/+++++++++++++++++++++++++++++++++++++++++++++++++-+++AmitriptylineAmoxapineClomipramineDesipramineDothiepinDoxepinImipramineLofepramineNortriptylineProtriptylineTrimipramine

15. Pharmacokinetics:Pharmacokinetics: Lipophilic with High protein binding; basic in nature, Lipophilic with High protein binding; basic in nature, metabolized in liver. metabolized in liver. Nowadays, this group of antidepressants became less Nowadays, this group of antidepressants became less popular than it was, due to the unwanted effects. Treatment of overdose of Tricyclic AntidepressantsTreatment of overdose of Tricyclic Antidepressants Why hemodialysis is not effective for Rx of TCA toxicity?.

16. Selective Serotonin Uptake Blockers (SSRI) e.g. Fluoxetine; Fluvoxamine; Paroxetine; Sertraline; Citalopram (see table 3). e.g. Fluoxetine; Fluvoxamine; Paroxetine; Sertraline; Citalopram (see table 3). Pharmacological Activities: Pharmacological Activities: MOA : Selective uptake of 5-HT in the presynaptic cleft. MOA : Selective uptake of 5-HT in the presynaptic cleft. Why they are better choice as compared to TCA?

17. Table 3: Effect of SSRIs on Reuptake and 5-HT2 5-HT2 antagonists Noradrenaline reuptake 5-HT reuptake ----------+++++ Selective serotonin reuptake inhibitors CitalopramFluoxetineFluvxamineParoxetineSertraline What is the clinical significant of the antagonistic effect on 5-HT2 receptors?

18. Side Effects of SSRI (see Table 4) Almost have no cardiovascular manifestations as compared to TCA. Almost have no cardiovascular manifestations as compared to TCA. Nausea and vomiting and decrease appetite How? Nausea and vomiting and decrease appetite How? Insomnia and anxiety (with Fluoxetine ; Citalopram; but not with Paroxetine. So What? Insomnia and anxiety (with Fluoxetine ; Citalopram; but not with Paroxetine. So What? Impotence and sexual dysfunction (in male and female) Impotence and sexual dysfunction (in male and female) How these occur and what are their clinical significant ? Decrease weight. How? Decrease weight. How?

19. Side effects of SSRIs cont’d Nausea; vomiting and anorexia. How ? Nausea; vomiting and anorexia. How ? Can SSRIs be used together with TCA ? Can SSRIs be used together with TCA ? Drugs interactions due to their significant inhibitory action at CYP450 (Except Citalopram.) Drugs interactions due to their significant inhibitory action at CYP450 (Except Citalopram.) Which one of SSRIs does produce active metabolite? Which one of SSRIs does produce active metabolite? Which one has the longest t 1/2 ? Which one has the longest t 1/2 ?

20. Drug Cardiotoxicty Nausea Anticholinergic Sedation effects effects Citalopram ? ++ _ _ Fluoxetine - ++ _ _ Fluvoxamine _ +++ _ + Paroxetine _ ++ + + Sertraline _ ++ _ _ Table 4: Side effects of SSRIs

21. α 2 – adrenoceptors antagonists e.g. Mirtazepine (Romeron ®); Mianserin e.g. Mirtazepine (Romeron ®); Mianserin act by increasing the release of 5-HT and NE act by increasing the release of 5-HT and NE Via……… Via……… Differ from SSIR in Differ from SSIR in Increase appetite (good for patients taking cancer chemotherapy) NO N/V why? No Sexual dysfunction Why ? ; sedation. Also, produces constipation and rarely leads to agranulocytosis Increase appetite (good for patients taking cancer chemotherapy) NO N/V why? No Sexual dysfunction Why ? ; sedation. Also, produces constipation and rarely leads to agranulocytosis

22. Other non classified Antidepressants Venlavaxine ( Effexor R ) : Act by blocking 5- HT and NE uptake but it has side effects profile similar to SSRI. However, it may produce seizure and constipation. Why? Venlavaxine ( Effexor R ) : Act by blocking 5- HT and NE uptake but it has side effects profile similar to SSRI. However, it may produce seizure and constipation. Why? Desvenlafaxine PristiqR (metabolite of Venlavaxine) Trazodone: Selective blocker of 5-HT uptake but has significant α- blocking effect (hypotension and sedation); Blocks 5-HT2 receptors (Priapism) Trazodone: Selective blocker of 5-HT uptake but has significant α- blocking effect (hypotension and sedation); Blocks 5-HT2 receptors (Priapism)

23. Table 5: Effects of atypical antidepressants on Reuptake and 5-HT2 5-HT2 antagonism Noradrenaline reuptake 5-Ht reuptake +--++-+-+-+--+-+-----/+-+++AmoxapineBuproprionMaprotilineMianserinNafazodoneNomifensineTrazodoneVenlafaxine

24. Nefazodone: Structurally related to trazodone but does not has the sedative effect and does not block α- adrenoceptors, however; it likes most SSRI inhibit P450 3A4 isoenzyme. Nefazodone: Structurally related to trazodone but does not has the sedative effect and does not block α- adrenoceptors, however; it likes most SSRI inhibit P450 3A4 isoenzyme.

25. 3. Monoamine Oxidase Inhibitors: History: The anti TB Iproniazide exhibited mood elevating properties and latter found to inhibit MOA. History: The anti TB Iproniazide exhibited mood elevating properties and latter found to inhibit MOA.

26. Table 6: Side effects of atypical antidepressants Anticholinergic effects HypotensionSedationToxicityDrug ++--+--++++-++++++++++---++MianserinMirtazepineNefazodoneTrazodoneVenlafaxine

27. Classifications of MAOIs Either: Either: Hydralazine Derivatives (Phenelzine (Nardil®) Non –hydralazine DER.(Tranylcypramine (Parnate®) Non –hydralazine DER.(Tranylcypramine (Parnate®) Or as irreversible non –selective (Phelzine and Tranylcypramine) vs reversible selective ( Mclobemide) Or as irreversible non –selective (Phelzine and Tranylcypramine) vs reversible selective ( Mclobemide) Side Effects: ↑ appetite (Phenelzine like) ↓ appetite (Tranylcypramine; hepatotoxicity; SLE like; Side Effects: ↑ appetite (Phenelzine like) ↓ appetite (Tranylcypramine; hepatotoxicity; SLE like; Drug and Food interactions (very important). Drug and Food interactions (very important).

28. Hypotensin Anticholinergic effects SedationDrug +++-+++++-++--IsocarboxazidPhenelzineTranylcypromine Non-selective irreversible Moclobemide Selective reversible

29. Clinical uses of Antidepressant Drugs. Clinical uses of Antidepressant Drugs. A.Endogenous Depression ( SSRIs (first Choice) Tricyclics. A.Endogenous Depression ( SSRIs (first Choice) Tricyclics. B.Panic Disorders ( Imipramine or SSRIs) B.Panic Disorders ( Imipramine or SSRIs) C.Obsessive Compulsive Disorders (SSRIs Clomipramine),Migraine; Chronic pain, IBS and Anxiety (Amityiptyline) C.Obsessive Compulsive Disorders (SSRIs Clomipramine),Migraine; Chronic pain, IBS and Anxiety (Amityiptyline) D.Anorexia nervosa and Bulemia (SSRIs) D.Anorexia nervosa and Bulemia (SSRIs) E.Schizo-Afective Disorders (Amoxapine or SSRI + Haloperidol) E.Schizo-Afective Disorders (Amoxapine or SSRI + Haloperidol) F. Premature ejaculation G. Anxiety disorders H. Migraine I. Nocturnal Enuresis in children e.g. Imipramine

30. Drugs for mania e.g. Lithium carbonate; Valproic Acid; Lamotrigine; Carbamazipine; Gabapentin e.g. Lithium carbonate; Valproic Acid; Lamotrigine; Carbamazipine; Gabapentin LITHIUM : LITHIUM : MOA : Remember its similarity to sodium thus it: MOA : Remember its similarity to sodium thus it: - inhibits the release of NE -Increases re-uptake of NE -Decreases second messenger in postsynaptic neurons (decrease c-AMP; IP3 and DAG)) -Decreases second messenger in postsynaptic neurons (decrease c-AMP; IP3 and DAG))

31. Side effects 1) Endocrine side effects 1) Endocrine side effects -Nephrogenic Diabetes insipidus (antagonize the activity of ADH via inhibition of c-AMP). -Hypothyroidism 2) Other Side effects: 2) Other Side effects: -Irreversible renal damage (very important) N/V; Mental confusion; leucocytosis; and congenital cardiac anomalies (Ebsteins Malformation) Clinical Uses : - Rx of mania; Bipolar depression - Rx of mania; Bipolar depression - SIADH ; Hyperthyroidism ? - SIADH ; Hyperthyroidism ? - Schizophrenia - Schizophrenia - Leucopenia - Leucopenia

32. – Plasma level :  Therapeutic level 1.2 – 1.4 mg/l  Prophylactic level = 0.5-0.8 mg /l  Lithium takes 3-4 days to act, thus sedative and calming drugs like haloperidol I.V should be given at ER. Drug interactions:  Plasma level of Lithium and toxicity, increase in: –Lithium + low salt diet –Lithium + diuretics - Lithium + NSAIDs –Postpartum

33. Why lithium is not popular as before? Why lithium is not popular as before? What are the alternatives of lithium? What are the alternatives of lithium?Why? Lithium and pregnancy? Lithium and pregnancy?

34. Signs and symptoms of Lithium Toxicity Mild to moderate intoxication ( lithium livel 1.5 -2 mEq/l) Mild to moderate intoxication ( lithium livel 1.5 -2 mEq/l) Gastrointestinal: Gastrointestinal: -Vomitnig -Vomitnig -Abdominal pain -Abdominal pain -Dryness of mouth -Dryness of mouth Neurological : Neurological : -Ataxia -Dizziness -Dizziness -Slurred speech -Slurred speech -Nystagmus -Nystagmus -Lethargy or excitement -Muscle weakness

35. Moderate to severe intoxication (Lithium level 2.0-2.5 mEq /l) (Lithium level 2.0-2.5 mEq /l) Gatrointestinal: Gatrointestinal: -Anorexia nervosa -Persistent nausea and vomiting Neurological : Neurological : -Blurred vision -Muscle fasciculations -Clonic limb movements -Hyperactive deep tendon reflexes -Choreoathetoid movements -convulsions -Delirium -Syncope -Electroencephalographic changes -Stuper -Coma

36. Circulatory failure ( lowered blood pressure, cardiac arrhythmias, and conduction abnormalities. Circulatory failure ( lowered blood pressure, cardiac arrhythmias, and conduction abnormalities. Severe intoxication Severe intoxication (Litium level < 2.5 mEq /l) -Generalized convulsions -Oliguria and renal failure -Death