AN  UPDATE  ON PSYCHOPHARMACOLOGY Prof. Dr. Haroon Rashid Chaudhry FACHARZT (Psych & Neurology) MRCPsych (London),  FACP (...
<ul><li>Anti-depressants </li></ul><ul><li>Mood stabilizers </li></ul><ul><li>Anti-anxiety drugs </li></ul><ul><li>Anti-ps...
ANTI-DEPRESSANTS
<ul><li>Imipramine (Kuhn 1957)  1 st  TCA </li></ul><ul><li>Iproniazide (Loomer  Saunders & Kline 1957)  1 st  MAOA </li><...
<ul><li>Serotonin </li></ul><ul><li>Norepinephrine </li></ul><ul><li>Imipramine </li></ul><ul><li>Amitryptiline </li></ul>...
<ul><ul><li>Time Tested </li></ul></ul><ul><ul><li>Established Efficacy </li></ul></ul><ul><li>BUT HIGH RISK FOR </li></ul...
<ul><li>SIDE EFFECTS </li></ul><ul><li>Dryness of mouth </li></ul><ul><li>Constipation </li></ul><ul><li>Blurring </li></u...
<ul><li>Maprotiline </li></ul><ul><li>Mianserin </li></ul>SEARCH  FOR  SAFER ANTIDEPRESSANTS EFFICACY vs. SAFETY =± TCAs  ...
<ul><li>Irreversible MAOIs </li></ul><ul><ul><li>Phenelzine </li></ul></ul><ul><ul><li>Tranylcypromine   </li></ul></ul><u...
<ul><li>IMPROVED SAFETY </li></ul><ul><ul><li>Reversible MAOIs </li></ul></ul><ul><ul><li>Moclobamide </li></ul></ul><ul><...
SINGLE NEUROTRANSMITTER ADDRESSED SEROTONIN
<ul><li>Fluoxetine </li></ul><ul><li>Fluvoxamine </li></ul><ul><li>Paroxetine </li></ul><ul><li>Sertraline </li></ul><ul><...
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) <ul><li>Fluoxetine </li></ul><ul><li>Fluvoxamine </li></ul><ul><li>Citalop...
SSRIs EFFICACY  vs.  SAFETY = TCAs  >TCAs
<ul><li>Fluoxetine Weekly </li></ul><ul><li>Escitalopram </li></ul><ul><li>Paroxetine SR </li></ul>IMPROVED  EFFICACY
SINGLE RECEPTOR SELECTIVITY SEROTONIN-REUPTAKE INHIBITORS/ RECEPTOR BLOCKERS TRAZODONE NEFAZODONE
EFFICACY  vs  SAFETY =TCAs  >>TCAs
<ul><li>Readdressed   </li></ul><ul><ul><li>Norepinephrine </li></ul></ul><ul><li>Reboxetine </li></ul>SINGLE  NEUROTRANSM...
SELECTIVE DOPAMINE REUPTAKE INHIBITORS  (SDRIs) <ul><li>BUPROPION </li></ul><ul><li>Major Depression </li></ul><ul><li>Pro...
<ul><li>Venlafaxine </li></ul><ul><li>Milancipran </li></ul><ul><li>Duloxetine </li></ul>DUAL ACTION READDRESSED  SNRIs <u...
EFFICACY vs SAFETY ( =/>?TCAs  (>>TCAs)
<ul><li>Mirtazepine </li></ul>NASSA EFFICACY vs. SAFETY (=/> TCAs  (>>>TCAs)
MOOD STABLIZERS
HOW SHOULD WE DEFINE  A “MOOD STABILIZERS”? <ul><li>No common definition exists today </li></ul><ul><li>Debate about key f...
MOOD STABILIZERS: POSSIBLE FEATURES <ul><li>Acute antimanic  effects </li></ul><ul><li>Prevention of manic episodes </li><...
EFFECTIVENESS OF POSSIBLE MOOD STABLIZERS Acute Acute Acute Maint- Mania Mixed Rapid  enance States Cyclers Lithium Yes No...
VALPROATE: AD EFFICACY <ul><li>Open study 1 (N=55) </li></ul><ul><ul><li>Moderate to Marked Improvement = 47% </li></ul></...
PRECIPITATION OF MOOD EPISODES Mania Depression Lithium No No Valproate No No Carbamazepine No No Olanzapine/ No No Clozap...
EASE OF USE OF MOOD STABILIZERS Simple   Frequent Lab  Prescribing Monitoring Lithium No Yes Valproate Somewhat Somewhat C...
SIDE EFFECTS OF MOOD STABILIZERS Lithium Weight gain, tremor, Gl symptoms,     thyroid function, cognitive complaints Val...
OPTIMAL WORKING DEFINITION OF MOOD STABILIZER <ul><li>Primary considerations </li></ul><ul><ul><li>Effective in acute mani...
PUTATIVE/INNOVATIVE MOOD STABILIZERS  FOR REFRACTORY BIPOLAR PATIENTS Anticonvulsants Ca2+Channel Blockers Gabapentin Vera...
Atypical Antipsychotics  Hormonal Clozapine thyroxine Risperidone Estrogen/progesterone Olanzapine Tamoxifen Quetiapine (Z...
MOOD STABILIZER: MANIA <ul><li>Mania with psychosis:  *  Divalproex  -  * Lithium </li></ul><ul><li>(Olanzapine, Risperido...
MOOD STABILIZER: DEPRESSION <ul><li>Without an AD: * Lithium  * Divalproex </li></ul><ul><li>*Lamotrigine  * Carbamazepine...
Lithium Divalproex Carbamazepine First Line Lamotrigine ?  Gabapentin Olanzapine Topiramate Efficacy in Depression Clinica...
BIPOLAR DISORDERS: RELAPSE PREVENTION <ul><li>Bipolar disorders are recurrent </li></ul><ul><ul><li>Recurrence has clinica...
BIPOLAR RECURRENCE: CLINICAL EFFECTS <ul><li> Rate of substance abuse comorbidity </li></ul><ul><li> Rate of alcoholism ...
BIPOLAR RECURRENCE:  MEDICAL EFFECTS <ul><li> Risk of cardiac disease </li></ul><ul><li> Risk of drug interactions </li>...
BIPOLAR RECURRENCE:  PSYCHOSICAL EFFECTS <ul><li>   Rates of divorce, separation </li></ul><ul><li>   Possibility of jai...
BIPOLAR RECURRENCE:  ECONOMIC EFFECTS <ul><li>   Job performance </li></ul><ul><li>   Medical treatment costs </li></ul>...
BIPOLAR DISORDERS: RELAPSE PREVENTION <ul><li>Bipolar disorders are recurrent </li></ul><ul><ul><li>Recurrence has clinica...
PREDICTORS OF POOR LONG-TERM  RESPONSE WITH LITHIUM <ul><li>Psychosis </li></ul><ul><li>Substance abuse </li></ul><ul><li>...
PROBLEMS OF CURRENT MOOD STABILIZERS <ul><li>Limited efficacy </li></ul><ul><li>Toxicity </li></ul><ul><li>Side effects: r...
BIPOLAR DISORDERS: TREATMENTS THAT DECREASE RISK OF RECURRENCE <ul><li>Lithium </li></ul><ul><li>Anticonvulsant mood stabl...
<ul><li>Tricyclic antidepressants </li></ul><ul><li>“ Typical” neuroleptics </li></ul><ul><li>Gabapentin </li></ul><ul><li...
<ul><li>“ Atypical” neuroleptics </li></ul><ul><li>Risperidone </li></ul><ul><li>Olanzapine </li></ul><ul><li>Quetiapine <...
<ul><li>Improve illness awareness </li></ul><ul><li>Early identification of new episodes </li></ul><ul><li>Enhance complia...
<ul><li>Treat the illness, not just the episodes </li></ul><ul><li>Help the patient learn about destabilizing factors </li...
Case Vignette <ul><li>Ms. X is an attractive 21 year old final semester engineering student, an active member of her colle...
Case Vignette <ul><li>Psychiatric examination revealed </li></ul><ul><ul><li>Increased PMA </li></ul></ul><ul><ul><li>Flig...
Case Vignette <ul><li>A consultant Psychiatrist made a diagnosis of Mania with psychotic symptoms (ICD 10) [DSM IV TR Bipo...
<ul><li>What will be your drug regime </li></ul><ul><ul><li>Mood stabilizers alone (LI/DVX) </li></ul></ul><ul><ul><li>Ant...
Rapid cycling 10 – 20% Mixed (dysphoric) 30 – 50% Pure mania 30 – 50%  VPA VPA Li, VPA Olanz, VPA ? GB BP II Dep Lamotrigi...
ANTI-ANXIETY DRUGS
a) BENZODIAZEPINES <ul><li>Short Acting </li></ul><ul><li>Intermediate </li></ul><ul><li>Long Acting </li></ul>b) NON BENZ...
BENZODIAZEPINES   PROS / CONS <ul><li>Established Efficacy </li></ul><ul><li>Safety in Over Dose </li></ul><ul><li>Withdra...
BENZODIAZEPINES A FRIEND FOE ? OR
History of Anxiolytic Development ALCOHOL  1903 - BARBITURATES 1950’s – NON BARBITURATES (Meprobamate) LATE 50’s - BENZODI...
SIX ISSUES <ul><li>Do we have any neuropsychiatric disorders without contribution of the GABA-BZD receptor complex? </li><...
<ul><li>4. Do we have enough evidence on </li></ul><ul><ul><li>BZD and cognitive dysfunction? </li></ul></ul><ul><ul><li>B...
<ul><li>Do we have any neuropsychiatric disorders without contribution of the GABA-BZD receptor complex? </li></ul>ISSUE  1
<ul><li>Anxiety </li></ul><ul><ul><li>Preclinical and clinical evidence is robust </li></ul></ul><ul><ul><li>BZD are effec...
<ul><li>Schizophrenia </li></ul><ul><ul><li>Several lines of evidence support the role of an epigenetic-induced GABAergic ...
<ul><li>Other disorders </li></ul><ul><ul><li>Epilepsy </li></ul></ul><ul><ul><li>Catatonia </li></ul></ul><ul><ul><li>ADH...
<ul><li>Wouldn’t a world without benzodiazepines make the patients anxious, the psychiatrists restless, the pharma industr...
<ul><li>Benzodiazepines have often been called the most widely prescribed group of drugs in the world and the biggest sell...
<ul><li>Don’t we think that the ‘GOOD’ that benzodiazepines have provided, are providing and will provide far outweigh the...
<ul><li>Do we have enough evidence on </li></ul><ul><ul><li>BZD and cognitive dysfunction? </li></ul></ul><ul><ul><li>BZD ...
<ul><li>Cognitive effects  of long-term benzodiazepine use: a meta-analysis </li></ul><ul><li>Moderate-to-large weighted e...
<ul><li>The effects of benzodiazepines on cognition. </li></ul><ul><li>Neuroimaging studies have found transient changes i...
<ul><li>Benzodiazepine use, abuse, and dependence. </li></ul><ul><li>It is important to distinguish between addiction to a...
<ul><li>Assessing the risks and benefits of benzodiazepines for anxiety  </li></ul><ul><li>disorders in patients with a hi...
<ul><li>In 1990, the APA task force on BZD’s concluded that BZD are not drugs of abuse though it is common among people ac...
<ul><li>Retrospective analysis of hypnotic overdose in 1989-90 found a decrease in BZD overdose and a statistically signif...
<ul><li>Don’t we have antipsychotics that produce cognitive dysfunction </li></ul><ul><li>Don’t we have antidepressants th...
<ul><li>Is it not therefore a question of  </li></ul><ul><ul><li>Rational/irrational use ? </li></ul></ul><ul><ul><li>Use/...
<ul><li>Are we aware of what we are talking about? </li></ul>ISSUE  5
<ul><li>BZDs allosterically modulate GABA neurotransmission by potentiating  GABA’s ability to increase conductance of  ch...
<ul><li>19 different sub units grouped into 5 classes according to the degree of amino acid identity </li></ul><ul><li>Alp...
<ul><li>BDZ1 (Omega - 1) -preferentially labelled by triazolopyridazines, imidazolopyridine and pyrazoloqinolines. Also, b...
BZD-2 receptors (Omega-2)   - caudate putamen, olfactory bulb, cerebral cortex, hippocampus and dentategyrus Related to co...
BDZ GABA Cl  Channel GABA  BENZODIAZEPINE  RECEPTOR
<ul><li>   1  – Sedative, amnestic, ataxic and partly anticovulsant </li></ul><ul><li>   2 and 3 –  Anxiolytic </li></ul...
GABA  RECEPTOR
GABAergic System Morris B et al (2005) Current Opinion in Pharmacology 5 : 101 - 106  2 CCK/VIP+  1
GABAergic System
<ul><li>Prescribing is not carefree but requires monitoring to obtain optimal risk benefit ratio </li></ul><ul><li>Benzodi...
<ul><li>So Benzodiazepine is a friend not a foe </li></ul><ul><li>However it is maybe an evil albeit necessary if not rati...
<ul><li>“ Apply your breaks” </li></ul>CONCLUSION Don’t blame the machine If the driver is at fault
The most deserving six-letter word....... “ THANKS&quot; for your patient listening.
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An update on psychopharmacology part i 22 june 2007 fountain house

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An update on psychopharmacology part i 22 june 2007 fountain house

  1. 1. AN UPDATE ON PSYCHOPHARMACOLOGY Prof. Dr. Haroon Rashid Chaudhry FACHARZT (Psych & Neurology) MRCPsych (London), FACP (USA), FAPA (USA), FRCP (Ireland) <ul><li>Head Department of Psychiatry </li></ul><ul><li>FJMC & SGRH </li></ul><ul><li>Zonal Representative World Psychiatric Association (WPA) </li></ul><ul><li>Vice President World Federation for Mental Health (WFMH) </li></ul><ul><li>Honorary Executive Director </li></ul><ul><li>Fountain House, Lahore </li></ul><ul><li>President Elect Pakistan Psychiatric Society (PPS) </li></ul>
  2. 2. <ul><li>Anti-depressants </li></ul><ul><li>Mood stabilizers </li></ul><ul><li>Anti-anxiety drugs </li></ul><ul><li>Anti-psychotic drugs </li></ul><ul><li>Anti-epileptic drugs </li></ul><ul><li>Anti-dementia drugs </li></ul>
  3. 3. ANTI-DEPRESSANTS
  4. 4. <ul><li>Imipramine (Kuhn 1957) 1 st TCA </li></ul><ul><li>Iproniazide (Loomer Saunders & Kline 1957) 1 st MAOA </li></ul>HISTORY
  5. 5. <ul><li>Serotonin </li></ul><ul><li>Norepinephrine </li></ul><ul><li>Imipramine </li></ul><ul><li>Amitryptiline </li></ul><ul><li>Clomipramine </li></ul><ul><li>Dothiepin </li></ul><ul><li>Nortriptyline </li></ul>NEUROTRANSMITTERS ADDRESSED TRICYCLIC ANTI- DEPRESSANTS (TCAS )
  6. 6. <ul><ul><li>Time Tested </li></ul></ul><ul><ul><li>Established Efficacy </li></ul></ul><ul><li>BUT HIGH RISK FOR </li></ul><ul><ul><li>Cardiac Pts </li></ul></ul><ul><ul><li>Epileptic Pts </li></ul></ul><ul><ul><li>Glaucoma Pts </li></ul></ul><ul><ul><li>Patients with Enlarged Prostate </li></ul></ul><ul><ul><li>Overdose </li></ul></ul><ul><li>ADDITIONAL RISK FOR </li></ul><ul><ul><li>Cancer Pts </li></ul></ul><ul><ul><li>Hepatitis pts </li></ul></ul><ul><ul><li>Old Age </li></ul></ul>TCAs
  7. 7. <ul><li>SIDE EFFECTS </li></ul><ul><li>Dryness of mouth </li></ul><ul><li>Constipation </li></ul><ul><li>Blurring </li></ul><ul><li>Urine Retention </li></ul><ul><li>Tachycardia </li></ul><ul><li>Postural Hypotension </li></ul><ul><li> Conduction </li></ul><ul><li> Contractility </li></ul>TCAs
  8. 8. <ul><li>Maprotiline </li></ul><ul><li>Mianserin </li></ul>SEARCH FOR SAFER ANTIDEPRESSANTS EFFICACY vs. SAFETY =± TCAs >TCAs
  9. 9. <ul><li>Irreversible MAOIs </li></ul><ul><ul><li>Phenelzine </li></ul></ul><ul><ul><li>Tranylcypromine </li></ul></ul><ul><li>Precautions </li></ul><ul><ul><li>Dietary Restrictions </li></ul></ul><ul><ul><li>Serious Interactions </li></ul></ul>MONOAMINE OXIDASE INHIBITORS (MAOIs )
  10. 10. <ul><li>IMPROVED SAFETY </li></ul><ul><ul><li>Reversible MAOIs </li></ul></ul><ul><ul><li>Moclobamide </li></ul></ul><ul><ul><li>Befloxatone </li></ul></ul>MAOIs
  11. 11. SINGLE NEUROTRANSMITTER ADDRESSED SEROTONIN
  12. 12. <ul><li>Fluoxetine </li></ul><ul><li>Fluvoxamine </li></ul><ul><li>Paroxetine </li></ul><ul><li>Sertraline </li></ul><ul><li>Citalopram </li></ul>SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)
  13. 13. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) <ul><li>Fluoxetine </li></ul><ul><li>Fluvoxamine </li></ul><ul><li>Citalopram </li></ul><ul><li>Sertraline </li></ul><ul><li>Paroxetine </li></ul><ul><li>Major Depression </li></ul><ul><li>Prophylaxis of Recurrent Major Depression </li></ul><ul><li>Treat. Of Secondary Depression e.g., Schizophrenia, Dementia </li></ul><ul><li>Bulimia </li></ul><ul><li>OCD </li></ul><ul><li>Phobic Disorder </li></ul><ul><li>Panic Disorder </li></ul><ul><li>Alcohol /Sub. Abuse </li></ul>
  14. 14. SSRIs EFFICACY vs. SAFETY = TCAs >TCAs
  15. 15. <ul><li>Fluoxetine Weekly </li></ul><ul><li>Escitalopram </li></ul><ul><li>Paroxetine SR </li></ul>IMPROVED EFFICACY
  16. 16. SINGLE RECEPTOR SELECTIVITY SEROTONIN-REUPTAKE INHIBITORS/ RECEPTOR BLOCKERS TRAZODONE NEFAZODONE
  17. 17. EFFICACY vs SAFETY =TCAs >>TCAs
  18. 18. <ul><li>Readdressed </li></ul><ul><ul><li>Norepinephrine </li></ul></ul><ul><li>Reboxetine </li></ul>SINGLE NEUROTRANSMITTER
  19. 19. SELECTIVE DOPAMINE REUPTAKE INHIBITORS (SDRIs) <ul><li>BUPROPION </li></ul><ul><li>Major Depression </li></ul><ul><li>Prophylaxis of Recurrent Major Depression </li></ul><ul><li>Bipolar Depression </li></ul><ul><li>ADHD </li></ul><ul><li>Alcohol, Nicotine Dependence </li></ul>
  20. 20. <ul><li>Venlafaxine </li></ul><ul><li>Milancipran </li></ul><ul><li>Duloxetine </li></ul>DUAL ACTION READDRESSED SNRIs <ul><li>Serotonin </li></ul><ul><li>Norepinephrine (Dopamine) </li></ul>
  21. 21. EFFICACY vs SAFETY ( =/>?TCAs (>>TCAs)
  22. 22. <ul><li>Mirtazepine </li></ul>NASSA EFFICACY vs. SAFETY (=/> TCAs (>>>TCAs)
  23. 23. MOOD STABLIZERS
  24. 24. HOW SHOULD WE DEFINE A “MOOD STABILIZERS”? <ul><li>No common definition exists today </li></ul><ul><li>Debate about key features </li></ul>
  25. 25. MOOD STABILIZERS: POSSIBLE FEATURES <ul><li>Acute antimanic effects </li></ul><ul><li>Prevention of manic episodes </li></ul><ul><li>Acute antidepressant effects in mixed patients </li></ul><ul><li>Prevention of depressive episodes </li></ul><ul><li>Prevention of rapid cycling </li></ul><ul><li>amelioration of residual symptoms </li></ul><ul><li>Do not precipitate manic episodes </li></ul><ul><li>Do not precipitate depressive episodes </li></ul>
  26. 26. EFFECTIVENESS OF POSSIBLE MOOD STABLIZERS Acute Acute Acute Maint- Mania Mixed Rapid enance States Cyclers Lithium Yes No? No? Yes Valproate Yes Yes Yes Yes Carbamazepine (Yes) Yes Yes Yes Olanzapine/ Yes Yes Yes Pending* Clozapine * Open extension data positive for olanzapine
  27. 27. VALPROATE: AD EFFICACY <ul><li>Open study 1 (N=55) </li></ul><ul><ul><li>Moderate to Marked Improvement = 47% </li></ul></ul><ul><li>Open study 2  (N=103) </li></ul><ul><ul><li>Moderate improvement = 22% </li></ul></ul><ul><li>1 calabrese JR, Delucchi GA, Am J Psychiatry. 1990; 147(4)431-434. </li></ul><ul><li>Lambert, 1984. </li></ul>
  28. 28. PRECIPITATION OF MOOD EPISODES Mania Depression Lithium No No Valproate No No Carbamazepine No No Olanzapine/ No No Clozapine Antidepressants Yes No Typial antipsychotics No Probable
  29. 29. EASE OF USE OF MOOD STABILIZERS Simple Frequent Lab Prescribing Monitoring Lithium No Yes Valproate Somewhat Somewhat Carbamazepine No Yes Olanzapine/ Yes No Clozapine No Yes
  30. 30. SIDE EFFECTS OF MOOD STABILIZERS Lithium Weight gain, tremor, Gl symptoms,  thyroid function, cognitive complaints Valproate Weight gain, (  thyroid function), Gl upset, pancreatitis, ? Polycystic ovaries Carbamazepine  WBC, rashes, nausea Olanzapine/ Weight gain, sedation ? Hyperglycemia Clozapine Weight gain, sedation, agranulocytosis,  salivation, ? hyperglycemia
  31. 31. OPTIMAL WORKING DEFINITION OF MOOD STABILIZER <ul><li>Primary considerations </li></ul><ul><ul><li>Effective in acute mania </li></ul></ul><ul><ul><li>Effective in acutely reducing depressive symptoms in mixed states </li></ul></ul><ul><ul><li>Prevents episodes of both mania and depression </li></ul></ul><ul><ul><li>Does not precipitate mania or depression </li></ul></ul><ul><li>Secondary considerations </li></ul><ul><ul><li>Efficacy in rapid cycling </li></ul></ul><ul><ul><li>Reduction of residual symptoms </li></ul></ul>
  32. 32. PUTATIVE/INNOVATIVE MOOD STABILIZERS FOR REFRACTORY BIPOLAR PATIENTS Anticonvulsants Ca2+Channel Blockers Gabapentin Verapamil Lamotrigine Nifedipine topiramate Nimodipine Tiagabine Acetazolamide
  33. 33. Atypical Antipsychotics Hormonal Clozapine thyroxine Risperidone Estrogen/progesterone Olanzapine Tamoxifen Quetiapine (Ziprasidone) Other Tryptophan Choline Donepezil Omega-3 fatty acids PUTATIVE/INNOVATIVE MOOD STABILIZERS FOR REFRACTORY BIPOLAR PATIENTS
  34. 34. MOOD STABILIZER: MANIA <ul><li>Mania with psychosis: * Divalproex - * Lithium </li></ul><ul><li>(Olanzapine, Risperidone, High potency conventional) </li></ul><ul><li>Dysphoric mania: * Divalproex - * Lithium </li></ul><ul><li>Epuphoric mania: * Lithium - * Divalproex </li></ul><ul><li>Hypomania: * Lithium - * Divalproex </li></ul>
  35. 35. MOOD STABILIZER: DEPRESSION <ul><li>Without an AD: * Lithium * Divalproex </li></ul><ul><li>*Lamotrigine * Carbamazepine </li></ul><ul><li>With an AD: * Lithium - * Divalproex </li></ul><ul><li>* Lamotrigine * Caramazepine </li></ul><ul><li>With psychosis: * Olanzapine - * Risperidone </li></ul><ul><li>* Quetiapine * Conventional </li></ul>
  36. 36. Lithium Divalproex Carbamazepine First Line Lamotrigine ? Gabapentin Olanzapine Topiramate Efficacy in Depression Clinical Features ?
  37. 37. BIPOLAR DISORDERS: RELAPSE PREVENTION <ul><li>Bipolar disorders are recurrent </li></ul><ul><ul><li>Recurrence has clinical, medical, psychosocial, and economic effects. </li></ul></ul><ul><ul><li>Recurrence results in hospitalization </li></ul></ul><ul><ul><ul><li>Mania or depression (Bipolar I) </li></ul></ul></ul><ul><ul><ul><li>Depression (Bipolar II) </li></ul></ul></ul><ul><li>Recurrence results in cycle shortening </li></ul>
  38. 38. BIPOLAR RECURRENCE: CLINICAL EFFECTS <ul><li> Rate of substance abuse comorbidity </li></ul><ul><li> Rate of alcoholism comorbidity </li></ul><ul><li> Rate of suicide </li></ul><ul><li>Possible treatment refractoriness </li></ul>
  39. 39. BIPOLAR RECURRENCE: MEDICAL EFFECTS <ul><li> Risk of cardiac disease </li></ul><ul><li> Risk of drug interactions </li></ul>
  40. 40. BIPOLAR RECURRENCE: PSYCHOSICAL EFFECTS <ul><li> Rates of divorce, separation </li></ul><ul><li> Possibility of jail/prison or hospitalization </li></ul>
  41. 41. BIPOLAR RECURRENCE: ECONOMIC EFFECTS <ul><li> Job performance </li></ul><ul><li> Medical treatment costs </li></ul><ul><li> Psychiatric treatment costs </li></ul>
  42. 42. BIPOLAR DISORDERS: RELAPSE PREVENTION <ul><li>Bipolar disorders are recurrent </li></ul><ul><ul><li>Recurrence has clinical, medical, psychosocial, and economic effects. </li></ul></ul><ul><ul><li>Recurrence results in hospitalization </li></ul></ul><ul><ul><ul><li>Mania or depression (Bipolar I) </li></ul></ul></ul><ul><ul><ul><li>Depression (Bipolar II) </li></ul></ul></ul><ul><li>Recurrence results in cycle shortening </li></ul>
  43. 43. PREDICTORS OF POOR LONG-TERM RESPONSE WITH LITHIUM <ul><li>Psychosis </li></ul><ul><li>Substance abuse </li></ul><ul><li>Rapid cycling </li></ul><ul><li>More than 3 episodes </li></ul><ul><li>Mixed mania (depression and mania) </li></ul><ul><li>Poor compliance </li></ul>
  44. 44. PROBLEMS OF CURRENT MOOD STABILIZERS <ul><li>Limited efficacy </li></ul><ul><li>Toxicity </li></ul><ul><li>Side effects: renal, thyroid, hematologic, hepatic </li></ul><ul><li>Monitoring </li></ul><ul><li>Interactions </li></ul><ul><li>Teratogenicity </li></ul><ul><li>Weight gain </li></ul><ul><li>Poor compliance </li></ul><ul><li>Refractoriness </li></ul>
  45. 45. BIPOLAR DISORDERS: TREATMENTS THAT DECREASE RISK OF RECURRENCE <ul><li>Lithium </li></ul><ul><li>Anticonvulsant mood stablizers (carbamazepine, divalproex, Lamotrigine) </li></ul><ul><li>Possibly benzodiazepines (clonazepam) </li></ul><ul><li>Possibly ECT </li></ul><ul><li>Possibly clozapine </li></ul>
  46. 46. <ul><li>Tricyclic antidepressants </li></ul><ul><li>“ Typical” neuroleptics </li></ul><ul><li>Gabapentin </li></ul><ul><li>Nonmood stablizing anticonvulsants </li></ul><ul><li>Alprazolam </li></ul>BIPOLAR DISORDERS: TREATMENTS THAT INCREASE RISK OF RECURRENCE
  47. 47. <ul><li>“ Atypical” neuroleptics </li></ul><ul><li>Risperidone </li></ul><ul><li>Olanzapine </li></ul><ul><li>Quetiapine </li></ul><ul><li>Ziprasidone </li></ul>BIPOLAR DISORDERS: Treatments Being Studied to Determine Risk of Recurrence
  48. 48. <ul><li>Improve illness awareness </li></ul><ul><li>Early identification of new episodes </li></ul><ul><li>Enhance compliance </li></ul><ul><li>Stress management </li></ul><ul><li>Avoid substance abuse </li></ul>GOALS OF PSYCHOEDUCATION IN BIPOLAR PATIENTS
  49. 49. <ul><li>Treat the illness, not just the episodes </li></ul><ul><li>Help the patient learn about destabilizing factors </li></ul><ul><li>Be empathetic, but blunt, about illness and denial </li></ul><ul><li>Work to achieve recovery, not limited improvement. </li></ul><ul><li>Use regimens that yield excellent tolerability and adherence </li></ul><ul><li>Acute episode drug needs are often different from maintenance, but they interact significantly </li></ul>PRINCIPLES OF BIPOLAR DISORDER
  50. 50. Case Vignette <ul><li>Ms. X is an attractive 21 year old final semester engineering student, an active member of her college literary and drama club presented with a 10 day history of excessive cheerfulness, over talkativeness, spending sprees, endless partying, insomnia, and suspicions of being teased and harmed. </li></ul><ul><li>She has no past history of medical/ mental illness/ no substance use. </li></ul><ul><li>Family history revealed an episodic illness in mother stabilized on lithium. </li></ul>
  51. 51. Case Vignette <ul><li>Psychiatric examination revealed </li></ul><ul><ul><li>Increased PMA </li></ul></ul><ul><ul><li>Flight of ideas </li></ul></ul><ul><ul><li>Elated mood </li></ul></ul><ul><ul><li>Inflated self esteem </li></ul></ul><ul><ul><li>Delusions of persecution and reference </li></ul></ul><ul><li>Detailed medical evaluation, investigations ruled out any organic / systemic dysfunction </li></ul>
  52. 52. Case Vignette <ul><li>A consultant Psychiatrist made a diagnosis of Mania with psychotic symptoms (ICD 10) [DSM IV TR Bipolar I disorder Single manic episode severe with psychotic features] and she was hospitalized. </li></ul>
  53. 53. <ul><li>What will be your drug regime </li></ul><ul><ul><li>Mood stabilizers alone (LI/DVX) </li></ul></ul><ul><ul><li>Antipsychotics alone (AAP/TAP) </li></ul></ul><ul><ul><li>Mood stabilizers (Li/DVX) + Antipsychotics (AAP/TAP) </li></ul></ul><ul><ul><li>Mood stabilizers + Benzodiazepines </li></ul></ul><ul><ul><li>Mood stabilizers + Antipsychotics + Benzodiazepines </li></ul></ul>MANIA WITH PSYCHOTIC SYMPTOMS
  54. 54. Rapid cycling 10 – 20% Mixed (dysphoric) 30 – 50% Pure mania 30 – 50% VPA VPA Li, VPA Olanz, VPA ? GB BP II Dep Lamotrigine Not listed in DSM IV TR. Anxiety, Hostility, Impulsivity, Poor insight, Confusion, Memory impairment Sensory hyper acuity Mania with psychotic Features 25 – 75% Mood Stabilizer Combinations Phenomenological Domains
  55. 55. ANTI-ANXIETY DRUGS
  56. 56. a) BENZODIAZEPINES <ul><li>Short Acting </li></ul><ul><li>Intermediate </li></ul><ul><li>Long Acting </li></ul>b) NON BENZODIAZEPINES <ul><li>Buspirone </li></ul><ul><li>Etifoxine HCI </li></ul>
  57. 57. BENZODIAZEPINES PROS / CONS <ul><li>Established Efficacy </li></ul><ul><li>Safety in Over Dose </li></ul><ul><li>Withdrawal Effects </li></ul><ul><li>Dependence </li></ul><ul><li>Tolerance </li></ul><ul><li>Memory Disturbance </li></ul><ul><li>Rebound Anxiety </li></ul>
  58. 58. BENZODIAZEPINES A FRIEND FOE ? OR
  59. 59. History of Anxiolytic Development ALCOHOL 1903 - BARBITURATES 1950’s – NON BARBITURATES (Meprobamate) LATE 50’s - BENZODIAZEPINES NONBENZODIAZEPINE HYPNOTICS GABA MIMETICS SELECTIVE GABA A TARGETS
  60. 60. SIX ISSUES <ul><li>Do we have any neuropsychiatric disorders without contribution of the GABA-BZD receptor complex? </li></ul><ul><li>Wouldn’t a world without benzodiazepines make the patients anxious, the psychiatrists restless, the pharma industry insomniacs, and the society bewildered? </li></ul><ul><li>Don’t we think that the ‘GOOD’ that benzodiazepines have provided, are providing and will provide far outweigh the questionable ‘BAD’ about benzodiazepines? </li></ul>
  61. 61. <ul><li>4. Do we have enough evidence on </li></ul><ul><ul><li>BZD and cognitive dysfunction? </li></ul></ul><ul><ul><li>BZD and oversedation? </li></ul></ul><ul><ul><li>BZD and dependence potential? </li></ul></ul><ul><ul><li>BZD withdrawal? </li></ul></ul><ul><li>5. Are we aware of what we are talking about? </li></ul><ul><li>6. Can we balance the options? </li></ul>
  62. 62. <ul><li>Do we have any neuropsychiatric disorders without contribution of the GABA-BZD receptor complex? </li></ul>ISSUE 1
  63. 63. <ul><li>Anxiety </li></ul><ul><ul><li>Preclinical and clinical evidence is robust </li></ul></ul><ul><ul><li>BZD are effective anxiolytics </li></ul></ul><ul><li>Depression </li></ul><ul><ul><li>Behavioural models have shown depression in animal can be manipulated by GABA agents </li></ul></ul><ul><ul><li>Stress is key to depression and stress induced changes occur in GABAergic function </li></ul></ul>GABA BZD IN NEUROPSYCHIATRY
  64. 64. <ul><li>Schizophrenia </li></ul><ul><ul><li>Several lines of evidence support the role of an epigenetic-induced GABAergic cortical dysfunction </li></ul></ul><ul><ul><li> in schizophrenia psychopathology </li></ul></ul><ul><li>Addiction </li></ul><ul><ul><li>Decreased GABAergic function is a major etiologic step in the maintenance of addictive state </li></ul></ul>GABA BZD IN NEUROPSYCHIATRY
  65. 65. <ul><li>Other disorders </li></ul><ul><ul><li>Epilepsy </li></ul></ul><ul><ul><li>Catatonia </li></ul></ul><ul><ul><li>ADHD </li></ul></ul><ul><ul><li>PMDD </li></ul></ul><ul><ul><li>Dyskinesias/Akathisia </li></ul></ul><ul><ul><li>Tourettes </li></ul></ul><ul><ul><li>Parkinsons </li></ul></ul><ul><ul><li>Huntington’s disease </li></ul></ul>GABA BZD IN NEUROPSYCHIATRY
  66. 66. <ul><li>Wouldn’t a world without benzodiazepines make the patients anxious, the psychiatrists restless, the pharma industry insomniacs, and the society bewildered? </li></ul>ISSUE 2
  67. 67. <ul><li>Benzodiazepines have often been called the most widely prescribed group of drugs in the world and the biggest selling drugs in the history of medicine. </li></ul><ul><li>Worldwide sales of benzodiazepines are estimated at in excess of $21 billion. </li></ul><ul><li>1980’s 1 billion alprazolam prescription worldwide </li></ul><ul><li>Non psychiatric prescriptions account for 70% of benzodiazepine </li></ul><ul><ul><li>Physicians </li></ul></ul><ul><ul><li>Cardiologists </li></ul></ul><ul><ul><li>Gastroenterologists etc </li></ul></ul>BENZODIAZEPINE IN PRACTICE
  68. 68. <ul><li>Don’t we think that the ‘GOOD’ that benzodiazepines have provided, are providing and will provide far outweigh the questionable ‘BAD’ about benzodiazepines? </li></ul>ISSUE 3
  69. 69. <ul><li>Do we have enough evidence on </li></ul><ul><ul><li>BZD and cognitive dysfunction? </li></ul></ul><ul><ul><li>BZD and oversedation? </li></ul></ul><ul><ul><li>BZD and dependence potential? </li></ul></ul><ul><ul><li>BZD withdrawal? </li></ul></ul>ISSUE 4
  70. 70. <ul><li>Cognitive effects of long-term benzodiazepine use: a meta-analysis </li></ul><ul><li>Moderate-to-large weighted effect sizes were found for all cognitive domains suggesting that long-term benzodiazepine users were significantly impaired, compared with controls, in all of the areas that were assessed. However, this study has several limitations, one being that it includes a relatively small number of studies. </li></ul><ul><li>Barker et al, (2004), CNS Drugs, 18(1) 37-48 </li></ul>BENZODIAZEPINE AND COGNITION
  71. 71. <ul><li>The effects of benzodiazepines on cognition. </li></ul><ul><li>Neuroimaging studies have found transient changes in the brain after benzodiazepine administration but no brain abnormalities in patients treated long term with benzodiazepines. </li></ul><ul><li>Such findings suggest that patients should be advised of potential cognitive effects when treated long term with benzodiazepines, although they should also be informed that the impact of such effects may be insignificant in the daily functioning of most patients. </li></ul><ul><li>Stewart SA (2005) J Clin Psychiatry, 66 Suppl 2: 9-13 </li></ul>BENZODIAZEPINE AND COGNITION
  72. 72. <ul><li>Benzodiazepine use, abuse, and dependence. </li></ul><ul><li>It is important to distinguish between addiction to and normal physical dependence on benzodiazepines. </li></ul><ul><li>Few cases of addiction arise from legitimate use of benzodiazepines. </li></ul><ul><li>Pharmacologic dependence, a predictable and natural adaptation of a body system long accustomed to the presence of a drug, may occur in patients taking therapeutic doses of benzodiazepines. </li></ul><ul><li>Due to the chronic nature of anxiety, long-term low-dose benzodiazepine treatment may be necessary for some patients; this continuation of treatment should not be considered abuse or addiction. </li></ul><ul><li>O'brien CP. (2005)J Clin Psychiatry,66 Suppl 2:28-33. </li></ul>BENZODIAZEPINE DEPENDENCE
  73. 73. <ul><li>Assessing the risks and benefits of benzodiazepines for anxiety </li></ul><ul><li>disorders in patients with a history of substance dependence. </li></ul><ul><li>There is much ambiguity over appropriate definitions for benzodiazepine abuse and dependence </li></ul><ul><li>Furthermore, benzodiazepines do not appear to induce relapse of substance abuse in these patients. </li></ul><ul><li>The position that benzodiazepines are contraindicated in former substance abusers appears to lack empirical justification. </li></ul><ul><li>Benzodiazepines may be indicated in certain patients with anxiety disorders and a history of substance abuse or dependence. </li></ul><ul><li>Posternak MA (2001) Am J Addict, 10(1):48-68. </li></ul><ul><li>The presence or absence of a history of alcohol use disorders is not a strong predictor of the use of benzodiazepines in subjects with anxiety disorders over 12 months of prospective follow-up. </li></ul><ul><li>Mueller TI (1996) J Clin Psychiatry, 57(2):83-9. </li></ul>BENZODIAZEPINE DEPENDENCE
  74. 74. <ul><li>In 1990, the APA task force on BZD’s concluded that BZD are not drugs of abuse though it is common among people actively abusing alcohol, opiates, sedative hypnotics. </li></ul><ul><li> Selzman C (1991) Am. J Psychiatry, 148:151-52 </li></ul><ul><li>In early 1980’s studies indicated that long term administration of BZD at therapeutic doses produce physical dependence. So in 1990’s it was recommended that these agents should (esp. short t 1/2 ) be tapered gradually when discontinuing them </li></ul><ul><li> Rosenbaum JR (2005) J. Clin. Psychiatry, 66 Suppl 2: 4-8 </li></ul><ul><li>By 1999 International group of experts recommended the use of BZD for anxiety disorders even for long periods </li></ul><ul><li> Uhlenhuth EH (1999) J Clin. Psychopharmacol, 19 (6): 23S-29S </li></ul>BENZODIAZEPINE DEPENDENCE
  75. 75. <ul><li>Retrospective analysis of hypnotic overdose in 1989-90 found a decrease in BZD overdose and a statistically significant rise in non BZD sedative overdose </li></ul><ul><li>Hofman RS (1991) NY State J Med, 91:436-439 </li></ul><ul><li>BZD are less toxic in overdose than alternatives, are safe, and have little liability for abuse among patients without history of abuse </li></ul><ul><li>Rosenbaum JR (2005) J. Clin. Psychiatry, 66 Suppl 2: 4-8 </li></ul>BENZODIAZEPINE OVERDOSE CHANGING ATTITUDE TO BZD
  76. 76. <ul><li>Don’t we have antipsychotics that produce cognitive dysfunction </li></ul><ul><li>Don’t we have antidepressants that produce cognitive dysfunction </li></ul><ul><li>Doesn’t anxiety produce cognitive dysfunction </li></ul><ul><li>Don’t we read about cognitive dysfunction in schizophrenia and bipolar </li></ul><ul><li>Haven’t we heard of withdrawal of antipsychotics, antidepressants and anticonvulsants </li></ul>CRITIQUE
  77. 77. <ul><li>Is it not therefore a question of </li></ul><ul><ul><li>Rational/irrational use ? </li></ul></ul><ul><ul><li>Use/misuse/abuse ? </li></ul></ul><ul><ul><li>Combinations that are useful and dirty? </li></ul></ul><ul><ul><li>And what of useful and dirty combinations in neurobiology </li></ul></ul>CRITIQUE
  78. 78. <ul><li>Are we aware of what we are talking about? </li></ul>ISSUE 5
  79. 79. <ul><li>BZDs allosterically modulate GABA neurotransmission by potentiating GABA’s ability to increase conductance of chloride through its channel </li></ul>BASICS
  80. 80. <ul><li>19 different sub units grouped into 5 classes according to the degree of amino acid identity </li></ul><ul><li>Alpha 1-6, Beta 1-3, gamma1-3,Delta, Theta, epsilon, pi and Rho1-3 </li></ul><ul><li>Alpha subunits, especially 1 ,2 and 5 are important for receptor activation by GABA </li></ul><ul><li>Most GABA A receptor complexes are α 1 β 2 γ 2 </li></ul><ul><li>Specifically α and γ subunits are thought to determine GABA A-BZD receptor pharmacology </li></ul>GABA RECEPTOR
  81. 81. <ul><li>BDZ1 (Omega - 1) -preferentially labelled by triazolopyridazines, imidazolopyridine and pyrazoloqinolines. Also, beta carbolines. </li></ul><ul><li>BDZ1 rich areas - lamina IV of cerebral cortex, cingulate cortex , globus pallidus, nucleus basalis, substantia nigra pars reticulata, molecular layer of the cerebellum, Amygdaloid nucleus , periaqueductal gray matter, ventral pallidum and inferior colliculus. </li></ul><ul><li>Implicated in sleep wakefulness mechanism </li></ul>BENZODIAZEPINE RECEPTOR
  82. 82. BZD-2 receptors (Omega-2) - caudate putamen, olfactory bulb, cerebral cortex, hippocampus and dentategyrus Related to cognitive, memory and psychomotor function. BZD-3(Omega-3) are not directly associated with GABA receptors or with chloride channels . They may regulate the synthesis of neuroactive steroids. BENZODIAZEPINE RECEPTOR
  83. 83. BDZ GABA Cl Channel GABA BENZODIAZEPINE RECEPTOR
  84. 84. <ul><li> 1 – Sedative, amnestic, ataxic and partly anticovulsant </li></ul><ul><li> 2 and 3 – Anxiolytic </li></ul><ul><li> 3 – DA system receives GABAergic inhibitory input </li></ul><ul><li> 5 – Cognitive </li></ul><ul><li> 3 – Immobilisation action of propofol and etomidate. </li></ul><ul><li> 2 - Hypnotic and respiratory depression </li></ul><ul><li>GABA A receptor subtype selective anxiolytics </li></ul><ul><ul><li>L-838417 </li></ul></ul><ul><ul><li>SL 651498 (Full agonist at  2 and  3, partial agonist at  1 and 5) </li></ul></ul><ul><ul><li>GLB139-  3 selective BZ agonist </li></ul></ul>GABA RECEPTOR - SELECTIVITY Whiting PJ (2006) Curr Opinion Pharmacol 6: 24-29 Rudolf U & Mohler H (2006) Curr Opinion Pharmacol, 6:18-23
  85. 85. GABA RECEPTOR
  86. 86. GABAergic System Morris B et al (2005) Current Opinion in Pharmacology 5 : 101 - 106  2 CCK/VIP+  1
  87. 87. GABAergic System
  88. 88. <ul><li>Prescribing is not carefree but requires monitoring to obtain optimal risk benefit ratio </li></ul><ul><li>Benzodiazepines are therefore ‘GOOD’ and are here to stay </li></ul>ISSUE 6 BALANCING THE OPTIONS
  89. 89. <ul><li>So Benzodiazepine is a friend not a foe </li></ul><ul><li>However it is maybe an evil albeit necessary if not rationally prescribed </li></ul>CONCLUSION
  90. 90. <ul><li>“ Apply your breaks” </li></ul>CONCLUSION Don’t blame the machine If the driver is at fault
  91. 91. The most deserving six-letter word....... “ THANKS&quot; for your patient listening.

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