Hani hamed dessoki art, antipsychotic


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Hani hamed dessoki art, antipsychotic

  1. 1. Prof. Hani Hamed Dessoki, M.D.Psychiatry Prof. Psychiatry Chairman of Psychiatry Department Beni Suef University Supervisor of Psychiatry Department El-Fayoum University APA member
  2. 2. Schizophrenia Core Symptoms Psychotic Positive Symptoms Mesolimbic pathway Deficit Cognitive Negative Symptoms DLPC &VMPFC Cognitive Dysfunction DLPFC Affective VMPFC
  3. 3. Symptoms May Match To Malfunctioning Brain Circuits Mesocortical /prefrontal cortex Nucleus Negative accumbens symptoms reward circuits Mesolimbic Positive symptoms Affective Ventromedial symptoms Prefrontal cortex Aggressive symptoms Orbitofrontal cortex (Conlry.R, 2007) Cognitive symptoms Dorsolateral prefrontal cortex Amygdala Dopamine
  4. 4. Developments in the Treatment of Schizophrenia ’30s ’40s ’50s ’60s Haloperidol Electroconvulsive Fluphenazine Thioridazine therapy Loxapine Perphenazine Chlorpromazine First Generation Antipsychotics (FGAs) ’70s ’80s ’90s & ’00 ’06-’08 Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Asenapine Bifeprunox Paliperidone Iloperidone Second Generation Antipsychotics (SGAs)
  5. 5. Introduction Knowing how antipsychotic drugs work at specific receptor sites helps the clinician select the drug of choice for an individual patient. Older and newer antipsychotics show, in general, approximately the same efficacy in countering psychotic symptoms.
  6. 6. Principles of Antipsychotic Access, Efficient Utilization and Prescribing 1. Treatment with antipsychotic medications, like any other treatment, should be individualized in order to optimally promote recovery. 2. Treatment with antipsychotic medication should be as effective, safe and well-tolerated as possible. 3. Treatment with antipsychotic medication should consider personal preference and vulnerabilities.
  7. 7. Principles cont’d 4. Treatment with antipsychotic medication should provide value in terms of improved quality of life to the consumer. 5. Treatment choices should be informed by the best current evidence and must evolve in response to new information. 6. Cost considerations should guide antipsychotic medication selection if the preceding principles are met.
  8. 8. Binding to Receptors Agonists & Antagonists bind competitively - beware misunderstandings from binding data without further functional analysis Endogenous agonists often bind weakly (enthalpy driven) Successful antagonists often bind tightly (entropy driven) Agonist Partial Agonist Antagonist Inverse Partial Agonist Inverse Agonist
  9. 9. Inverse Agonist 100 % Effect 80 Full agonist 60 40 Partial agonist 20 0 -20 Inverse agonist -40 Dose
  10. 10. Receptor Systems Affected by Atypical Antipsychotics risperidone D2, 5-HT2A, 5-HT7, 1, 2 D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, sertindole ziprasidone D2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5HT7, D3, 1, NRI, SRI D2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, 1, loxapine M1, H1, NRI zotepine D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D1, D3, D4, 1, H1, NRI clozapine D2, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT3, 5HT6, 5-HT7, D1, D3, D4, 1, 2, M1, H1 olanzapine D2, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, D1, D3, D4, D5, 1, M1-5, H1 quetiapine D2, 5-HT2A, 5-HT6, 5-HT7, 1, 2, H1 aripiprazole D2, 5-HT2A, 5-HT1A, 1, 2, H1 1
  11. 11. loosely bound; fast release from receptor tightly bound; slow release from receptor DA receptor Drug psychlotron.org.uk Typical vs. atypical
  12. 12. Difference Between Low and High States cont’d The affinity, or more precisely, the dissociation constant (K) of dopamine for the high-affinity state of the D2 receptor is between 1.7 and 1.8 nM (nanomoles of dopamine per liter of water). The traditional antipsychotics generally have dissociation constants lower than 1.75 nM, which means that they are more tightly bound to D2 compared with dopamine.
  13. 13. Does 65% Occupancy Need to Be Maintained Full Time? (cont.) The new so-called atypical antipsychotics, such as clozapine, quetiapine, amisulpride, and remoxipride merely "block and run” (but at different speeds). For instance, the atypical, sertindole, and olanzapine, dissociates from the D2 receptor more slowly than clozapine or quetiapine, but more quickly than haloperidol or chlorpromazine.
  14. 14. Relative Binding of Antipsychotics To D2 Receptors K at D2 (nM) 100 10 Quetiapine Clozapine Olanzapine Sertindole “Loose” “Intermediate” Dopamine K (1.5nM) 1 Risperidone Ziprasidone Chlorpromazine Haloperidol Fluphenazine 0.1 “Tight”
  15. 15. Relevant Occupancy The blockade needed to alleviate psychotic symptoms is approximately two thirds or 65% of the population of D2 receptors (e.g. basal ganglia or striatum). When fewer than 60% of receptors are occupied (ie, when subthreshold doses are prescribed or when medication is not taken as prescribed), the symptoms of psychosis return.
  16. 16. Motor Side Effects The emergence of motor side effects with using of typical antipsychotics depends on the exact percentage of occupied D2 receptors (80% occupancy of D2). However, patients on the new atypical compound, Sertindole and aripiprazole, may not exhibit parkinsonism even with 90% occupation of D2 receptors.
  17. 17. Motor Side Effects (Cont.) In general, for first-generation antipsychotics, the effective dose range before motor side effects set is relatively narrow. So raising the dose of haloperidol, for instance, from 2 mg per day to 4 mg per day may overshoot the 80% occupancy place a patient over the threshold for the development of EPS.
  18. 18. Does 65% Occupancy Need to Be Maintained Full Time? (cont.) Brain imaging studies indicate that the traditional antipsychotics stay attached to dopamine D2 receptors for at least 1 or 2 days following an oral dose (daily administration is unnecessary & problematic). Receptor proliferation not only requires progressively higher doses in order to maintain efficacy but, in addition, is probably responsible for the development of tardive dyskinesia.
  19. 19. Does 65% Occupancy Need to Be Maintained Full Time? cont’d Clozapine and quetiapine should be taken daily. Sertindole, olanzapine and risperidone should probably be taken every second day. Haloperidol and chlorpromazine every third day. Thus maintaining intermittent 65% occupancy.
  20. 20. Why Psychotic Symptoms Wane With Age? Under untreated conditions, the number of receptors diminishes as the person ages. This explains, perhaps, the age-related reduction of speed of arousal, of peaks of pleasure, of frequency of impulsive behavior -all experiences mediated by dopamine.
  21. 21. Why Higher Doses Are Required Over Time In patients treated over long periods of time with antidopaminergic drugs, receptor proteins adapt to blockade by creating more D2 receptors (receptor proliferation). So that, in chronically treated schizophrenia patients, receptor numbers rise and maintenance doses increase at the same time.
  22. 22. Choosing antipsychotic & why?  Treating patients who are undergoing stress.  Treating first episode  Treating non adherent patients  Treating patients with a family history of osteoporosis  Treating cardiac patients or those with a family history of cardiac disease.
  23. 23. Choosing antipsychotic & why? (cont.)  Treating patients with a family history of diabetes  Avoiding obesity  Treating patients with sexual dysfunction  Treating treatment refractory patients  Treating women  Treating child and adolescents
  24. 24. Treating Patients Who Are Undergoing Stress Those whose stress levels are high (ie, increased levels of endogenous dopamine are being released) may find that the attachment period to the receptor of these 2 drugs (quetiapine and clozapine) is too short for symptom control. The therapeutic concentration of the antipsychotic in the presence of abundant dopamine will need to be proportionally higher than that needed in periods of calm.
  25. 25. Treating First Episodes Young patients with a first episode of psychosis respond equally well to first- and secondgeneration drugs, but tolerability of the drug regime is especially important in this population.
  26. 26. Treating Non Adherent Patients Patients known to be non adherent to regular medication will do better on those drugs that are relatively tightly bound to the D2 receptor (where relapse due to a brief period of noncompliance is a lesser risk). Monthly depot medication is still the treatment of choice for the extremely non adherent.
  27. 27. Problems Hinder Achieving Non adherence to treatment 41% Compliant 39% Non- compliant 20% Partially compliant Medication compliance is poor in patients with Schizophrenia Coldham EL, et al. Acta Psychiatr Scand 2002;106:286–90
  28. 28. NICE guidelines; For people with newly diagnosed (first episode) schizophrenia, National Clinical Practice Guideline Number 82. National Institute for Health and Clinical Excellence 2009.
  29. 29. Treating Patients With a Family History of Osteoporosis Patients with a family history of osteoporosis are best not treated with drugs that raise prolactin levels. This is especially true for women because they develop osteoporosis at a younger age than men. Normal serum prolactin levels are considered to be between 5 and 25 micrograms/L.
  30. 30. Potential consequences of prolactin elevation Erectile dysfunction Amenorrhoea Gynaecomastia Loss of libido Impotence Prolactin Elevation Osteoporosis  bone density Galactorrhoea
  31. 31. Treating Cardiac Patients or Those With a Family History of Cardiac Disease The QTc interval (approximate range is 350-440 milliseconds [ms]) represents the duration of ventricular depolarization and repolarization. It is generally accepted that QTc intervals exceeding 500 ms are associated with an increased risk of a lethal paroxysmal ventricular tachycardia (torsades de pointes).
  32. 32. Drug effects on QTc interval QTc prolongation occurs with: Thioridazine > 35 msec Pimozide > 30 msec Sertindole > 20 msec Ziprasidone > 17 msec Haloperidol > 11 msec Risperidone > 3 msec Olanzapine > 2 msec
  33. 33. Treating Patients With a Family History of Diabetes The base rate of diabetes in the schizophrenia population is thought to be between 5.6% and 6.7%. It is substantially higher than in the general population, probably because of relative inactivity and the high prevalence of smoking, poor diet and obesity.
  34. 34. Treating Patients With a Family History of Diabetes cont’d The novel antipsychotics have more propensity for inducing insulin resistance: clozapine, olanzapine, and quetiapine cause the highest rates of diabetes; sertindole, risperidone and ziprasidone are associated with lower rates. Patients with a family history of diabetes and with other concurrent risk factors should be treated with sertindole, risperidone, or ziprasidone.
  35. 35. Metabolic Highway Stahl S M, Essential Psychopharmacology (2002) Metabolically un friendly antipsychotics
  36. 36. Avoiding Obesity Weight gain increases not only the risk of diabetes, but also of coronary artery disease, a variety of cancers, gallbladder disease, gout, osteoarthritis, sexual dysfunction, infertility, and sleep apnea. Weight gain has a pronounced negative effect on self-esteem and affects compliance with antipsychotics.
  37. 37. Weight gain  (H1 & 1) antagonism  5HT2c antagonism  Dysregulation of leptin Stahl M.S. 2002: Psychopharmacology of antipsychotics
  38. 38. ac eb o do Zi ne pr as id A rip on e ip r Fl up azo le he na zi H n al op e er id R is pe ol rd Se on C e hl rt or in do op le ro m az Th in io rid e az Q i ue ne tia pi O ne la nz ap in C e lo za pi ne ol in M Pl Change from baseline weight (KG) Weight Gain: Short-Term (10 Weeks) Treatment 5 4 3 2 1 0 -1 -2
  39. 39. Treating Patients With Sexual Dysfunction Approximately half of all people taking antipsychotic drugs complain about sexual dysfunction but the mechanisms are poorly understood. Hyperprolactinemia seems to play a large part in the causation.
  40. 40. Treating Patients With Sexual Dysfunction cont’d A decline in erectile frequency was found to be especially prevalent in patients treated with risperidone. Women's sexuality is as affected as that of men.
  41. 41. Sertindole • Sertindole is not associated with decreased libido, erection or orgasm • This is due to its ability to maintain prolactin levels within normal limits • 22% of male sertindole patients experience a decreased ejaculatory volume (DEV) • However, a discontinuation rate of 3% due to DEV indicates that DEV is not a barrier to continuing treatment • Sertindole does not cause decreased fertility van Kammen 1996, Kasper 2002, Summary of product characteristics 2010
  42. 42. Treating Treatment-Refractory Patients While all the new drugs have been alleged to show superior efficacy to the older drugs, this claim has only been convincingly substantiated for clozapine . This poses a problem for patients with a personal or family history of type 2 diabetes or cardiovascular illness who have not responded to standard treatment (so, monitor of cholesterol, triglycerides and sugar levels).
  43. 43. Treating Women (Pregnancy) FDA: “Use in Pregnancy”- Drug categories Category A: Controlled studies show no risk Category B: No evidence of risk in humans Category C: Risk to humans cannot be ruled out Category D: positive evidence of risk but it is possible in some situations the benefits may outweigh the risks {benifit > risk} Category X: Toxic, Contraindicated in pregnancy. Risks outweigh the benefits in almost every situation {risk > benifit} A drug-free first trimester is ideal but not always achievable.
  44. 44. Treating Women (Pregnancy) Because of rising estrogen levels at this time and estrogen modulation of the dopamine receptor, there is relative protection against psychotic relapse . If antipsychotics are necessary, low-dose haloperidol has the best safety record throughout pregnancy, with dose reduction prior to the anticipated day of birth (to facilitate labor and minimize drug withdrawal effects in the neonate). Clozapine is unwise during pregnancy because of the theoretical possibility of seizure induction and agranulocytosis in the fetus.
  45. 45. Treating Women (Lactation) cont’d  Breast feeding will mean that the baby is exposed to the drug to some extent (infant sedation levels will need monitoring).  No long-term developmentally adverse effects on children exposed to the older antipsychotics.  Women with psychosis who may temporarily benefit from high prolactin levels (those who do not want to conceive or, conversely, postpartum women whose milk is insufficient for breast feeding) may preferentially benefit from first-generation antipsychotics or risperidone.
  46. 46. Antipsychotics during adolescents and childhood A frequently used antipsychotic medication in the treatment of Tourette’s is Risperdal and Haloperidol . Monitor for extrapyramidal symptoms, akathisia, and acute dystonias as well as longer-term side effects such as tardive dyskinesia and gynecomastia in males. Other atypical antipsychotics that have been used in the treatment of Tourette’s Disorder include Seroquel, Zyprexa, amd Aripiprazole.
  47. 47. When Serdolect??? Patients are likely to benefit from Sertindole:  If positive/negative symptoms are not controlled  If sedation, EPS or TD are present  If they experience excessive weight gain  If they are experiencing anticholinergic side effects  If their sexual functioning is impaired  If their cognitive function is impaired
  48. 48. Take-home Messages • Conventional antipsychotic drugs bind tightly to the dopamine D2 receptors, thereby eliciting EPS, elevated prolactin and tardive dyskinesia. • The atypical antipsychotic attach more loosely to the D2 receptors, thus resulting in less or no EPS, elevation of prolactin, and risk of tardive dyskinesia.
  49. 49. Shift in Risk Perception of Antipsychotics Past Areas of Concern Current Medical Realities Diabetes Weight Gain Weight Gain Sedation Tardive Dyskinesia Insulin Resistance CHD Prolactin Hyperlipidemia Prolactin TD Hyperlipidemia Insulin Resistance Sedation Coronary Heart Disease
  50. 50. Take-home Messages Good clinical practice involves using both types of medication at different times, depending on the specific needs of the patient taking in consideration Efficacy, Safety and Tolerability.
  51. 51. Future Directions
  52. 52. TODAY…. trials and errors diagnosis effective treatment TOMORROW…. tailor made
  53. 53. Future of Behavioral Health has Arrived  Patients with depression and anxiety are frustrated with drug treatments because of poor response (up to 5 trials).  Also, some of these medications increase anxiety, resistance to treatment, insomnia, and sexual dysfunction.  Sometimes they may quit medications.  It is better to choose psychotropic medications based on the individual genetic characteristics, metabolizing pathways leading to better medication tolerance.  This give the patient the confidence to continue treatment.  Test can done by a simple cheek swab (Assure Rx- GeneSightRx).
  54. 54. Future  The FDA has approved several drug labels to contain information about pharmacogenetic biomarkers.  Currently, approximately 17% of these pharmacogenetic labels are for psychiatric drugs, and most of them contain information about the CYP450 enzymes.  However, most of these labels do not offer any clinical recommendations or require the use of this information before treatment prescription.  The ultimate goal of future studies is to expand the pharmacogenetic information on antidepressant labels and incorporate them into wide clinical use.  However, there are several limitations that need to be considered before the field can advance to this stage.
  55. 55. Probiotics Probiotics may offer an alternative treatment option for depression and other psychiatric disorders, new research suggests. Investigators reviewed studies that examined the effect of "psychobiotics," live organisms that when ingested may produce health benefits in patients suffering from mental illness.
  56. 56. Probiotics Several preclinical studies showed a link between specific probiotics and beneficial behavioral effects. These included one in which rats with depressive behaviors resulting from maternal separation displayed normalized behavior and an improved immune response after ingesting the Bifidobacterium infantis probiotic. "
  57. 57. Probiotics Dr. Dinan noted that there are approximately 1 to 2 kg of bacteria in the adult gut that are capable of producing hundreds of essential chemicals. "Our preclinical studies suggest that depression is also associated with an alteration in the microbiota. Psychobiotics are good bacteria that have the potential to increase microbial diversity and treat the symptoms of depression," he said. The review is published in the November 15 issue of Biological Psychiatry.