1. Therapeutic classPharmacological action, dosing and interactions Indications and contraindications, Adverese effects, Warning/Precaution Teratogenicity

2. Mood vs. Reason The idea that mood is different from reason comes from Plato. He described logos (reason) and thumos (spiritedness or mood). From logos we derive the word logic. From thumos we derive words such as dysthymic, euthymic etc. In the Phaedrus, Plato depicts logos as a charioteer driving the twohorses eros and thumos (i.e. love and mood ). Meaning: love and mood are to be guided by rationality. 3. Distinction between mood disorders and thoughtdisorders comes from Emil Kraepelin In Kraepelinian model schizophrenia and bipolar disorder are separateentities. Schizophrenia is a chronic unremitting illness with poor outcome and adecline in function(non restitutio ad integrum) whereas bipolardisorder is a cyclical illness with a better outcome and good restorationof function between episodes (restitutio ad integrum). 4. The physiology of the prefrontal cortex supportKraepelins theorydorsolateral prefrontal cortex(DLPFC)-regulates cognitive functioningventromedial prefrontal cortex(VMPFC) involved in emotional processinganterior cingulate cortex(ACC) involved in selective attention(dorsal ACC)emotional regulation(ventral ACC)orbital frontal cortex (OFC)regulates impulses and compulsions 5. Circuits The areas of the prefrontal cortex are connected with the subcortical areas by loops or circuits (limbic circuits, striatal circuits, etc.). Emotion is regulated by cortico- striato-thalamic- cortical (CSTC) circuits. 6. Cortico-Striato-Thalamic-Cortical (CSTC) circuitregulating Emotion 7. Emotional symptoms such as sadness or hapiness areregulated by VMPFC and the amygdala (the activity ishigh in the resting state of depressed patients). 8. Manic patients neuronal response to no-go task:impulsive symptoms of mania, such as risk taking andpressured speech are related to activity in the OFC. 9. Elevated/irritable mood circuits reflect inefficient informationprocessing in VMPFC, Amygdala, OFCThey are modulated by serotonergic, noradrenergicand dopaminergic projectionsfrom brainstem nuclei.Symptoms such as risk taking andpressured speech are manifestations of poor impulse control, thus regulated by the orbital frontal cortex(OFC). 10. Grandiosity, flight of ideas, and racing thoughtscircuits Are linked to inefficient information processing in the same brain regions associated with psychosis(nucleus accumbens) and DLPFC.These areas receiveserotonergic, dopaminergic andnoradrenergic projections 11. Sleep circuitsReflect inefficient informationprocessing in the hypothalamus, thalamus, basal forebrain Entire prefrontal cortex.All of these brain regions aremodulated by serotonin,dopamine and norepinephrine. 12. Distractibility circuitsReflect inefficient informationprocessing in the striatum and DLPFC which causes increased goal directed activity or agitation. The striatum receives only serotonergic and dopaminergic innervation, while DLPFC receives also serotonergicinput. 13. FDA: There is no such thing as a moodstabilizer.Psychiatrists: Long live mood stabilizers! 14. What is a Mood Stabilizer Originally, a mood stabilizer was a drug that treated mania and prevented itsrecurrence, thus stabilizing the manic pole of bipolar disorder. More recently, the concept of mood stabilizer has been defined in a wide-rangingmanner, from something that acts like lithium to an anticonvulsant used totreat bipolar disorder to an atypical antipsychotic used to treat bipolardisorder.An ideal mood stabilizer would need to be efficacious for both the acute phase ofbipolar mania/depression as well as for the maintenance phase of bipolarillness. At the present time no single drug meets these criteria. In reality different agents are efficacious for different phases of the bipolar illness. Some agents are more mania minded and thus able to treat from above, otheragents are more depression minded and thus able to treat from below. 15. Treating from above vs. treatingfrom below 16. FDA approved Drugs for Mania andMaintenance Therapy in Bipolar Disorder The following drugs are FDA approved for the treatment of acute mania in bipolar disorder: Aripeprazole, Carbamazepine ER, Chlorpromazine, Divalporex ER, Lithium, Olanzapine, Quetiapine, Risperidone and Ziprazidone.The following drugs are FDA approved for maintenance therapy in bipolar disorder: Aripeprazole, Lithium, Divalporex, Lamotrigine and Symbiax (Olanzapine /Fluoxetine combination). Quetiapine has FDA approval for the treatment of the acute phase of both bipolar mania and bipolar depression, but not for the maintenance phase. 17. The ideal mood stabilizer? 18. Clinically the following medication groupsare used for affective stabilization Lithium Anticonvulsants Atypical Antipsychotics Other Agents:MemantineAmantadineKetamineCacium Channel Blockers (L type)Riluzole 19. Lithium in Acute Mania Lithium efficacy: 49-79% Onset of action: 5-21 days Predictors of response: classic mania, fewepisodes, initial manic episode Tolerability: cognitive dulling, tremor, renalfailure, polyuria, GI upset, thyroid suppression, weightgain, sick sinus syndrome. Keck PE Jr., McElroy St. Nathan PE, Gorman JM. A guide to treatments that work 1997; Dinesen H et al. Acta Neurol Scand. 1984 20. Lithium drug interactions Antipsychotics : may increase lithium toxicity Bupropion: may increase seizure risk Carbamazepine : rare neurotoxicity Diuretics: increase lithium level. Iodine salts: increase in hypothyroidism Neuromuscular blockers: respiratory depression NSAIDs: increase in lithium levels SSRIs: rare serotonin syndrome Theophylline: decrease in lithium levels Urinary alkalinizers: decrease in lithium levels Verapamil: can both increase or decrease lithiumlevels 21. Lithium-Mechanism of Action Works on at least three systems in the brain (possibly four). 1. Second messengers: modulates the balance between GABA and Glutamate (inhibitory vs. excitatory neurotransmitters). 2. Prevents apoptosis by inhibiting GSK 3 enzyme and facilitating BDNF.3. Enhances serotonergic transmission. 4. Possible antipsychotic effect by blocking the postsynaptic dopamine receptors hypersensitivity . 22. Both Lithium and Valproate have neuro-protective effectsPRO -APOPTOTICNovel GSK3 inhibitorsFACTORS: GSK3(currently beingenzyme, BAD(bcl-developed) mightassociated-death-prove to be effectivepromoter) and stressantimanic agents.PRUNE the dendritictree and the number ofsynapses.ANTI-APOPTOTICFACTORS: BDNF, Bcl-2gene. Increase dendriticarborization and thenumber of synapses. 23. Apoptosis vs. Neurogenesis in the AdultHippocampus Stress, depression or drugs activate apoptosis in thehippocampus by promoting GSK3(resulting indecreased size of the hippocampus) Lithium, Valproate and Lamotrigine stimulate BDNFwhich promotes adult neurogenesis in the dentatenucleus of hippocampus. 24. Stress and apoptosis 25. Anticonvulsants Sodium Channel Blockers Calcium Channel BlockersSodium channels helppropagatethe electricalimpulse.Calcium channels release theneurotransmitter into theSynapse. 26. Sodium Channels - propagation ofelectrical impulses down the axon 27. Calcium channels -VSCCs can have multiple regulatory proteins.Beta units are intracellular. Gama units span themembrane.The alpha2 delta unitconsists of two parts:a delta part thatspans the membrane and analpha2 part that isextracellular.VSCCs ha have a snare that punctuatesthe presynaptic vesicle, releasing theneurotransmitter (excitation-secretioncoupling). 28. FDA Indications of Anticonvulsants Different anticonvulsants have different indications asmood stabilizers. Divalporex ER: acute mania, maintanance treatment ofbipolar d/o(Divalporex), migraine prophylaxis. Lamotrigine: maintenance treatment of bipolar 1 d/o, Carbamazepine ER: acute mania (as controlled releaseformulation Equetro). 29. Divalporex in Acute Mania Efficacy: 49-70% Onset of action: 3-10 days Predictors of response: comparable efficacy in classic, mixed, and rapid cycling. Keck PE Jr., McElroy St. Nathan PE, Gorman JM. A guide to treatments that work 1997; Dinesen H et al. Acta Neurol Scand. 1984 30. Valproate: Side Effects andToxicology Good News first:Several studies indicated that Valproate reduces totalcholesterol, LDLs and HDLs and protects against theadverse effects of some antipsychotic drugs on lipidfunction.Casey et al. 2003 showed that as an adjunct of Olanzapineor Risperidone, Valproate lowered cholesterol levels inpatients with schizophrenia and schizoaffective d/o.Improves cognition - Aldenkamp et al. 2000 completed adouble blind 20 week randomized clinical trial in whichValproate caused improvement in short term verbalmemory. 31. Pancreatitis Valproate is associated with infrequent idiosyncratic acute pancreatitis. In three migraine trials, the rates of elevation of amylase were similarbetween the Valproate and placebo groups (Pellock et al. 2002). Thesestudies showed that precautionary amylase levels provide little benefitin predicting pancreatitis. For this reason psychiatrists should beguided by clinical symptoms. Hepatotoxicity usually limited to patients younger than 2.Bowden et al. in 2000 completed a 1 year study of 187 patients onValproate. This study showed improvement in laboratory indices forhepatic function and no hepatotoxicity.Tohen et al. in 2003 in a 47 week study had similar results.Risk for hepatotoxicity combination with Carbamazepine. 32. And the bad news about Valproate GI effects (nausea, vomiting, diarrhea, dyspepsia and anorexia)are dose dependent and occur early in the treatment. Tremor resembles benign essential tremor and is seen more inpatients with seizure d/o. Sedation mild to moderate sedation is common. Hair loss is due to chelation of trace metals in the intestines. Hematological effects leukopenia and thrombocytopenia aredirectly related to serum levels above 100 microgrames/ml. Weight gain 3-4 lb weight gain is seen in 3-29% of patientstreated with Valproate over 3-12 months Polycystic ovarian syndrome occurs in 4-12% of women, butappears to be more frequent in women with epilepsy. 33. Lamotrigine as Monotherapy inBipolar Mania Lamotrigine has FDA approval for maintenance treatment for Bipolar 1 disorder. Both Lamotrigine and Lithium were superior to placebo in preventing recurrence of mood episodes. Lamotrigine has also been studied as maintenance monotherapy in Bipolar 2 disorder. 41% of Lamotrigine patients vs. 26% of placebo patients were stable without relapse for the 6 months duration of two studies (2000, 2003).Special consideration:When given with Valproate the dose needs to be lowered by 50 %. Also with valproate the risk for rash is higher. Bowden et al. Arch. Gen. Psychiatry 2003; Calabrese et al. J. Clin. Psychiatry 2000 34. Carbamazepine, Oxcarbazepine andLizcarbazepine Oxacarbazepine has two enantiomers(R and S). The S enantiomer is active (Lizcarbazepine). Binding site in the VSSC 35. Carbamazepine indications, side effectsand drug-drug interractions Carbamazepine and Oxcarbazepine have no FDA indications for Bipolardisorder. However in 2004 FDA approved Equetro (carbamazepine ER) for the treatmentof acute manic and mixed episodes. Adverse effects:-Black box warning regarding the risk for aplastic anemia (16/1,000.000 pt./year) and agranulocytosis (48/1,000.000 pt./year).-Hyponatremia-Increase in cholesterol and triglycerides (unlike Valproate). Drug-Drug interactions: CBZ is a potent CYP enzyme inducer 3A3 and 3A4, forthis reason it decreases its own serum concentration(autoinduction) and thatof many other medications including antipsychotics and antidepressants. 36. Anticonvulsants and folatedeficiency Older anticonvulsants decrease folate levels, leading toanemias, increased homocysteine levels and psychiatricproblems. Data are beginning to emerge that even the neweranticonvulsants and also Valproate may deplete folate. Measuring homocysteine levels is a more accurate way ofdetermining if someone has folate deficiency(becausefolate has to be methylated into L-methyltetrahydrofolatein order to be used by the brain). 37. Atypical antipsychotics Established efficacy for both psychotic and nonpsychotic mania. Antagonism at D2 receptor explains antipsychotic properties. Antagonism at 5HT2A receptors (which indirectly reduce glutamate) mayaccount for the reduction of manic symptoms. 38. ChlorpromazineFDA approved for:Manic type of manic depressive illnessCombativenessExplosive/hyperexcitable behavior in childrenPsychosis 39. Other Agents Memantine Amantadine Ketamine Cacium Channel Blockers (L type) Riluzole 40. Evidence Based Prescribing of DrugCombinations for Bipolar DisorderAtypical-Lithium ComboLithium with any atypical antipsychotic(especiallyOlanzapine, Risperidone and Quetiapine).Atypical-Depakote ComboDivalporex(Depakote) with any atypicalantipsychotic(especially Olanzapine, Risperidone andQuetiapine).Olanzapine-Fluoxetine ComboSymbyax 41. Reasonable Adjunctive Uses forAnticonvulsants without Mood StabilizingProperties Any combination containingGabapentin, Pregabalin, Topiramate, Levetiracetam, Zonisamide, Tiagabine . Can be used for treating anxiety: adjunctivegabapentin, pregabalin. Can be used for weight loss: adjunctive Topiramate orZonisamide. Can be used for improving sleep: adjunctiveGabapentin, Pregabalin or Tiagabine. 42. Mood De-stabilizers Many psychotropics and nonpsychotropic drugs affect mood. Isoniazid(mania) Prednison(mania, psychosis or depression) Acyclovir (psychosis) Hydroxychloroquine(psychosis, mania, depression, anxiety) Cycloserine(agitation, depression, psychosis) Interleukin-2 (psychosis) Quinolones (psychosis, paranoia, mania, agitation) Cephalosporines (euphoria) Clarithromycin (mania) Bactrim (Psychosis) Gentamycin (psychosis) Some Drug-Drug interactions: Isoniazid increases haloperidol and carbamazepine levels Quinolones increases clozapine and benzodiazepine levels Erythromycin, Clarithromycin increase Buspar and Clozaril levels 43. Are antidepressants mood de-stabilizers? Bipolar patients usually spend much more time in the depressed phase than in the manicphase. Antidepressants may be effective for bipolar depression. But not everyone agrees about if/how/when antidepressants should be used. Sachs et al. 2007 completed a study (part of the STEP-BD Systematic TreatmentEnhancement Program for Bipolar Disorder) an NIMH sponsored study in which 23% ofpatients with bipolar depression treated with an antidepressant in combination with amood stabilizer achieved euthymia for at least 8 consecutive weeks. 27% of patients who had placebo added to a mood stabilizer achieved euthymia. Other large studies confirmed these findings. Risk of rapid cycling and switch to mania limit the use of antidepressants in bipolardepression (slippery slope).Gijsman et al. Am J Psychiatry 2004. 44. Antidepressants in Bipolar Disorder slippery slope 45. Future Antipsychotics/MoodStabilizers Anticonvulsants: lizcarbazepine (active metabolite of oxcarbazepine), JPZ-4 (acompound related to lamotrigine). GSK 3 inhibitors Glucocorticoid antagonists Mefepristone(RU-486) CRF1 antagonists/V1B antagonists(vasopressin 1 B). Peptide-linked agents: Neurokinin 1, Neurokinin 2antagonists(saredutant), Neurokinin 3 antagonists. Acetylcholine-linked agents: partial agonists at alpha 7 nicotinic cholinergicreceptors may be procognitive, Varenicline an alpha4-beta2 partial agonistapproved for smoking cessation may be effective in bipolar d/o. Gly T1 inhibitors: glycine transporter inhibitors such as sarcosine blockreuptake of glycine, leading to decreased NMDA neurotransmission. 46. Thank You Lets Stop here