Therapeutic classPharmacological action, dosing and interactions Indications and contraindications, Adverese effects, Warning/Precaution Teratogenicity
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 two horses eros and thumos (i.e. love and mood ). Meaning: love and mood are to be guided by rationality.
Distinction between mood disorders and thoughtdisorders comes from Emil Kraepelin In Kraepelinian model schizophrenia and bipolar disorder are separate entities. Schizophrenia is a chronic unremitting illness with poor outcome and a decline in function(non restitutio ad integrum) whereas bipolar disorder is a cyclical illness with a better outcome and good restoration of function between episodes (restitutio ad integrum).
The physiology of the prefrontal cortex supportKraepelin’s theory dorsolateral prefrontal cortex(DLPFC)- regulates cognitive functioning ventromedial prefrontal cortex(VMPFC)– involved in emotional processing anterior cingulate cortex(ACC)– involved in selective attention(dorsal ACC) emotional regulation(ventral ACC)orbital frontal cortex (OFC)–regulates impulses and compulsions
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.
Emotional symptoms such as sadness or hapiness areregulated by VMPFC and the amygdala (the activity ishigh in the resting state of depressed patients).
Manic patient’s neuronal response to no-go task:impulsive symptoms of mania, such as risk taking andpressured speech are related to activity in the OFC.
Elevated/irritable mood circuits reflect inefficient informationprocessing in VMPFC, Amygdala, OFC They are modulated by serotonergic, noradrenergic and dopaminergic projections from brainstem nuclei.Symptoms such as risk taking andpressured speech are manifestations of poor impulse control, thus regulated by the orbital frontal cortex(OFC).
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
Sleep circuitsReflect inefficient informationprocessing in the hypothalamus, thalamus, basal forebrain Entire prefrontal cortex.All of these brain regions aremodulated by serotonin,dopamine and norepinephrine.
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.
FDA: “There is no such thing as a moodstabilizer.”Psychiatrists: “Long live mood stabilizers!”
What is a Mood Stabilizer Originally, a mood stabilizer was a drug that treated mania and prevented its recurrence, thus “stabilizing” the manic pole of bipolar disorder. More recently, the concept of “mood stabilizer” has been defined in a wide-ranging manner, from “something that acts like lithium” to “an anticonvulsant used to treat bipolar disorder” to “an atypical antipsychotic used to treat bipolar disorder.” An ideal mood stabilizer would need to be efficacious for both the acute phase of bipolar mania/depression as well as for the maintenance phase of bipolar illness. 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”, other agents are more “depression minded” and thus able to treat “from below”.
Treating “from above” vs. “treatingfrom below”
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.
Clinically the following medication groupsare used for affective stabilization Lithium Anticonvulsants Atypical Antipsychotics Other Agents: Memantine Amantadine Ketamine Cacium Channel Blockers (L type) Riluzole
Lithium in Acute Mania Lithium efficacy: 49-79% Onset of action: 5-21 days Predictors of response: classic mania, few episodes, initial manic episode Tolerability: cognitive dulling, tremor, renal failure, polyuria, GI upset, thyroid suppression, weight gain, 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
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 lithium levels
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 .
Both Lithium and Valproate have neuro-protective effects PRO -APOPTOTICNovel GSK3 inhibitors FACTORS: GSK3(currently being enzyme, BAD(bcl-developed) might associated-death-prove to be effective promoter) and stressantimanic agents. PRUNE the dendritic tree and the number of synapses. ANTI-APOPTOTIC FACTORS: BDNF, Bcl-2 gene. Increase dendritic arborization and the number of synapses.
Apoptosis vs. Neurogenesis in the AdultHippocampus Stress, depression or drugs activate apoptosis in the hippocampus by promoting GSK3(resulting in decreased size of the hippocampus) Lithium, Valproate and Lamotrigine stimulate BDNF which promotes adult neurogenesis in the dentate nucleus of hippocampus.
Sodium Channels - propagation ofelectrical impulses down the axon
Calcium channels - VSCCs can have multiple regulatory proteins. Beta units are intracellular. Gama units span the membrane. The alpha2 delta unit consists of two parts: a delta part that spans the membrane and an alpha2 part that is extracellular. VSCCs ha have a snare that punctuates the presynaptic vesicle, releasing the neurotransmitter (excitation-secretion coupling).
FDA Indications of Anticonvulsants Different anticonvulsants have different indications as mood stabilizers. Divalporex ER: acute mania, maintanance treatment of bipolar d/o(Divalporex), migraine prophylaxis. Lamotrigine: maintenance treatment of bipolar 1 d/o, Carbamazepine ER: acute mania (as controlled release formulation Equetro).
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
Valproate: Side Effects andToxicology Good News first: Several studies indicated that Valproate reduces total cholesterol, LDLs and HDLs and protects against the adverse effects of some antipsychotic drugs on lipid function. Casey et al. 2003 showed that as an adjunct of Olanzapine or Risperidone, Valproate lowered cholesterol levels in patients with schizophrenia and schizoaffective d/o. Improves cognition - Aldenkamp et al. 2000 completed a double blind 20 week randomized clinical trial in which Valproate caused improvement in short term verbal memory.
Pancreatitis Valproate is associated with infrequent idiosyncratic acute pancreatitis. In three migraine trials, the rates of elevation of amylase were similar between the Valproate and placebo groups (Pellock et al. 2002). These studies showed that precautionary amylase levels provide little benefit in predicting pancreatitis. For this reason psychiatrists should be guided by clinical symptoms. Hepatotoxicity – usually limited to patients younger than 2. Bowden et al. in 2000 completed a 1 year study of 187 patients on Valproate. This study showed improvement in laboratory indices for hepatic function and no hepatotoxicity. Tohen et al. in 2003 – in a 47 week study had similar results. Risk for hepatotoxicity – combination with Carbamazepine.
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 in patients 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 are directly related to serum levels above 100 microgrames/ml. Weight gain – 3-4 lb weight gain is seen in 3-29% of patients treated with Valproate over 3-12 months Polycystic ovarian syndrome – occurs in 4-12% of women, but appears to be more frequent in women with epilepsy.
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
Carbamazepine, Oxcarbazepine andLizcarbazepine Oxacarbazepine has two enantiomers(R and S). The S enantiomer is active (Lizcarbazepine). Binding site in the VSSC
Carbamazepine indications, side effectsand drug-drug interractions Carbamazepine and Oxcarbazepine have no FDA indications for Bipolar disorder. However in 2004 FDA approved Equetro (carbamazepine ER) for the treatment of 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, for this reason it decreases its own serum concentration(autoinduction) and that of many other medications including antipsychotics and antidepressants.
Anticonvulsants and folatedeficiency Older anticonvulsants decrease folate levels, leading to anemias, increased homocysteine levels and psychiatric problems. Data are beginning to emerge that even the newer anticonvulsants and also Valproate may deplete folate. Measuring homocysteine levels is a more accurate way of determining if someone has folate deficiency(because folate has to be methylated into L-methyltetrahydrofolate in order to be used by the brain).
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) may account for the reduction of manic symptoms.
Chlorpromazine FDA approved for:Manic type of manic depressive illnessCombativenessExplosive/hyperexcitable behavior in childrenPsychosis
Evidence Based Prescribing of DrugCombinations for Bipolar DisorderAtypical-Lithium Combo Lithium with any atypical antipsychotic(especially Olanzapine, Risperidone and Quetiapine).Atypical-Depakote Combo Divalporex(Depakote) with any atypical antipsychotic(especially Olanzapine, Risperidone and Quetiapine).Olanzapine-Fluoxetine Combo Symbyax
Reasonable Adjunctive Uses forAnticonvulsants without Mood StabilizingProperties Any combination containing Gabapentin, Pregabalin, Topiramate, Levetiracetam, Zonis amide, Tiagabine . Can be used for treating anxiety: adjunctive gabapentin, pregabalin. Can be used for weight loss: adjunctive Topiramate or Zonisamide. Can be used for improving sleep: adjunctive Gabapentin, Pregabalin or Tiagabine.
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
Are antidepressants mood de-stabilizers? Bipolar patients usually spend much more time in the depressed phase than in the manic phase. 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 Treatment Enhancement Program for Bipolar Disorder) an NIMH sponsored study in which 23% of patients with bipolar depression treated with an antidepressant in combination with a mood 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 bipolar depression (slippery slope). Gijsman et al. Am J Psychiatry 2004.
Antidepressants in Bipolar Disorder– slippery slope
Future Antipsychotics/MoodStabilizers Anticonvulsants: lizcarbazepine (active metabolite of oxcarbazepine), JPZ-4 (a compound related to lamotrigine). GSK 3 inhibitors Glucocorticoid antagonists – Mefepristone(RU-486) CRF1 antagonists/V1B antagonists(vasopressin 1 B). Peptide-linked agents: Neurokinin 1, Neurokinin 2 antagonists(saredutant), Neurokinin 3 antagonists. Acetylcholine-linked agents: partial agonists at alpha 7 nicotinic cholinergic receptors may be procognitive, Varenicline an alpha4-beta2 partial agonist approved for smoking cessation may be effective in bipolar d/o. Gly T1 inhibitors: glycine transporter inhibitors such as sarcosine block reuptake of glycine, leading to decreased NMDA neurotransmission.