Mania Madness, frenzy “A Phase of Bipolar disorders characterized by expansiveness, elation, agitation, hyper excitability, hyperactivity, and increased speed of thought or speech(flight of ideas)”. A mood disorder, In a senses opposite to depression. “A period of seven or more days of unusually and continuously effusive and open elated or irritable mood, where the mood is not caused by drugs/medication or a medical illness and(a) is causing obvious difficulties at work or in social relationships and activities, or(b) requires admission to hospital to protect the person or others, or(c) the person is suffering psychosis.”
Bipolar disorder Bipolar disorder, or manic-depressive illness (MDI), is one of the most common, severe, and persistent mental illnesses. Bipolar disorder is a serious lifelong struggle and challenge. Bipolar disorder is characterized by periods of deep, prolonged, and profound depression that alternate with periods of an excessively elevated or irritable mood known as mania.
Unipolar major depressive disorder and bipolar disorder share depressive symptoms, but bipolar disorder is defined by episodes of mania or hypomania. Bipolar disorder constitutes 1 pole of a spectrum of mood disorders that includes including bipolar I (BPI), bipolar II (BPII), cyclothymia (oscillating high and low moods), and major depression.
Manic Episode characterized by at least 1 week of profound mood disturbance, characterized by elation, irritability, or expansiveness . At least 3 of the following symptoms must also be present: Grandiosity Diminished need for sleep Excessive talking or pressured speech Racing thoughts or flight of ideas Clear evidence of distractibility Increased level of goal-focused activity at home, at work, or sexually Excessive pleasurable activities, often with painful consequences
Hypomanic Episode Hypomanic episodes are characterized by an elevated, expansive, or irritable mood of at least 4 days‟ duration. At least 3 of the following symptoms are also present: Grandiosity or inflated self-esteem Diminished need for sleep Pressured speech Racing thoughts or flight of ideas Clear evidence of distractibility Psychomotor agitation at home, at work, or sexually Engaging in activities with a high potential for painful consequences
Neurobiology OF MANIA AND BIPOLAR DISORDER* Ambiguous till dateBiogenic amine neurotransmitters:Noradrenergic system:NE turnover increase in the cortical and thalamic areas of BD subjects where decrease in depression Serotogenic system:Reduced 5-hydroxytryptamine (5- HT)1A receptor binding potential in raphe and hippocampus- amygdala of brain in depressed patientsDopaminergic system DA agonists are effective antidepressants and are able to precipitate mania. D2 receptor found in caudate, putamen, nucleus accumbens, cerebral cortex and hypothalmus is negativly coupled to adenylyl cyclase. Older antipsychotics act through blockage of D2 receptors , which eventualy result in extrpyramidal system (muscle rigidty , involuntry movement, pseudoparkinsonism)
Cholinergic system cholinergic tone decrease during mania , pilocarpine elicit pupillary constriction , The response of pilocarpine enhance after lithium and VPA ,adding evidence on the effects of lithium perhaps potentiating brain cholinergic systems relative inferiority of noradrenergic compared to cholinergic tone was associated with depression, while the reverse was associated with maniaReceptor Nature PathwayD2 Inhibitory Presynaptic: decr Ca+ conduct Postsynaptic:Gi, incr K+ conduct ,decr cAMPM3 Excitatory Gq ,incr IP3 & DAGAlpha 1 Excitatory Gq ,incr IP3 & DAG5 HT-2 Excitatory Gq ,incr IP3 & DAG
Signal pathways abnormalities*cellular signaling pathways interact at various levels, allow the cell to receive, process, and respond to information signaling pathways represent major targets for a number of hormones, including glucocorticoids, thyroid hormones, and gonadal steroids , may explain mood disorder with alterd hormonal level. (e.g. the frequent onset of bipolar disorder in puberty, triggering of episodes in the postpartum period)G Protein abnormalities:Postmortem brain studies have reported increased levels of the stimulatory G protein (Gαs) accompanied by increases in post-receptor stimulated adenylyl cyclase (AC) activity in BD.
The protein kinase C signaling pathway:PKC is one of the major intracellular mediators of signals generated upon external stimulation of cells via a variety of neurotransmitter receptors M1, M3, M5 α1 5-HT2A . PKC induce the hydrolysis of various membrane phospholipids.increased PKC activity and translocation found in different experiments of BD brains moreover attenuation of PKC activity may play a role in the antimanic effects of lithium and VPA.Novel selective PKC inhibitors if devolped may have very useful action against mania. Tamoxifen is underinvestigation.Abnormalities of calcium signaling Calcium ions play a critical role in regulating the synthesis and release of neurotransmitters, neuronal excitability, elevations in both resting and stimulated intracellular Ca2+ levels in platelets, lymphocytes and neutrophils of patients with BD.*The underlying neurobiology of bipolar disorder, world psychiatryHUSSEINI K MANJI,1 JORGE A QUIROZ,1 JENNIFER L PAYNE,1 JASKARAN SINGH,1 BARBARA P LOPES,1 JENILEE S VIEGAS,1 and
Genetic abnormalities*Genes associated with mania and BP include:Glycogen synthase kinase 3 (GSK-3):GSK3β is a central regulator of the circadian clock. Negative mutation in the CLOCK gene normally contributing to circadian periodicity in humans results in behavior mimicking mania.ANK3(ANKYRIN G):ANK3 is an adaptor protein found at axon initial segments that regulates the assembly of voltage- gated sodium channels. CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel)ANK3 and subunits of the calcium channel are down-regulated in mouse brain in response to lithium, which indicates a possible therapeutic mechanism of action
Genetic abnormalities*Diacylglycerol kinase eta (DGKH) gene: GWAS published by 2011 pointed first intron of diacylglycerol kinase eta (DGKH) gene, a key protein in the lithium-sensitive phosphatidyl inositol pathway. Lithium-mediated inhibition of GSK3β is thought to result in downregulation of molecules involved in cell death and upregulation of neuroprotective factors.
1:Stephen Soreff, MD President of Education Initiatives, Nottingham, NH; Faculty, Boston University, Boston, MA and Daniel Webster College, Nashua, NH
Differential Diagnosis∂ Acute intoxication with recreational drugs, such CLINICAL FEATURES OF MANIA as amfetamines, amfetamine derivatives (MDMA:Characteristicand cocaine appearance mania. Ecstasy), Clinical can mimicMood Elevated or irritableTalk Chronic use of cannabis can of ideas ∂ Fast, pressurized, flight induce manic like features.Energy Excessive ∂ Cushings syndrome had a secondarywealth, power, influence orIdeas Grandiose, self-confident, delusions of manic illness of religious significance, sometimes persecutory ∂ corticosteroids can induce mania ∂ Dopamine agonists (e.g. bromocriptine) are alsoCognition Disturbance of registration of memories known to sometimes induce secondary mania.Physical Insomnia, mild to moderate weight loss, increased libido ∂ The excited phase of catatonic schizophrenia can sometimes be mistaken for mania. excessive drinking orBehaviour Disinhibition, increased sexual activity, spendingHallucinations Fleeting auditory or, more rarely, visual
TreatmentPharmacotherapyDrug Mania Mixed Maintenance DepressionLithium X XValporate XR XCarbamazepine X XLamotrigine XArippiprazole X X XZiprasidone X XResperidone X XAsenapine X XQuetiapine X XChlorpromazine XOlanzapine X X XTable. FDA-Approved Bipolar Treatment Regimens
Acute treatment of mania: an update on new medications.Case School of Medicine, Mood Disorders Program, University Hospitals Case Medical Center, 11400 Euclid Avenue, Suite 200, Cleveland, OH 44106, USA. Prashant.Gajwani@uhhs.com
Mood Stabilizer LITHIUM: In use since the 1870s. Initially used to treat depression, gout, and neutropenia, and for cluster headache prophylaxis, In 1940s FDA banned the use of lithium because of fatalities but lifted in 1970. Narrow therapeutic index that predisposes poisoning with relatively minor changes in medications or health status. May protect and preserve the hippocampal volumes, also claimed neuroprotective.
Indications & Uses Acute manic or mixed episodes in patients with BPI and BPII. Major Depression Schizoaffective and Schizophrenic Disorders Disorders of Impulse Control Psychiatric Disorders in Children Neutropenia and Anemiasecondary to antineoplastic drugs Hyperthyroidismradioactive iodine, surgery, propylthiouracil are preferred.a SIADHDemeclocycline is preferred for syndrome of inappropriate ADH secretion.
Contraindication Renal or cardiovascular disease, Severe debilitation, dehydration, sodium depletion, Concomitant therapy with diuretics; very high risk of lithium toxicity under such conditions. History of Leukemia
Mechanism of Action:Effects on Electrolytes and Ion Transport Lithium is closely related to sodium in properties. It can substitute for sodium in generating action potentials and in Na+-Na+ exchange across the membrane. It inhibits the latter process, but does not significantly affect the Na+/Ca2+ exchange or Na+/K+ ATPase .Effects on Neurotransmitters Lithium appears to enhance some of the actions of serotonin, though findings have been contradictory. Its effects on norepinephrine are variable. The drug may decrease norepinephrine and dopamine turnover, and these effects. Lithium also appears to block the development of dopamine receptor supersensitivity that may accompany chronic therapy with antipsychotic agents. Finally, lithium may augment the synthesis of acetylcholine, perhaps by increasing choline uptake into nerve terminals.
Mechanism of Action:Effects on Second messenger: One of the best-defined effects of lithium is its action on inositol phosphates. IP3 and DAG are important 2nd messengers for both -adrenergic and muscarinic transmission. Lithium inhibits several important enzymes in the normal recycling of membrane phosphoinositides, including conversion of IP2 to IP1 (inositol monophosphate) and the conversion of IP to inositol.This block leads to a depletion of phosphatidylinositol-4,5- bisphosphate (PIP2), the membrane precursor of IP3 and DAG. Over time, the effects of transmitters on the cell will diminish in proportion to the amount of activity in the PIP2-dependent pathways.Iisolated brain tissue study indicate that lithium can inhibit norepinephrine-sensitive adenylyl cyclase. Such an effect could relate to both its antidepressant and its antimanic effects
Lithium may uncouple receptors from their G proteins; indeed, two of lithium„s most common side effects, polyuria and subclinical hypothyroidism, may be due to uncoupling of the vasopressin and TSH receptors from their G proteins.
Dosage: May start with lower dose to minimize adverse drug reactions 900-2400 mg/day divided q6-8hr (immediate release tabs) OR 900-1800 mg divided q12hr PO if using extended release tabs Desirable serum lithium concentrations are 0.6- 1.2 mEq/L; although higher serum concentration may be needed not to exceed 1.5 mEq/L Administration: Take preferably with foodMonitor Serum lithium 12 hr after dose; 2 times/week until serum concentration and clinical condition stabilizes; thereafter q2month
Interaction:Drug Severity Possible interactionSibutramine Contraindicated Increase toxicity by Pharmacodynamics synergismCandesarttan Use Alternative Increase Li levelLinezolid Use Alternative Increase serotonin level by inhibiting MAOLocaserin Use Alternative Both Increase serotonin levelFurazolidone Use Alternative Increase serotonin levelTranylcypromine Use Alternative Increase serotonin levelVilazodone Use Alternative Serotonin syndromeAspirin Monitor closely Decrease renal clearence of LiCarbamazepine Monitor closely Risk of neurotoxicityCitalopram Monitor closely Enhance serotonergic effectHaloperidol Monitor closely Risk of neurotoxicity
Over Dose/Poisoning:The likelihood of toxicity increases with increasing serum Lithium levels.Threshold level:1.5mEq/l Serum Signs of toxicity: Below 2.0mEq/l Diarrhea, vomiting, drowsiness, muscular weakness and lack of coordination Higher Level 2.0/3.0mEq/l giddiness, ataxia, blurred vision, tinnitus and a large output of dilute urine Treatment: No Specific Antidote, discontinue drug, Eliminate ion Follow protocol as for Barbiturate poisoning, Correct fluid /Electrolyte
Anticonvulsants: VALPROIC ACIDFDA Seizure/Epilepsy 78, BiPolar disorder „961st marketed AED, Effective ant manic, BP depressionTherapeutic effect level 50-125 mg/lFetal Hepatotoxic ,pancreatitis (free radical effect)Not to used for Posttraumatic seizureBest for rapid-cycling and acute-mania
Pharmacokinetics: Bioavailability: 81-89% of delayed-release Peak Plasma Concentration: 115-145 mcg/mL (IV) Protein Bound: 10-19% Volume of distribution: 92 L Metabolism: Liver, Excretion: Liver Metabolites: 2-propyl-3-ketopentanoic acid Half-Life: 6-16 hr; 10-67 hr (neonates)
•Indication& Dosage: Bipolar ManiaInitial 25 mg/kg/day POIncrease rapidly to achieve lowest therapeutically effective dose,Maximum: 60 mg/kg/day Partial SeizuresPO: 10-15 mg/kg/day PO initially, THEN up to 30- 60 mg/kg/day Migraine, Prophylaxis250 mg PO q12hr Status Epilepticus SchizophreniaMaximum dose for an adult is 60mg/kg daily except 1g/kg/daily for migraine*Dose adjustment require in hepatic impairement.*Abbott Laboratories. Depakene (valproic acid) solution and liquid-filled capsules prescribing information. North Chicago, IL; 2009 Nov.
•Mechanism Of Action: GABA level in the brain facilitate glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, An inhibitory effect on the GABA transporter GAT-1b thus blocking degradation of GABA. hyperpolarize membrane potentials by increasing membrane k conductance. 1(katzung pharmacology)
Drug interaction: Doripenum, eratopenum, imipenem, meropenem,vorinostat, have serious interaction ,increase hepatic metabolism1 . Protein bounded drugs increase free VPA level e.g. Aspirin, carbamazepine,warfarin,digoxin etc VPA decrease level of liver metabolized drugs(cytochrome p450) e.g. carbamazepine, phenytoin,TCA,lamotrigine P450 inducers decrease VPA level. Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats journal of health sciences 2007
Teratogenic potential : Pregnancy Category: D; known to cause neural tube defects in fetus Lactation: excreted in milk
Carbamazepine :An anticonvulsant and specific analgesic for trigeminal neuralgia,psychomotor, seizure. Stabilizes inactivated state of sodium channels, thereby making neurons less excitable May reduce activity of necleus ventralis of the thalamus or decrease synaptic transimisssion or summation of temporal stimulation dose range: 800-1200 mg/day PO in divided doses Therapeutic range: 4-12 mg/L [16.9-50.8 micromoles/L] Maximum dose of 1600 mg/day Pregnency category D, enter in breast milk.
Indications & Dosage: Bipolar I Disorder, ManiaMonotherapy or as an adjunct to lithium or divalproexDose :400-800 mg/day Bipolar I Disorder, MaintenanceImmediate-release: 400-800 mg/day PO q12hr Insomnia (Off-label)Usually start 25 mg PO qHS Major Depressive DisorderDosage range: 150-300 mg/day Alcohol Dependence (Off-label)25-50 mg PO qHS; not to exceed 300 mg
Mechanism of Action: interact with serotonin (5HT2) and dopamine D1 and D2 receptors. higher selectivity for 5HT2 relative to D2 to low EPS high affinity at histaminergic and adrenergic alpha1 receptors, with a lower affinity at adrenergic alpha2 receptors.
Drug Interaction: Increased risk of drowsiness and postural hypotension when used with alcohol. CYP3A4 inducers Phenytoin,CBZ decrease level CYP3A4 inhibitors Ketoconazole ,erythromycin increase level.Pregnancy Category: C Neonates exposed in 3rd trimester are at risk for EPS or withdrawal symptoms Lactation: excreted in breast milk, breast feeding is not recommended
Tardive dyskinesia : Tardive dyskinesias are involuntary movements of the tongue, lips, face, trunk, and extremities. TD can be caused by long-term treatment with dopamine antagonists. Neuroleptics, Amisulpride, antiemetic metoclopramide, a potent D2 dopamine receptor antagonist, may cause TD, particularly in elderly patients. antihistamines, fluoxetine, Atypical antipsychotics particularly Quetiapine and clonazapine are used to reduced the tardive dyskinesia.* * A single-blind, randomized trial comparing quetiapine and haloperidol in the treatment of tardive dyskinesia Emsley R, Turner HJ, Schronen J, Botha K, Smit R, Oosthuizen PP.Department of Psychiatry, University of Stellenbosch, Cape Town, South Africa
Ziprasidone : 2nd generation antipsychotic Used for bipolar I, schizophrenia, Acute agitation MOA:Antagonist at dopamine (D2), serotonin (5HT1D, 5HT2A) receptorsAgonist at serotonin 5HT1A receptorModerately inhibits reuptake of norepinephrine and serotoninAlso has alpha-blocking & antihistaminic activity Risk of QT prolongation. Less chance of hyperglycemia or diabetes and EPS.
Loxapine : 1st generation antipsychotics Dibenzoxazepine antipsychotic; blocks mesolimbic D1 and D2 receptors in the brain; also has anti-serotonin 5HT2 activity extrapyramidal disease, parkinsonian, somnolence, tardive dyskinesia 10—20 mg PO q 24hr Inhaled preparation is in pipeline ,10mg Od, but FDA has Pulmonary saftey concerns1 Loxapine, as with all other antipsychotics has label warning “Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death”2 European medicine agency recmnded loxapine for the rapid control of agitation in adult with BP or schizophernia.(2012) 1 . Inhaled loxapine for agitation revisited: focus on effect sizes from 2 Phase III randomised controlled trials in persons with schizophrenia or bipolar disorder. Citrome L. New York Medical College, Valhalla 2. Antipsychotic drugs: sudden cardiac death among elderly patients. Narang P, El-Refai M, Parlapalli R, Danilov L, Manda S, Kaur G, Lippmann S.2010
Prospective antimanic drugs: Tamoxifena nonsteroidal antiestrogen used to treat breast cancer, is a potent and selective PKC inhibitor that crosses the blood-brain barrier. AsenapineIncrease level of dopamine, NE and acetylcholine in cortical and limbic brain areas. also prevent from depression and protect cognitive function.