PHARMACOTHERAPY OF PSYCHOSIS & MANIAMELDI A. ANUTA, M.D., FPNA, FPCPMarch 10, 2015Davao Medical School Foundation

PSYCHOSISA symptom of mental illnesses characterized by a distorted or non-existent sense of realityDifferent etiologies, unique treatment approach

COMMON PSYCHOTIC DISORDERSMood disorders (major depression or mania) with psychotic featuresSubstance-induced psychosisDementia with psychotic featuresDelirium with psychotic featuresBrief psychotic disorderDelusional disorderSchizoaffective disorderSchizophrenia

SCHIZOPHRENIAWorldwide prevalence of 1%Prototypic disorder for understanding the phenomenology of psychosis and the impact of antipsychotic treatment

SCHIZOPHRENIAPOSITIVE SYMPTOMSHallucinationsDelusionsDisorganized speechDisorganized or agitated behavior are typically responsive to pharmacotherapyNEGATIVE SYMPTOMSApathyAvolitionAlogiaCOGNITIVE DEFICITSWorking memoryProcessing speedSocial cognitionProblem solving (1.5-2 SD below population norms)

Cognitive dysfunction is the strongest predictor of functional impairment among schizophrenia patients, yet negative symptoms and cognitive deficits show limited improvement with antipsychotic treatment (Buchanan et al., 2007).

ANTIPSYCHOTICS / NEUROLEPTICSGROUP OF DRUGS THAT HAVE BEEN USED MAINLY FOR TREATING SCHIZOPHRENIA BUT ARE ALSO EFFECTIVE IN SOME OTHER PSYCHOSES & AGITATED STATES

THE DOPAMINE HYPOTHESIS

The DA hypothesis of psychosis derived from the fortuitous discovery of chlorpromazine's therapeutic efficacy in schizophrenia, and the subsequent elucidation by Carlsson that postsynaptic DA D2 receptor antagonism was the common mechanism that explained antipsychotic properties.

HISTORY50 YEARSRESERPINE & CHLORPROMAZINEPSYCHIATRIC THINKING NOW HAS SHIFTED TO A MORE BIOLOGIC BASIS.

Reserpine (Rauwolfia ) exhibited antipsychotic properties by decreasing dopaminergic neurotransmission; however, unlike D2 receptor antagonists, reserpine exerted its effects through depletion of monoamines from presynaptic nerve terminals.

DOPAMINE THEORY OF PSYCHOSISreinforced by the high risk for drug-induced psychosis among substances that directly increased synaptic dopamine availability, including cocaine, amphetamines, and the Parkinson's disease treatment L-dopa

TYPICAL OR FIRST-GENERATION ANTIPSYCHOTICSBasis : The dopamine (DA) overactivity hypothesis These medications differed in potency, but shared the common mechanism of significant DA D2 blockade and associated risk for extrapyramidal side effects. Neuroleptic" - "take hold of the nerves" in Greek (past term)

LIMITATIONS OF THE D.A. HYPOTHESISDoes not account for the cognitive deficits associated with schizophrenia that appear to be related to decreased DA signaling in the prefrontal cortex.Does not explain the psychotomimetic effects of agonists of other pathways (e.g., d-lysergic acid, a potent serotonin 5-HT2 receptor agonist), or the effects of phencyclidine and ketamine, antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor. Alternatives (non-dopaminergic) explored : e.g. clozapine.

NONDOPAMINERGIC ANTIPSYHOTICSPotently antagonize the 5-HT2 receptor, while blocking D2 receptors less potently than older typical antipsychotic agentsResults in the atypical clinical profile of antipsychotic efficacy with limited extrapyramidal side effects.

In the horizon . . .Medications that target glutamate and 5-HT7 receptor subtypesreceptors for -aminobutyric acid (GABA)Receptors for acetylcholine (both muscarinic and nicotinic)peptide hormone receptors (e.g., oxytocin) (Carpenter and Koenig, 2008).

RELEVANT PATHOPHYSIOLOGYThe effectiveness of dopamine D2 antagonists for the positive symptoms of psychosis seen in most psychotic disorders suggests a common etiology for these symptoms related to excessive dopaminergic neurotransmission in mesolimbic dopamine pathways.

RELEVANT PATHOPHYSIOLOGYThe psychoses related to delirium and dementia, particularly dementia of the Alzheimer type, may share a common etiology: the deficiency in cholinergic neurotransmission, either due to anticholinergic properties of medications.

Among hospitalized elderly patients, increased plasma concentrations of anticholinergic medications are directly associated with increased delirium risk (Flacker and Lipsitz, 1999); however, unlike in Alzheimer's dementia, where psychotic symptoms are directly related to cholinergic neuronal loss and may respond to acetylcholinesterase therapy, delirium may have numerous precipitants besides medication-associated anticholinergic properties, all of which require specific treatment (e.g., infection, electrolyte imbalance, metabolic derangement) in addition to removal of offending anticholinergic medications.

Dopaminergic nerve terminal

Sites of action of antipsychotic agents and Li+.

In varicosities ("terminals") along terminal arborizations of dopaminergic neurons projecting from midbrain to forebrain, DA is synthesized and stored in vesicles. Following exocytotic release, DA interacts with postsynaptic receptors (R) of D1 and D2 types, and presynaptic D2 and D3 autoreceptors.

Termination of DA action occurs primarily by active transport of DA into presynaptic terminals via the DA transporter DAT, with secondary deamination by mitochondrial monoamine oxidase (MAO). Stimulation of postsynaptic D1 receptors activates the Gs-adenylyl cyclase-cAMP pathway. D2 receptors couple through Gi to inhibit adenylyl cyclase and through Gq to activate the PLC-IP3-Ca2+ pathway. Activation of the Gi pathway can also activate K+ channels, leading to hyperpolarization

Lithium inhibits the phosphatase that liberates inositol (I) from inositol phosphate (IP). Li+ can also inhibit depolarization-evoked release of DA and NE, but not 5-HT.

D2-like autoreceptors suppress synthesis of DA by diminishing phosphorylation of rate-limiting TH, and by limiting DA release. In contrast, presynaptic A2 adenosine receptors (A2R) activate AC and, through cyclic AMP production, TH activity.

All antipsychotic agents act at D2 receptors and autoreceptors; some also block D1 receptors . Stimulant agents inhibit DA re-uptake by DAT, thereby prolonging the dwell time of synaptic DA.

Initially in antipsychotic treatment, DA neurons release more DA, but following repeated treatment, they enter a state of physiological depolarization inactivation, with diminished production and release of DA, in addition to continued receptor blockade. , inhibition or blockade; +, elevation of activity; , reduction of activity.

SCHIZOPHRENIAa neurodevelopmental disorder with complex genetics and incompletely understood pathophysiology. Certain environmental exposures confer an increased risk of developing schizophreniafetal second-trimester viral and nutritional insults,birth complicationssubstance abuse in the late teen or early adult years

SCHIZOPHRENIAKIND OF PSYCHOSIS CHAR. MAINLY BY A CLEAR SENSORIUM BUT A MARKED THINKING DISTURBANCEPATHOGENESIS UNKNOWNGENETIC PREDISPOSITION PROPOSED (NEUROGULIN 1 GENE,ETC)MOLECULAR BASIS - ???AMINE NEUROTRANSMITTER FUNCTION - ???

GOALS OF THERAPY

For many psychotic disorders the state of psychosis is transient, and antipsychotic drugs are only administered during and shortly after periods of symptom exacerbation. Patients with delirium, dementia, mania or major depressive disorder with psychotic features, substance-induced psychoses, and brief psychotic disorder - short-term antipsychotic treatmentMost substance-induced psychoses - removal of the offending agent results in prompt improvement of psychotic symptoms with no further need for antipsychotic therapy. (May not apply to advanced Parkinson's disease patients)

Patients with psychosis related to mood disorders (manic patients ) extended antipsychotic treatment Chronic psychotic symptoms in dementia patients may also be amenable to drug therapy.

Delusional disorder, schizophrenia, and schizoaffective disorder are chronic diseases that require long-term antipsychotic treatment.Individuals with monosymptomatic delusions (e.g., paranoia, marital infidelity) do not have neurocognitive dysfunction and may continue to perform work and social functions unaffected by their illness, aside from behavioral consequences related to the specific delusional belief.

Goal of treatment for schizophrenia and schizoaffective disorderto maximize functional recovery by decreasing the severity of positive symptoms and their behavioral influence, improving negative symptoms, decreasing social withdrawal, and remediating cognitive dysfunction.

15% employed ;11% married Relatively limited effect of treatment on core negative and cognitive symptoms of the illness Continuous antipsychotic treatment reduces 1-year relapse rates from 80% among unmedicated patients, to ~15%.Poor adherence to antipsychotic treatment increases relapse risk, and is often related to adverse drug events, cognitive dysfunction, substance use, and limited illness insight.

the immediate goal of antipsychotic treatmentdecrease in acute symptoms that induce patient distressbehavioral symptoms (e.g., hostility, agitation) that may present a danger to the patient or others

Lack of response to adequate antipsychotic drug doses for adequate periods of time may indicate treatment-refractory illness. Refractory schizophrenia is defined using the Kane criteria: failed 6-week trials of two separate agents and a third trial of a high-dose typical antipsychotic agent (e.g., haloperidol or fluphenazine 20 mg/day). In this patient population, response rates to typical antipsychotic agents, defined as 20% symptom reduction using standard rating scales (e.g., Positive and Negative Syndrome Scale [PANSS]), are 0%, and for any atypical antipsychotic except clozapine, are < 10% (Leucht et al., 2009).

Electroconvulsive therapy is considered a treatment of last resort in refractory schizophrenia and is rarely employed.

Despite widespread clinical use of combining several antipsychotic agents, there is virtually no data supporting this practice, and metabolic risk increases with use of multiple antipsychotic agents (Correll et al., 2007). In one of few instances where a sound pharmacological rationale exists for combination treatment, the addition of a potent D2 antagonist (e.g., risperidone, haloperidol) to maximally tolerated doses of clozapine (a weak D2 blocker), the results have been decidedly mixed. That multiple antipsychotic agents ("polypharmacy") are commonly used in clinical practice attests to the limitations of current treatment.

Antipsychotic drug therapy is the foundation of schizophrenia treatment, yet adequate management of schizophrenia patients requires a multimodal approach that also includes psychosocial, cognitive, and vocational rehabilitation to promote functional recovery.

CHEMICAL TYPESPHENOTHIAZINE DERIVATIVES ALIPATHIC (CHLORPROMAZINE)PIPERIDINE (THIORIDAZINE)THIOXANTHENE DERIVATIVESTHIOTHIXENEBUTYROPHENONE DERIVATIVESHALOPERIDOLMORE POTENT WITH FEWER AUTONOMIC EFFECTSMISCELLANEOUS (NEWER DRUGS)

NEWER DRUGSPIMOZIDEMOLINDONELOXAPINECLOZAPINEOLANZAPINEQUETIAPINERISPERIDONEZIPRASIDONEARIPIPRAZOLE

PHARMACOLOGY

Phenothiazines have a tricyclic structure in which two benzene rings are linked by a sulfur and a nitrogen atom.The chemically related thioxanthenes have a carbon in place of the nitrogen at position 10 with the R1 moiety linked through a double bond. Substitution of an electron-withdrawing group at position 2 increases the antipsychotic efficacy of phenothiazines (e.g., chlorpromazine). The nature of the substituent at position 10 also influences pharmacological activity.

The phenothiazines and thioxanthenes can be divided into 3 groups on the basis of substitution at site 10. Those with an aliphatic side chain include chlorpromazine and are relatively low in potency. Those with a piperidine ring in the side chain include thioridazine, which has lower EPS risk, possibly due to increased central antimuscarinic activity, but is rarely used due to concerns over QTc prolongation and risk of torsade de pointes.

Several potent phenothiazine antipsychotic compounds have a piperazine group in the side chain (fluphenazine, perphenazine, and trifluoperazine) and have reduced affinity for H1, M, and 1 receptors. Those with a free hydroxyl can also be esterified to long-chain fatty acids to produce LAI antipsychotic medications (e.g., fluphenazine decanoate).

Additional tricyclic antipsychotic agents are the benzepines, containing a 7-member central ring, which includeloxapine (a dibenzoxazepine) & clozapine (a dibenzodiazepine). Clozapine-like atypical antipsychotic agents may lack a substituent on the aromatic ring (e.g., quetiapine, a dibenzothiazepine), have an analogous methyl substituent (olanzapine), or have an electron-donating substituent at position 8 (e.g., clozapine).

Clozapine has antipsychotic activity with low EPS risk. Atypical antipsychotic agents with certain pharmacological similarities to clozapine have lower affinity for D2 receptors than typical antipsychotic drugs and high 5-HT2 antagonist effects. Olanzapine, quetiapine, and clozapineBenzisoxazoles risperidone, its active metabolite paliperidone, and iloperidoneZiprasidone (a benzisothiazolpiprazinylindolone derivative)Asenapine (a dibenzo-oxepino pyrrole)Aripiprazole (a quinolinone derivative)

PHARMACOKINETICS

ABSORPTION & DISTRIBUTIONREADILY BUT INCOMPLETELY ABSORBEDWITH SIGNIFICANT FIRST-PASS METABOLISMCHLORPROMAZINE & THIORIDAZINE (25 TO 35%)HALOPERIDOL (65%)MOST HIGHLY LIPID-SOLUBLE & PROTEIN-BOUND (92-99%)TEND TO HAVE LARGE VOLUMES OF DISTRIBUTION (>7 L/KG)WITH MUCH LONGER CLINICAL DURATION OF ACTION THAN ESTIMATED FROM PLASMA HALF-LIVES (PARALLELLED BY PROLONGED OCCUPANCY OF D2 RECEPTORS IN BRAIN)RELAPSE AFTER DISCONTINUATION 6 WEEKS OR MORE

METABOLISMALMOST COMPLETELY METABOLIZEDMETABOLITES NOT CONSIDERED TO BE HIGHLY IMPORTANT TO THE ACTION OF THESE DRUGSEXCEPTION : MEZORIDAZINE, MAJOR METABOLITE OF THIORIDAZINE, IS MORE POTENT

MESOLIMBIC-MESOCORTICAL PATHWAYFORM CELL BODIES NEAR THE SUBSTANTIA NIGRA TO THE LIMBIC SYSTEM & NEOCORTEXMOST CLOSELY RELATED TO BEHAVIOR

EXCRETIONVERY LITTLE EXCRETED UNCHANGEDALMOST COMPLETELY METABOLIZED TO MORE POLAR SUBSTANCES

PHARMACOLOGIC EFFECTS

DOPAMINERGIC SYSTEMS OR PATHWAYSMESOLIMBIC-MESOCORTICAL PATHWAYNIGROSTRIATAL PATHWAYTUBEROINFUNDIBULAR SYSTEMMEDULLARY-PERIVENTRICULAR PATHWAYINCERTOHYPOTHALAMIC PATHWAY

NIGROSTRIATAL PATHWAYSUBSTANTIA NIGRA TO CAUDATE & PUTAMENCOORDINATION OF INVOLUNTARY MOVEMENT

TUBEROINFUNDIBULAR SYSTEMCONNECTS ARCUATE NUCLEI & PERIVENTRICULAR NEURONS TO THE HYPOTHALAMUS & POSTERIOR PITUITARYDOPAMINE FROM THESE NEURONS INHIBIT PROLACTIN SECRETION

MEDULLARY-PERIVENTRICULAR PATHWAYSNEURONS IN THE MOTOR PROJECTIONS OF THE VAGUS WHOSE PROJECTIONS ARE NOT WELL-DEFINEDMAYBE INVOLVED IN EATING BEHAVIOR

INCERTOHYPOTHALAMIC PATHWAYMEDIAL ZONA INCERTA TO HYPOTHALAMUS & AMYGDALAAPPEARS TO REGULATE ANTICIPATORY MOTIVATIONAL PHASE OF COPULATORY BEHAVIOR IN RATS

ANTIPSYCHOTIC ACTION IS PRODUCED BY ABILITY TO BLOCK DOPAMINE IN THE MESOLIMBIC & MESOFRONTAL SYSTEMS.PHARMACODYNAMIC ACTION MAY HAVE DISTINCT PSYCHIATRIC, NEUROLOGIC, & ENDOCRINOLOGIC CONSEQUENCES.

DOPAMINE RECEPTORSD1-like receptor groups D1 (chromosome 5) increases cAMP by activation of adenyl cyclase (Putamen, nucleus accumbens, olfactory tubercle)D5 (chromosome 4) also increases cAMP (hippocamous & hypothalamus)

DOPAMINE RECEPTORSD2-LIKE RECEPTOR GROUPSD2 (chromosome 11) decreases cAMP & inhibits Ca++ channels but opens K+ channels (caudate-putamen, nucleus accumbens, olfactory tubercle)D3 (chromosome 11) thought to decrease cAMP (frontal cortex, medulla, midbrain)D4 also decreases cAMP

D2 receptor agonists (amphetamines, levodopa, apomorphine) increase motor activity & stereotyped behavior in rates & aggravate schizophrenia.The antipsychotic agents block D2 receptors. Their binding affinity is clinically correlated with clinical antipsychotic & extrapyramidal potency.

PHENOTHIAZINESChlorpromazineMesoridazine ThioridazineFluphenazinePerphenazineTrifluoperazine

THERAPEUTIC USES

Anxiety Disorders

There are two anxiety disorders in which double-blind, placebo-controlled trials have shown benefit of adjunctive treatment with antipsychotic drugs: obsessive compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). While SSRI antidepressants remain the only psychotropic medication with FDA approval for PTSD treatment, adjunctive low-dose quetiapine, olanzapine, and particularly risperidone significantly reduce the overall level of symptoms in SSRI-resistant PTSD (Bartzokis et al., 2005). OCD patients with limited response to the standard 12-week regimen of high dose SSRI also benefit from adjunctive risperidone (mean dose 2.2 mg), even in the presence of comorbid tic disorders (McDougle et al., 2000). For generalized anxiety disorder, double-blind placebo controlled clinical trials demonstrate efficacy for quetiapine as monotherapy, and for adjunctive low-dose risperidone

Anxiety Disorders

Obsessive compulsive disorder (OCD) Post-traumatic stress disorder (PTSD)Double-blind, placebo-controlled trials have shown benefit of adjunctive treatment with antipsychotic drugs.While SSRI antidepressants remain the only psychotropic medication with FDA approval for PTSD treatment, adjunctive low-dose quetiapine, olanzapine, and particularly risperidone significantly reduce the overall level of symptoms in SSRI-resistant PTSD (Bartzokis et al., 2005).

Anxiety Disorders

For generalized anxiety disorder, double-blind placebo controlled clinical trials demonstrate efficacy for quetiapine as monotherapy, and for adjunctive low-dose risperidone.

Tourette's Disorder

Antipsychotic drugs suppress tics .Relates to reduced D2 neurotransmission in basal ganglia sites. In prior decades, the use of low-dose, high-potency typical antipsychotic agents (e.g., haloperidol, pimozide) was the treatment of choice, but these nonpsychotic patients were extremely sensitive to the impact of DA blockade on cognitive processing speed, and on reward centers.

Tourette's Disorder

Safety concerns regarding pimozide's QTc prolongation and increased risk for ventricular arrhythmias have large ended its clinical use.While lacking FDA approval for tic disorders, risperidone and aripiprazole have indications for child and adolescent schizophrenia and bipolar disorder (acute mania) treatment, and these agents (as well as ziprasidone) have published data supporting their use for tic suppression.

Huntington's DiseaseAnother neuropsychiatric conditionAssociated with basal ganglia pathologyDA blockade can suppress the severity of choreoathetotic movements, but is not strongly endorsed due to the risks associated of excessive DA antagonism that outweigh the marginal benefit. Inhibition of the vesicular monoamine transporter type 2 (VMAT2) with tetrabenazine has replaced DA receptor blockade in the management of chorea.

Autism

Neuropathology incompletely understoodIn some patients is associated with explosive behavioral outbursts, & aggressive or self-injurious behaviors that may be stereotypicalRisperidone has FDA approval for irritability associated with autism in child and adolescent patients ages 5-16, with common use for disruptive behavior problems in autism and other forms of mental retardation ( 0.25 mg for patients weighing < 20 kg, and 0.5 mg for others, with a target dose of 0.5 mg/day in those < 20 kg weight, and 1.0 mg/day for other patients, with a range 0.5-3.0 mg/day)

Anti-Emetic Use

Most antipsychotic drugs protect against the nausea- and emesis-inducing effects of DA agonists such as apomorphine that act at central DA receptors in the chemoreceptor trigger zone of the medulla. Antipsychotic drugs are effective antiemetics already at low doses. The commonly used antiemetic phenothiazines are weak DA antagonists (e.g., prochlorperazine) without antipsychotic activity, but can be associated with EPS or akathisia.

TREATMENT

DELIRIUM AND DEMENTIAgenerally treated with low medication doses, although doses may have to be repeated at frequent intervals initially to achieve adequate behavioral controlnot a single antipsychotic drug has received approval for dementia-related psychosis. they may increase mortality in this setting high-potency typical antipsychotic drugs (e.g., haloperidol) or atypical antipsychotic agents with limited antimuscarinic properties (e.g., risperidone) are often the drugs of choice

The best-tolerated doses in dementia patients One-fourth of adult schizophrenia doses (e.g., risperidone 0.5-1.5 mg/day)(EPS), orthostasis, and sedationBenefits seen in 60-120 minutes Optionsoral dissolving tablet (ODT) preparations for risperidone, aripiprazole, and olanzapine, or liquid concentrate forms of risperidone or aripiprazole, are options.

MANIA

MANIAA period of elevated, expansive or irritable mood with co-existing symptoms of increased energy and goal-directed activity, and decreased need for sleep Represents one pole of what had been termed manic-depressive illness, but is now referred to as bipolar disorder (American Psychiatric Association, 2000). May be induced by medications (e.g., DA agonists, antidepressants, stimulants) or substances of abuse, primarily cocaine and amphetamines, although periods of substance-induced mania should not be relied upon solely to make a diagnosis of bipolar disorder..

Agents for ManiaAntipsychotic Agents AnticonvulsantsBy functional blockade of voltage-gated Na+ channelsValproate exhibits non-specific binding to voltage-gated Na+ channelsCarbamazepine (and its congeners) & lamotrigine have specific high affinity for the open-channel configuration of the alpha subunit Lithium

MANIAAll atypical antipsychotic agents with the exception of clozapine and iloperidone have indications for acute mania, and doses are titrated rapidly to the maximum recommended dose over the first 24-72 hours of treatment (Acute mania patients high doses)Typical antipsychotic drugs also effective in acute mania but lead to EPS.

LithiumLightest of the alkali metals (group Ia)The salts of this monovalent cation share some characteristics with those of Na+ and K+. Li+ is readily assayed in biological fluids and can be detected in brain tissue by magnetic resonance spectroscopy (Soares et al., 2000). Traces of the ion occur normally in animal tissues, but it has no known physiological role. Lithium carbonate and lithium citrate currently are used therapeutically in the U.S.

LithiumTherapeutic concentrations of Li+ have almost no discernible psychotropic effects in individuals without psychiatric symptoms. Li+ develops a relatively small gradient across biological membranes (unlike Na+ & K+). Although it can replace Na+ in supporting a single action potential in a nerve cell, it is not a substrate for the Na+ pump and therefore cannot maintain membrane potentials. Therapeutic concentrations of Li+ (0.5-1.0 mEq/L)

LithiumLi+ is absorbed readily and almost completely from the GI tract. Complete absorption occurs in ~ 8 hours, with peak plasma concentrations occurring 2-4 hours after an oral dose (Sproule, 2002). Approximately 95% of a single dose of Li+ is eliminated in the urine.Periodic determination of serum concentrations is crucial.GI complaints are one compelling reason for multiple daily dosing or using delayed release Li+ preparations (polyuria risk).

Clinical response (decreased psychomotor agitation and irritability, increased sleep, and reduced or absent delusions and hallucinations) usually occurs within 7 days, but may be apparent as early as day 2.

MAJOR DEPRESSION

Patients with major depressive disorder with psychotic features require lower than average doses of antipsychotic drugs, given in combination with an antidepressant (Rothschild et al., 2004). Extended antipsychotic treatment is not usually required, but certain atypical antipsychotic agents provide adjunctive antidepressant benefit. It is worth noting that mood disorder patients may be more susceptible to EPS and other adverse drug events due to the fact that many of these individuals either have never taken antipsychotic drugs before ("drug-nave") or have had only limited lifetime exposure to antipsychotic drugs.

BIPOLAR DISORDER

Treatment with Li+ ideally is conducted in patients with normal cardiac and renal function. The need for diuretics, nonsteroidal anti-inflammatory agents, or other medications that pose potential kinetic problems often precludes lithium use in those with multiple medical problems.

Treatment of acute mania and the prevention of recurrences of bipolar illness in adults or adolescents are uses approved by the FDA. Li+ is the only mood stabilizer with data on suicide reduction in bipolar patients (Cipriani et al., 2005 Goodwin et al., 2003; Tondo et al., 2001)

PROPHYLAXISdetermined by the need for continued antipsychotic drug use and for use of a mood-stabilizing agentaripiprazole & olanzapine effective as monotherapy olanzapine use eschewed out of concern for metabolic effectsaripiprazole shows no benefit for prevention of depressive relapse

SCHIZOPHRENIA

The immediate goals of acute antipsychotic treatment reduction of agitated, disorganized, or hostile behavior, decreasing the impact of hallucinationsimprovement of organization of thought processes, and the reduction of social withdrawalDoses used are often higher than those required for maintenance treatment of stable patients. Despite considerable debate, newer atypical antipsychotic agents are not more effective in the treatment of positive symptoms than typical agents .

Newer, atypical antipsychotic agents do offer a better neurological side-effect profile than typical antipsychotic drugs.markedly reduced EPS risk (or nearly absent in the case of quetiapine and clozapine) Excessive D2 blockade, as is often the case with the use of high-potency typical agents (e.g., haloperidol), not only increases risk for motor neurological effects (e.g., muscular rigidity, bradykinesia, tremor, akathisia), but also slows mentation (bradyphrenia), and interferes with central reward pathways, resulting in patient complaints of anhedonia.

Rarely used are low-potency typical agents (e.g., chlorpromazine), which also have high affinities for H1, M, and 1 receptors that cause many undesirable effects (sedation, anticholinergic properties, orthostasis). QTc prolongation (e.g., thioridazine) Preferred - nonsedating antipsychotic agents, and low doses of benzodiazepines as necessary

Ziprasidone and aripiprazole are the most weight and metabolically neutral atypical agents, with asenapine and iloperidone also having favorable metabolic profiles. Ziprasidone and aripiprazole are available in IM form, thus permitting continuation of same drug treatment initiated parenterally in the ER.Schizophrenia patients have a 2-fold higher prevalence of metabolic syndrome and type 2 diabetes mellitus (DM) and 2-fold greater cardiovascular (CV) related mortality rates than the general population.

MECHANISM OF ACTION

REDUCTION IN DOPAMINERGIC NEUROTRANSMISSION :D2 antagonismPartial D2 agonism (e.g. aripiprazole)

The glutamate hypofunction hypothesis of schizophrenia has led to novel animal models that examine the influence of proposed antipsychotic agents, including those in clinical development with agonist properties at metabotropic glutamate receptors mGlu2 and mGlu3 and other subtypes.

Adverse Effects Not Predicted by Monoamine Receptor Affinities

METABOLICCARDIACOTHERSSEIZURESAGRANULOCYTOSIS (CLOZAPINE)QTc PROLONGATION (THIORIDAZINE)PIGMENTARY RETINOPATHY (THIORIDAZINE)PHOTOSENSITIVITY (PHENOTHIAZINES)CHOLESTATIC PICTURE (PHENOTHIAZINES)

METABOLIC EFFECTSAside from weight gain, the two predominant metabolic adverse seen with antipsychotic drugs are dyslipidemia, primarily elevated serum triglycerides, and impairments in glycemic control (prediabetic conditions & type 2 DM)

CARDIAC EFFECTSVentricular arrhythmias and sudden cardiac death (SCD) are a concern with the use of antipsychotic agents.A black box warning exists for thioridazine, mesoridazine, pimozide, IM droperidol, and IV (but not oral or IM) haloperidol due to reported cases of torsade de pointes and subsequent fatal ventricular arrhythmias.

Increased risk for cerebrovascular events and all-cause mortality among elderly dementia patients exposed to antipsychotic medicationsCV adverse event rates in 10-week dementia trials range from 0.4-0.6% for placebo to 1.3-1.5% for risperidone, olanzapine and aripiprazole (Jeste et al., 2008)Mortality warning indicates a 1.6-1.7 fold increased mortality risk for drug versus placebo (heart failure, sudden death, or pneumonia)Unknown underlying cause

PEDIATRIC USEBoth risperidone and aripiprazole have indications for child and adolescent bipolar disorder (acute mania) for ages 10-17, and for adolescent schizophrenia (ages 13-17). Risperidone and aripiprazole are FDA-approved for irritability associated with autism in child and adolescent patients ages 5-16.

USE IN THE ELDERLY POPULATIONThe increased sensitivity to EPS, orthostasis, sedation, & anticholinergic effects are important issues for the geriatric population, & often dictate the choice of antipsychotic medication. Avoidance of drug-drug interactions is also important.

USE DURING PREGNANCY & LACTATIONCLASS B OR C WARNINGSHuman data from anecdotal case reports and manufacturer registries indicate limited or no patterns of toxicity and no consistent increased rates of malformations.BALANCE BETWEEN FETAL IMPACT (ESP. FIRST TRIM.) & MENTAL STATE OF THE MOTHER

The more you learn, the more you know.

, the more you know, the more you forget. The more you forget, the less you know. So why bother to learn.

The more you know, the more you forget. The more you forget, the less you know. So why bother to learn?FOOD FOR THOUGHT . . . .

*E*