Transcript Epigenetics
Louis Wain, 20th century animal illustrator ◦ Background, stats, etc ◦ Biological Theories genetics CNS NT ◦ Pharmacological Treatments ◦ Current Issues Incidence – 1% worldwide ◦ more than 2.2 million Americans. Total financial cost of schizophrenia in US is estimated at up to $65 billion a year. 1 in 3 patients who start an antipsychotic will either switch medications or discontinue their medication within a year. 56% of patients in a survey admitted to extended periods of time when they are off medication and 32% of those patients cited side effects of their medication as the primary reason. Gender and Age differences Copyright © Allyn & Bacon 2007 Gender and Age differences increased mortality rate increased risk of substance abuse seasonal effect seasonal effect genetics Epigenetics How lifestyles and environment can change the way our genes are expressed How are symptoms characterized? ◦ Positive Symptoms Psychosis compromise syndrome of variety of possible combinations ◦ can include bizarre thought disorders, hallucinations, delusions, often accompanied by disorganized speech and behavior Other conditions that have psychosis as key symptom ◦ ◦ ◦ ◦ ◦ substance-induced psychosis psychotic disorders affiliated with medical condition schizoaffective or schizophreniform disorders mania, major depression, cognitive disorders, AD to name a few….. Negative symptoms◦ absence of response; flattened affect, anhedonia, social withdrawal positive and negative symptoms aggressive/hostile symptoms depressive/anxious symptoms cognitive symptoms cognitive deficits ◦ impediment to reintegration to society ◦ http://www.matrics.ucla.edu/ Copyright © Allyn & Bacon 2007 PET scans ◦ rCBF – regional cerebral blood flow ◦ 2DG- 2 deoxyglucose ◦ other radio isotopes radiotagged DA brains are smaller CT scans of patients with schizophrenia lateral and 3rd ventricles reduced volumes of cortical gray matter limbic system; found reductions in amygdala, hippocampus, prefrontal cortex - functional deficits and anatomical deficits found thalamus - some studies show volume shrinkage or neuronal loss basal ganglia and cerebellum - ◦ progressive or static changes - data unclear 1950’s – introduction of phenothiazines ◦ chlorpromazine first- antihistamine one of the least expensive for treating psychosis importance of the discovery Blocking DA receptors Resulted in the DA theory for schizophrenia D2 receptor affinity clearly linked to reduction in positive symptoms l-dopa amphetamine and cocaine reserpine alpha-methyl-para-tyrosine – ◦ blocks synthesis of DA, NE apomorphine ◦ stimulates DA autoreceptor classified based on chemical structure phenothiazines and butyrophenones Generic acetophenazine amisulpiride chlorpromazine chlorproxthixene flupentixol fluphenazine fluspirilene haloperiodol loxapine mesoridazine molindone perphenazine pimozide piperacetazine prochlorperazine thioridazine thiothixene trifluroperazine trifluoropromazine Trade name Tindal Solian Thorazine, Largactil Taractan Fluanxol Prolixin, Permitil Imap, Redeptin Haldol Loxitane Serentil Moban, Lidone Trilafon Orap Quide Compazine Mellaril Navane Stelazine Vesprin most antipsychotics – oral parenteral long-acting depot forms ◦ haloperidol decanoate (1/2 life 21 days) ◦ fluphenazine (14 days) at least 11 traditional antipsychotic drugs are available for injection Numerous other uses for chlorpromazine ◦ nausea and vomiting, hiccups, to relieve severe itching, manage psychotic component in acute mania, to treat alcohol hallucinosis refractory major depression anorexia Huntingtons disease Personality disorders differentiating drugs based on their potency ◦ specifically affinity for D2 receptors useful for positive symptoms – not for negative or cognitive deficits 100 mg of chlorpromazine ~ same results as 2 mg haloperidol ◦ haloperidol – high potency antipsychotic ◦ chlorpromazine – low potency antipsychotic low potency - more autonomic side effects (ie anti ACh, anti adrenergic) high potency - more motor side effects – called extrapyramidal syndrome (EPS) All antipsychotic drugs have common mechanism of action PET studies ◦ effective dose - drugs occupy 70 – 80% of available D2; ◦ much higher – significant adverse side effects; EPS - reports of 60 – 90% of patients receiving antipsychotic medication develop extrapyramidal symptoms up to 50% readmissions are due to these side effects Extrapyramidal Motor Side Effects Medication induced parkinsonism ~ 15-20% ◦ characteristics: rigidity, tremor, akinesia (lack of movement), and bradykinesia (slowness of movement); lead pipe rigidity, cogwheel rigidity, rabbit syndrome treatment – anticholinergic drugs dystonia – spastic contraction of discrete muscle groups ◦ occurs in 10% patients initiating therapy ◦ occurs most commonly in neck, eyes and torso ◦ reactions are sudden onset, dramatic in appearance, and cause great distress (laryngospasm) ◦ txt: anticholinergics or antihistaminergics hyperkinetic abnormal involuntary movement disorder caused by sustained exposure to antipsychotic medication most commonly affects oral facial region may arise after exposure to any med but clozapine occurs at a rate of ~ 4% per year akathisia◦ characterized by somatic restlessness ◦ 20 – 25% ◦ complain of an inner sensation of restlessness and an irresistible urge to move various parts of body (often seen as pacing and inability to sit still) ◦ frequent cause of noncompliance ◦ less responsive to treatment than parkinsonism or dystonia ◦ txt: anticholinergics, BZ also sometimes used hypotension dry mouth constipation urinary hesitancy or retention blurred near vision dry eyes narrow-angle glaucoma photophobia nasal congestion confusion and decreased memory sweating most anti ACh symptoms decrease in 1 – 4 weeks but don’t completely remit certain meds can reduce peripheral effects but not central traditional neuroleptics used less with the advent of the newer atypicals important difference is price second-generation (atypical) antipsychotic drugs, with $7·5 billion sales in the USA in 2003 atypicals - amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, and zotepine) history – first atypical clozapine- 1990 ◦ effective in proportion of patients that were unresponsive to previous medication ◦ reduced negative symptoms ◦ reduced tardive dyskinesias ◦ maybe reduces cognitive deficits much lower occupancy of D2 receptors (3040%); multiple actions on monoamine receptors in brain ◦ antagonist at both DA2 and 5HT 2A receptors. CLOZARIL interferes with the binding of DA D1, D2, D3 and D5 receptors, with a high affinity for D4 receptor It does not induce catalepsy nor inhibit apomorphine-induced stereotypy. This evidence, consistent with the view that CLOZARIL is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of CLOZARIL from EPS. CLOZARIL also acts as an antagonist at adrenergic, ACh, histaminergic and 5HT receptors. ◦ risky side effects – agranulocytosis ~ 1% leukopenia - clozapine – Clozaril – 1989 – generic 1998 risperidone – Risperdal - 1994 olanzapine – Zyprexa – 1996** quetiapine – Seroquel - 1999 ziprasidone – Geodon aripiprazole (Abilify)- approved 11/2002** ◦ ~339 for 30 pills ** - currently class action lawsuits - less D2 receptor blockade than traditional AND also antagonize other DA receptors and 5HT2 receptors. most (with the exception of clozapine) still can produce EPS and a variety of other side effects Background: ◦ blockade of more than 65% of D2 receptors key to antipsychotic efficacy ◦ occupation of 72% or more associated with elevations in PRL ◦ occupation of 78% or more associated with EPS and akathisia so – some balance – optimal therapeutic window? common characteristic of atypicals is the higher ratio of 5HT2 receptor blockade to D2 than conventional conventional antipsychotics and novel demonstrate comparable affinity for 5HT2 receptor but lower affinity for D2 atypicals have a faster rate of dissociation (unbinding) from D2 receptor rank ordering (clozapine, quetiapine dissociate faster followed by olanzapine, risperidone, haloperidol and chlorpromazine respectively) the faster the rate of drug dissociation, the lower the rate of the treatment-emergent side effects metabolic syndrome – ◦ atypical antipsychotics have been associated with a “metabolic syndrome” – insulin resistance, hypertension, high serum lipids, obesity and coagulation abnormalities, ◦ higher rates of diabetes ◦ *** olanzapine may produce this more than other atypicals Sedation- most common single side effect of antipsychotic medication ◦ often most pronounced early in treatment strategies: anticholinergic and antiadrenergic effects ◦ can occur in 10 – 50% of treated patients ◦ anticholinergic PNS effects occur via cranial nerves and autonomic ns increased seizure susceptability ◦ can be both 1st and 2nd generation although not all neuroleptics are the same and much of the data may be case reports Endocrine effects: ◦ all standard antipsychotics increase PRL secretion◦ galactorrhea – secretion of liquid from nipples (1 – 5% patients) ◦ oligomenorrhea – menstrual changes (up to 20% of women) atypicals – risperidone does; clozapine does not weight gain: up to 40% treated patients Individuals with schizophrenia are at increased risk for osteoporosis and fractures ◦ why: poor diet, lack of exercise, cigarette smoking, and polydipsia ◦ Some antipsychotic medications may further increase the risk of fractures by causing dizziness, orthostatic hypotension, and falls. •Studies in women with hyperprolactinemia (from pituitary tumors) have demonstrated high rates of osteoporosis believed to result from hypoestrogenism. • Similarly, hyperprolactinemia in men results in hypogonadism and bone loss. • Preliminary surveys suggest that schizophrenia patients also may have elevated rates of osteoporosis and pathological fractures hypotension orthostatic hypotension tachycardia neuroleptic malignant syndrome ◦ characterized by rigidity, hyperthermia and autonomic instability (hypertension and tachycardia) ◦ rare but potentially lethal reaction to neuroleptic ◦ onset can be sudden and unpredictable- usually within first 2 weeks of drug ◦ incidence 1 – 2 % ◦ usually occurs early in onset of treatment ◦ txt – discontinue antipsychotic med and provide txt for fever or cardiovascular symptoms – usually intensive care - txts used to accelerate reversal of condition – DA agonists ◦ Risk factors: young age, male, preexisting neurological disability, dehydration, raid escalation of dose, use of high potency meds or IM preps Sedation anti ACh orthostatic hypotension EPS chlorpromazine ++++ +++ ++++ ++ clozapine (*) ++++ ++++ ++++ +/0 fluphenazine + + + ++++ haloperidol + + + ++++ loxapine ++ ++ +++ +++ mesoridazine +++ ++++ +++ + olanzapine (*) +++ +++ +++ +/0 Sedation anti ACh orthostatic hypotension EPS perphenazine ++ ++ ++ +++ pimozide +++ +++ ++ ++++ quetiapine (*) ++ +++ ++ +/0 risperidone (*) + ++ + + thioridazine +++ ++++ ++++ + thiothixene + + + ++++ trifluoperazine + + + ++ ziprasidone (*) +++ + + ++ wide therapeutic index and OD is seldom fatal Smoking rate in the general population - just over 20 % Smoking rate among schizophrenics - may be as high as 90 % Nicotine increases alertness. ◦ may enhance concentration, thinking and learning- benefit due to illness or medication related cognitive problems. Nicotine can help relaxation and can reduce anxiety tension Nicotine might have an antidepressant effect. Nicotine may reduce positive symptoms, such as hallucinations for a short period. There is some evidence to suggest that smoking is associated with reduced levels of antipsychotic induced Parkinsonism. Alter negative symptoms (?) Smoking can help to relieve boredom and provide a framework for the day. Smoking can have an effect on pharmacokinetics ◦ CYP P450 1A2- induced by chronic smoking – also enzyme used for metabolizing certain antipsychotics, including clozapine, fluphenazine, haloperidol and olanzapine, thioridazine. ◦ This results in higher doses being needed. ◦ Smoking can also have an impact on the side effects of medication. keep up to date on current reviews…. 150 studies – mostly short term - from all parts of the world with a total of 21,533 participants. Looked at double-blind studies◦ excluded open studies ◦ compare nine second-generation (atypicals) with first-generation antipsychotics. ◦ examined symptom reduction; quality of life; side effects such as movement disorders, weight gain and sedation (sleepiness); and other factors. Although quality of life was not reported in most studies, the few that did report it indicated that only amisulpride, clozapine and sertindole improved patients’ quality of life more than first-generation medications. Amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole and zotepine … more weight gain than haloperidol Clozapine, quetiapine and zotepine were significantly more sedating than haloperidol, while aripiprazole was significantly less sedating than haloperidol. All nine atypical antipsychotics caused fewer movement disorders than the first- generation medication haloperidol, which is highly potent. However, when compared with low-potency, first-generation medications such as chlorpromazine and thioridazine, studies showed that only a few atypical medications (clozapine, olanzapine, and risperidone) caused fewer movement disorders, but the low-potency drugs also tended to induce weight gain and sedation like the atypicals. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) assessed the effects of antipsychotic medications on participants’ 10-year coronary heart disease (CHD) risk. examined atypicals - olanzapine (Zyprexa), quetiapine (Seroquel) risperidone (Risperdal) and ziprasidone (Geodon) and conventional antipsychotic perphenazine. standardized mortality ratios up to three times those for the general population (Felker et al., 1996; Brown, 1997). Why? ◦ Increased suicide rates, increased accidental death, increased smoking, ◦ cardiovascular disease? Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) ◦ designed to rigorously compare the efficacy and safety of a molindone (first generation), olanzapine and risperidone (2nd generation), in the treatment of early onset schizophrenia ◦ primary hypothesis: 2nd generation would show greater treatment response and greater tolerability ◦ double-blind multisite trial; randomly assigned pediatric patients with early-onset schizophrenia and schizoaffective disorder Sample: 119 youth randomly assigned to treatment. ◦ 116 received at least one dose of treatment Results: ◦ NSD among treatment groups in response rates (molindone: 50%; olanzapine: 34%; risperidone: 46%) or magnitude of symptom reduction. ◦ Olanzapine and risperidone – significantly greater weight gain. with Olanzapine showing the greatest risk of weight gain significant increases in fasting cholesterol, low density lipoprotein, insulin, and liver transaminase levels. ◦ Molindone led to more self-reports of akathisia. PORT – Patient Outcomes Research Team