Schizophrenia and Related Disorders and Antipsychotics PDF

Schizophrenia and Related Disorders and Antipsychotics Puru Thapa, M.B.B.S., M.P.H. Associate Professor of Psychiatry University of Arkansas for Medical Sciences Section Chief and Staff Psychiatrist Arkansas State Hospital Little Rock, Arkansas [email protected] Overview • Describe Ch...

Schizophrenia and Related Disorders and Antipsychotics Puru Thapa, M.B.B.S., M.P.H. Associate Professor of Psychiatry University of Arkansas for Medical Sciences Section Chief and Staff Psychiatrist Arkansas State Hospital Little Rock, Arkansas [email protected] Overview • Describe Characteristics of Psychosis • Review DSM-5 Psychotic Disorders • Describe Schizophrenia – Epidemiology, etiology, clinical features, prognosis, and treatment • Review pharmacology of common antipsychotics What is Psychosis? Psychosis • Can be considered to be a set of symptoms in which a person’s mental capacity, affective response, and capacity to recognize reality, communicate, and relate to others is impaired • Not a disorder by itself • Characterized by delusions, hallucinations, and disorganized speech, disorganized behavior and gross distortions of reality testing Delusions • Delusion – fixed, false belief; not amenable to logic, and not consistent with cultural values/beliefs – Bizarre – Non-bizarre • Types – – – – – – – Erotomanic Grandiose Jealous Persecutory Somatic Mixed Unspecified • Delusions of Reference – Ideas of Reference – Referential Thinking Hallucinations • Hallucination – abnormal perceptual experience in the absence of a stimulus – Auditory, Visual, Olfactory, Tactile/haptic, Gustatory – Command type – of clinical concern – Hypnogogic, hypnopompic - normal Hallucinations Type Auditory Visual Olfactory Tactile/ Haptic Significance Functional and organic psychoses Organic until proved otherwise Consider temporal lobe epilepsy Alcohol withdrawal, uremia, peripheral neuropathy, hepatic encephalopathy http://bimaristanalmansuri.files.wordpress.com/201 2/09/picture1.png Disorganized Thought Process • Thought process – how we get from point A to point B in sequencing our thoughts – rationial, relevant, and goal directed • Disorganized TP – – – – – – Circumstantial, Tangential Loose Association, Word Salad, Verbigeration Flight of Ideas Non Sequiter Neologisms Thought Blocking, Derailment DSM-IV – Schizophrenia and Other Psychotic Disorders • • • • • • • Schizophrenia Schizophreniform Disorder Schizoaffective Disorder Delusional Disorder Brief Psychotic Disorder Shared Psychotic Disorder Psychotic Disorder Due to General Medical Condition • Substance Induced Psychotic Disorder • Psychotic Disorder NOS • Other Specified Schizophrenia Spectrum and …… • Unspecified Schizophrenia Spectrum and …… DSM-5 Schizophrenia Spectrum and Other Psychotic Disorders • Schizotypal (Personality) Disorder • Delusional Disorder • Brief Psychotic Disorder • Schizophrenia • Schizophreniform Disorder • Schizoaffective Disorder • Substance/Medication-Induced Psychotics Disorder • Psychotic Disorder Due to Another Medical Condition • Catatonia Associated With Another Mental Disorder (Catatonia Specifier) • Catatonic Disorder Associated with Another Medical Condition • Unspecified Catatonia Other Conditions Associated with Psychosis Psychosis associated with (but NOT necessary for diagnosis): INDICATIOR OF SEVERITY • Mania • Depression • Cognitive disorders • Alzheimer’s dementia • Anxiety Disorders • Personality Disorders (e.g. Borderline PD) DSM-5 Criteria: Schizophrenia A. Characteristic symptoms: Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated). At least one of these must be (1), (2), or (3): 1. Delusions 2. Hallucinations 3. Disorganized speech 4. Grossly disorganized or catatonic behavior 5. Negative symptoms DSM-5 Criteria: Schizophrenia (contd) B. Social/occupational dysfunction C. Duration – continuous signs persist for at least six months D. Schizoaffective and Mood Disorder exclusion E. Substance/general medical condition exclusion F. Relationship to a Pervasive Developmental Disorder Schizophrenia Subtypes 1. 2. 3. 4. 5. Paranoid Type Disorganized Type Catatonic Type Undifferentiated type Residual Type Dropped in DSM-5 DSM-5 Criteria: Schizoaffective Disorder A. An uninterrupted period of illness during which,at some time, there is a major mood episode (major depressive or manic) concurrent with Criterion A of Schizophrenia. B. Delusions or hallucinations for two or more weeks in the absence of a major mood episode (depressive or manic) during the lifetime duration of the illness. C. Symptoms that meet criteria for a mood episode are present for the majority of the total duration of the active and residual portions of the illness D. The disturbance is not attributable to the effects of a substance (e.g., drug of abuse, a medication) or another medical condition. Schizoaffective Disorder • • • • • Characterized by features of both schizophrenia and mood disorders Unclear whether this is a type of schizophrenia, mood disorder or simultaneous expression of both or a distinct psychotic entity Life time prevalence <1.0% Better prognosis than schizophrenia, worse than mood disorders Two types: Bipolar, Depressive DSM-5 Criteria: Delusional Disorder  Presence of one (or more) delusion lasting one month or longer  Criterion A for schizophrenia never met  Apart from the impact of the delusion(s) or its remificaitons, functioning is not markedly impaired and behavior is not obviously bizarre or odd  If manic or major depressive episodes have occurred, these have been brief relative to the duration of the delusional period  Disturbance is not attributable to a medical condition or substance or better explained by another mental disorder Delusional Disorder  Onset later in life (after 40s)  Types:       Erotomanic Jealous Persecutory Grandiose Somatic Mixed Shared Psychotic Disorder Folie a Deux • Delusions develop in an individual in context of a close relationship with another individual who has an established delusion • Delusions are similar in content • Not better accounted for by a another psychotic disorder Dropped in DSM-5. Now under Delusional Disorder Other Psychoses  Brief Psychotic Disorder ◦ Presence of at least one of the following: delusions, hallucinations, disorganized speech, grossly disorganized behavior ◦ Duration of at least 1 day and no more than 1 month with return to premorbid level of functioning  Schizophreniform disorder ◦ Meets criteria for schizophrenia ◦ Duration of at least 1 month and no more than 6 months  Substance induced psychosis  Psychosis secondary to a General Medical Condition • • • • • Catatonia Associated With Another Mental Disorder (Catatonia Specifier) Catatonic Disorder Associated with Another Medical Condition Unspecified Catatonia Other Specified Schizophrenia Spectrum and …… Unspecified Schizophrenia Spectrum and …… Schizophrenia Schizophrenia – A little history…  Emil Kraeplin – “dementia praecox”  Eugene Bleuler – “schizophrenia” ◦ 4 A’s     Associations – loose Affect – flattening Autism – bizarre or magical thinking Ambivalence  Kurt Schneider – defines first rank symptoms; basically AH and delusions Epidemiology • Prevalence is approximately 1% world wide – ECA - 1.3% • Previous controversies: – low SES (downward drift) – urban residence (geographic drift) • M=F • Age of onset earlier in males • Season of birth – increase prevalence among those born in the spring and early winter Schizophrenia Etiology • Genetic Theories ◦ Familial transmission – risk of disease in firstdegree relatives is 10%  Twins – monozygotic concordance of 40-50%  Both Parents with schizophrenia – child’s risk is 40% • Gene variants found so far are responsible for small fraction of schizophrenia ◦ Polygenic transmission  Schizotypal personality disorder – more common in relatives of persons with schizophrenia (also schizoid PD, but less common)  Soft neurological signs also noted in families with schizophrenia (movement disorders, dyskinesias) Schizophrenia Etiology • Developmental Theories o Fetal Exposure to Risk Factors • Prenatal exposure to viruses – increase in schizophrenia in children born to women exposed to influenza A2 during 2nd trimester and in those exposed to flu during 1st trimester of pregnancy • Prenatal malnutrition – increase in schizophrenia in children born to Dutch mothers who were malnourished during WWII • Obstetric Complications – fetal hypoxia as in preeclampsia increases risk of schizophrenia Schizophrenia Etiology • Structural abnormalities possibly due to abnormal cell development or damage in multiple regions of the brain caused by excessive neuronal pruning ◦ Enlargement of lateral ventricles and widening of third ventricle ◦ Smaller than normal total brain volume, cortical atrophy, smaller hippocampus ◦ Abnormalities in cell architecture in prefrontal cortex Schizophrenia Etiology  Dopaminergic Pathway Abnormalities o There is an over expression of dopamine receptors , especially D2; traditional antipsychotics work by blocking D2 receptors o Increase in activity of mesolimbic system (leads to positive symptoms) o Decrease in activity of mesocortical system(leads to negative symptoms) Etiology - Summary • Genetic - prevalence of schizophrenia – – – – Where 1 parent has schizophrenia Dizygotic twin of schizophrenia patient Where both parents have schizophrenia Monozygotic twin of schizophrenia patient • Environmental – intrauterine trauma: physical, viral, drugs – birth trauma – ? later trauma • Biologic - Neurodevelopmental and/or Neurodegenerative 12.0% 12.0% 40.0% 47.0% Biological Basis of Schizophrenia – Major Dopamine Pathways 1. 2. 3. 4. Nigrostriatal Dopamine Pathway – controls movements Mesolimbic Dopamine Pathway – mediates many behaviors, pleasurable sensations, euphoria of drugs of abuse, hallucinations, delusions of psychosis Mesocortical Dopamine Pathway – mediates cognitive and negative symptoms of schizophrenia Tuberoinfundibular Dopamine Pathway – controls prolactin secretion Biological Basis of Schizophrenia – Dopamine Hypothesis • Positive symptoms believed to be mediated through excess dopamine in the mesolimbic dopamine pathway • Negative symptoms believed to be mediated through relative deficit of dopamine in the mesocortical dopamine pathway Stress-Diathesis Model (Two-Hit Model) • Diathesis – inherited vulnerability • Stress – any environment insult (stress, injury, infection, etc.) • Common model for disease causation Clinical Features • Positive Symptoms • • • • • Hallucinations Delusions Disorganized thoughts and behaviors Loose or illogical thoughts Agitation • Negative Symptoms • • • • Flat or blunted affect Concrete thoughts Anhedonia (inability to experience pleasure) Poor motivation, spontaneity, and initiative Onset and Course of Illness • Premorbid Adjustment • Age of onset – 18-20 males – 23-25 females • Chronic illness • Exacerbations and remissions • Long-term - stable or deteriorating? Schizophrenia – Course  Onset – late adolescence/early adulthood ◦ Separation from parents may unmask deficits ◦ Intense stresses activate processes responsible for schizophrenia ◦ Final maturation of brain ◦ Early onset – more disorganized and worse prognosis ◦ Late onset – more paranoid features and better prognosis Schizophrenia – Course • Precipitating Events – Psychosocial stressors – Traumatic events – Drug and alcohol use • Note: nicotine may alleviate negative symptoms of schizophrenia Schizophrenia – Clinical Course ◦ Initially –  Trema – anxious, irritable, and depressed that may last a few days to one month  Insidious prodromal phase – portends poor prognosis; seen as social withdrawal, impairment in role functions, peculiar behavior, neglect of grooming, inappropriate affect, change in speech, odd beliefs, lack of initiative, drive, ambition, interest or energy ◦ Acutely – cannot be dxed without an acute phase ◦ Stabilization – lasts 6 months or more, involving gradually decreaseing severity of sxs ◦ Stable phase – months to years; resolution of a lot of positive symptoms and negatives become more evident ◦ Deterioration from previous level of functioning – after acute break, residual symptoms usually interfere with previous level of functioning Suicide • 50% have attempted suicide • 10% completed suicide Good Prognostic Factors • • • • • • • Late age of onset Good pre-morbid functioning Acute onset - obvious precipitating factors Married Family history of mood disorders Positive symptoms Good support system Bad Prognostic Factors • • • • • • • Poor premorbid functioning Early age of onset Insidious onset - no precipitating factors Never married Family history of schizophrenia Negative symptoms Poor support system Treatment • Antipsychotic medication is the mainstay of treatment – Conventional antipsychotic medications – Novel antipsychotic medications • risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole • Family Psychoeducation helps • Assertive Community Treatment (PACT) works (cost-effective for high utilizers) VTA to nucleus accumbens; increased DA yields positive symptoms VTA to prefrontal cortex; decreased DA yields negative symptoms Substantia nigra to the basal ganglia; decreased DA yields EPS Hypothalamus to the anterior pituitary gland; decreased DA yields hyperprolactinemia Dopamine blockade by a D2 antagonist is hypothesized to mediate the ability of antipsychotic medications to diminish or block positive symptoms Dopamine blockade by a D2 antagonist causes emotional blunting and cognitive problems that mimic the negative symptoms of schizophrenia (neuroleptic-induced deficit syndrome Dopamine blockade by a D2 antagonist produces drug induced parkinsonism and EPS. Chronic D2 receptor blockade can produce a hyperkinetic movement disorder called tardive dyskinesia Dopamine blockade by a D2 antagonist produces hyperprolactinemia, with associated galactorrhea, amenorrhea, bone demineralization, sexual dysfunction, and weight gain α1 H1 DA D2 Antipsychotic properties, EPS Dry mouth, sedation, constipation, blurred vision Weight gain, sedation M1 Orthostatic hypotension, dizziness, sedation Antipsychotic efficacy contributed to the ability to block dopamine 2 receptors (pure D2 blockers). Promazine Droperidol Thiothixene Triflurpromazine Acetophenazine Trifluoperazine Chlorpromazine Loxapine Chlorprothixene Fluphenazine Molindone Thioridazine Haloperidol Perphenazine Mesoridazine Prochlorperazine Pimozide High potency agents = increased EPS, decreased antimuscarinic & antihistaminergic properties Low potency agents = decreased EPS, increased antimuscarinic & antihistaminergic properties Oral, IM, IV, or deconoate injection (q 4 weeks) Often given in emergency situations, delirium Oral, IM, or deconoate injection (q 2 weeks) First antipsychotic discovered in the 1950s Low doses have more sedative effects than antipsychotic effects IM:PO equivalency 2:1 Tic disorder treatment Onset most often within the 1st wk of treatment, with higher incidence in young (<40) males. Characterized by acute muscular rigidity and cramping (neck, tongue, face, and back). Onset most often after several weeks of therapy, with higher incidence in the elderly. Characterized by bradykinesia, rigidity, cogwheeling, tremor, masked facies, stooped posture, festinating gait, drooling, and if severe, akinesia. Characterized by an intensely unpleasant sensation of restlessness and need to move, especially the legs. Patients appear restless, with anxiety, agitation, or both. Major symptoms include fever, rigidity, autonomic instability, and delirium, occurring over a period of several hours to days. Myonecrosis, myoglobinuria, cardiac arrhythmias and renal failure may result. CPK and WBC count is often elevated. Risk factors include dehydration, poor nutrition, medical illness, and high potency antipsychotic use. Treatment is supportive, with IVF, cardiac monitoring, UOP monitoring,and cooling blankets. Dantrolene and bromocriptine can be administered. Chronic D2 receptor antagonism in the nigrostriatal pathway cause D2 receptors to up-regulate, leading to this hyperkinetic movement disorder. At least 20% of patients treated with typical antipsychotics develop TD, often within 4 years of chronic use. Characterized by involuntary athetoid movements of the tongue, facial, and neck muscles, UE, LE, and truncal musculature. Buccolingual-masticatory movements are usually seen early. F>M, with greater risk in patients >50yo. TD is generally mild and fluctuates over time, with rate of TD 5x less with atypical antipsychotics Treatment: no reliable treatment, try to avoid long-term typical antipsychotic use when possible. Vitamin E prophylaxis? 5HT 2A SDA D2 Serotonin inhibits dopamine release from dopaminergic axon terminals in various DA pathways, but the degree of this control differs between each DA pathway Atypical antipsychotics cause fewer EPS than typical antipsychotics Atypical antipsychotics improve positive symptoms as well as typical antipsychotics and may improve negative symptoms better than typical antipsychotics Serotonin 2A antagonism fails to reverse D2 antagonism in the mesolimbic system, with resultant D2 blockade-induced improvement of positive symptoms 5HT 2A blockade reverses D2 blockade by increasing DA activity in this pathway (5HT>D2 receptors in cerebral cortex). Negative symptoms improve 5HT 2A antagonism promotes DA release, reversing D2 blockade, leading to reduced or even absence of EPS or TD 5HT 2A blockade may reverse D2 blockade in this pathway, increasing DA induced prolactin inhibition. In practice, not all SDAs reduce prolactin secretion 5HT 1A 5HT 1D 5HT 2C H1 D1 α1 SDA α2 5HT 3 5HT 6 5HT 7 5HT 2A D2 M1 D3 D4 SRI NRI Clozapine (Clozaril) Risperidone (Risperdal) Paliperidone (Invega) Olanzapine (Zyprexa) Quetiapine (Seroquel) Ziprasidone (Geodon) Aripiprazole (Abilify) Iloperidone (Fanapt) 5HT 1A 5HT 2C 5HT 3 5HT 6 5HT 7 H1 5HT 2A α1 CLO α2 D2 M1 D1 D3 D4 Used in treatment resistant schizophrenia Few if any EPS with minimal to none TD or prolactin elevation Agranulocytosis in 0.5% to 2% of patients; WBC/ANC weekly for first 6mo, then q2 weeks for the duration of treatment Increased risk of seizures, especially at high doses, myocarditis risk Very sedating, great degree of weight gain Reduced risk of suicidal behavior 5HT 2A 5HT 7 RIS α1 α2 D2 Atypical at lower doses, with more typical characteristics at higher doses (EPS) Elevates prolactin to the same degree as typical antipsychotics despite dosage Long acting depot formulation (Consta) FDA approved for the treatment of schizophrenia, acute mania/mixed episodes, and irritability associated with autism (5-16yo) Paliperidone (Invega): Controlled osmotic release of the drug to produce consistent plasma levels over 24 hours 5HT 2C 5HT 3 5HT 6 H1 5HT 2A OLZ D2 α1 M1 D1 D3 D4 Associated with significant weight gain and increased risk for diabetes and dyslipidemia IM olanzapine can be given for breakthrough agitation Low incidence of TD and prolactin elevation FDA approved for treatment of schizophrenia, acute mania/mixed episodes, and as maintenance therapy for BPD (mono or adjunct) Symbyax (olanzapine/fluoxetine) FDA approved for bipolar depression 5HT 6 5HT 7 H1 5HT 2A QUET α1 α2 D2 Very atypical, causing virtually no EPS at any dose and no prolactin elevations (preferred antipsychotic for Parkinson’s disease patients) Some weight gain and possible metabolic side effects Possible cause of cataracts in animal models, but this has not been documented in humans FDA approved treatment for schizophrenia, acute mania/mixed episodes, and episodes of bipolar depression 5HT 1A 5HT 2A 5HT 1D 5HT 2C 5HT 7 ZIP D2 α1 D3 SRI NRI Little or no propensity to cause weight gain Proserotonergic and pronoradrenergic properties may predict antidepressant and anxiolytic properties IM formulation FDA approved for acute agitation in schizophrenia, FDA approved for the tx of schizophrenia and acute mania/mixed episodes Activating at low doses, sedating at high doses; dose with meals Monitor for QTc prolongation 5HT 2A 5HT 1A Partial agonism ARP D2 α1 D3 Partial agonism Partial agonism at presynaptic D2 autoreceptors; theoretically reducing DA output when DA concentrations are high (+ sxs) and reducing DA output when DA concentrations are low (negative symptoms) Minimal to no weight gain, diabetes, sedation, and dyslipidemia D2 partial agonism may cause motor side effects, such as akathisia FDA approved for schizophrenia, acute mania/mixed episodes, and adjunctive treatment of MDD Schizophrenic patients usually respond to treatment with any single antipsychotic drug (typical or atypical) by improving positive symptoms at least 30%-40% by 2 months of treatment If by 2 months, this improvement is not seen, switching agents via cross titration is prudent (cross titration reduces SE and rebound symptoms) The APA recommends atypical antipsychotic monotherapy, with two antipsychotics used only after several failed monotherapeutic attempts (including CLZ and typical antipsychotics) Typical antipsychotics are useful to “lead in” to atypical neuroleptic monotherapy, to be phased out when acute symptoms are controlled Typical antipsychotics are useful during acute episodes of agitation Encompasses a variety of methods to increase social abilities, self-sufficiency, practical skills, and interpersonal communication Social skills training: focuses on social performance & perception within the family, and extra-familial relationships Family oriented therapy: Treatment involving families to address potential problems, educate family members, reduce stress, improve coping skills, and reintegrate the patient into everyday life Case management: Ensures treatment coordination and compliance Assertive Community Treatment (ACT): Staff:PT 1:12, patient assigned to a multidisciplinary team providing services 24/7 Group therapy, CBT, Individual therapy, and vocational therapy Mesolimbic pathway Tuberoinfundibular pathway Nigrostriatal pathway Mesocortical pathway Negative symptoms Positive symptoms EPS, TD Prolactin elevation excess Positive symptoms are caused by ______ mesolimbic pathway; while dopamine in the ________ negative symptoms are caused by decreased dopamine in the _________ mesocortical _______ pathway. The antipsychotic effects of typical neuroleptics are attributed to: 1. Muscarinic blockade 2. D2 blockade 3. D2 agonism 4. H1 blockade Low potency typical antipsychotics cause less sedation, more EPS, and less antimuscarinic side effects than high potency antipsychotics. High potency agents = increased EPS, decreased antimuscarinic & antihistaminergic properties Low potency agents = decreased EPS, increased antimuscarinic & antihistaminergic properties 5HT 6 H1 5HT 2A 5HT 7 QUET 5HT 1A D2 5HT 2C ZIP D2 5HT 3 α1 α2 5HT 2A 5HT 1D 5HT 7 5HT 2C α1 D3 SRI NRI 5HT 2A H1 5HT 6 α1 OLZ D2 D3 D4 M1 5HT 2A 5HT 7 D2 RIS D1 α1 α2 Which of the following agents most likely induced the condition illustrated left: QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. 1. Quetiapine 2. Chlorpromazine 3. Olanzapine 4. Benztropine 5. Fluphenazine EPS such as acute dystonia, neurolepticinduced parkinsonism and akathisia are dopamine and an caused by a deficit in ________ acetylcholine in the nigrostriatal excess in ________ pathway. 32 year old man with DM II poorly controlled and schizophrenia treated with haloperidol presents with acute MS change. Vital signs reveal Tc 41C, BP 160/100 and HR 115. Physical exam reveals lead pipe rigidity. FSBS 140. Which of the following laboratory indices would be most likely abnormal? 1. WBC 2. LFT 3. CPK 4. PLT 5. K Which of the following is a characteristic of atypical antipsychotic medications? 1. Less EPS than typical antipsychotics 2. 5HT 2A and D2 blockade 3. Improved negative symptoms over placebo and atypical antipsychotics 4. Positive symptom improvement equivalent to typical antipsychotics 5. All of the above 5HT 2A antagonism by atypical antipsychotic medications increases DA release to the extent needed to reverse D2 blockade in all dopaminergic pathways in the brain? 5HT 2A antagonism wins in all dopaminergic pathways except the mesolimbic pathway. This allows for medication induced improvement of positive symptoms in schizophrenia and other psychotic disorders. Clozapine Quetiapine No weight gain D2 partial agonism Ziprasidone Agranulocytosis Risperidone EPS at high doses Aripiprazole DOC for psychosis in the Parkinson’s disease pt Which of the following medications would be considered a first line antipsychotic agent for treatment of first episode schizophrenia? 1. Haloperidol 2. Fluphenazine 3. Chlorpromazine 4. Olanzapine 5. Pimozide Psychosocial therapies, such as social skills training, family oriented therapy, and ACT, have no clinical utility. Psychosocial therapies are integral treatments for patients with schizophrenia and have been shown to reduce relapse rates as measured by need for hospitalization.