Schizophrenia Lecture Notes PDF

School of Chemistry, Food and Nutritional Sciences & Pharmacy PSYCHOSIS AND SCHIZOPHRENIA Click icon to add picture. Visit www.reading.ac.uk/imagebank for more. Francesco Tamagnini [email protected]...

School of Chemistry, Food and Nutritional Sciences & Pharmacy PSYCHOSIS AND SCHIZOPHRENIA Click icon to add picture. Visit www.reading.ac.uk/imagebank for more. Francesco Tamagnini [email protected] 1 Copyright University of Reading LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT LEARNING OUTCOMES After this lecture and further reading, students can: Define the difference between psychosis and schizophrenia Define and describe symptoms exhibited in schizophrenia Briefly describe the historical background to schizophrenia Describe the neuropathology, aetiology and treatment of schizophrenia. Describe the advantages and disadvantages to different treatment types in schizophrenia. 2 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT REFERENCE LITERATURE Stahl online: Chapter 4 and 5 3 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  The Scream Edvard Munch ”I was walking down the road with two friends when the sun set; suddenly, the sky turned as red as blood. I stopped and leaned against the fence, feeling unspeakably tired. Tongues of fire and blood stretched over the bluish black fjord. My friends went on walking, while I lagged behind, shivering with fear. Then I heard the enormous, infinite scream of nature.” “For several years I was almost mad…You know my picture, ‘’The Scream?’’ I was Was he psychotic, stretched to the limit - nature schizophrenic, “crazy” or was screaming in my blood… simply an artist? After that I gave up hope ever of being able to LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES love again.” | LIMITLESS IMPACT Let’s try to clear our ideas Psychosis and Schizophrenia have different meanings Psychosis As a term: 1. Difficult and misused (both in media and by healthcare professionals) 2. Stigma and fear associated to psychosis: sometimes the pejorative term “crazy” is used for psychosis 5 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Psychosis Syndrome (a set of symptoms): It Includes: Delusions Hallucinations Disorganized speech Disorganized behaviour Gross distortion of reality 6 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Psychosis It is the defining set of symptoms of: 7 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Psychosis It may or may not be associated to: 8 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT SCHIZOPHRENIA: HISTORICAL Until the early 20th century was simply considered to be ‘madness’ Bleuler (1911) gave a defined name to schizophrenia Psychosis is the principal symptom It is not ‘split personality’ which is a very rare, very specific disorder properly known as ‘multiple personality disorder’. LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT SCHIZOPHRENIA: AETIOLOGY AND PATHOLOGY Onset – adolescence/early adulthood Lifetime risk is ~1% Presentation of symptoms and outcome – highly varied No single, definable cause Problems of definition Subgroups within the syndrome? Compare with epilepsy (see previous lecture) Higher incidence in lower socioeconomic groups Attributed to downward drift of sufferers due to impaired function LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT GENETICS Genetics Schizophrenia tends to run in families, but no single gene is thought to be responsible. It's more likely that different combinations of genes make people more vulnerable to the condition. However, having these genes does not necessarily mean you'll develop schizophrenia. Evidence that the disorder is partly inherited comes from studies of twins. Identical twins share the same genes. In identical twins, if a twin develops schizophrenia, the other twin has a 1 in 2 chance of developing it, too. This is true even if they're raised separately. In non-identical twins, who have different genetic make-ups, 11 when a twin develops schizophrenia, LIMITLESS POTENTIAL | LIMITLESS the other only OPPORTUNITIES has a 1 | LIMITLESS in IMPACT SCHIZOPHRENIA: NEUROPATHOLOGY 1978 – modern imaging techniques (PET, fMRI, EEG, ECoG) Enlarged ventricles Post mortem – reduced temporal lobe volume Cerebral blood flow – reduced frontal function Not progressive LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT SCHIZOPHRENIA: SYMPTOMS IN BRIEF 13 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT SCHIZOPHRENIA: AETIOLOGY Inherited genetic factors Increased risk in families if one family member affected In twins: Dizygotic(fraternal) 17%; Monozygotic (identical) 48% Identification of susceptibility genes e.g. Neuregulin 1 Environmental factors Birth complications, viral infection, inner cities, immigration, drug misuse Neurodevelopmental model: Early environmental insult and/or genetic factors lead to changes in brain development with later environmental factors contributing to risk LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT AETIOLOGY: DOPAMINE HYPOTHESIS Production Degradation Transmission 15 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT FUNCTION OF D2 RECEPTORS 16 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT MESOLIMBIC DOPAMINERGIC HYPERACTIVITY AND SCHIZOPHRENIA POSITIVE SYMPTOMS 17 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT … WHILE MESOCORTICAL DOPAMINERGIC HYPOACTIVITY LEADS TO SCHIZOPHRENIA NEGATIVE SYMPTOMS 18 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT HAMLETIC (PHARMACOLOGICAL) DILEMMA DOPAMINE: INCREASE OR NOT INCREASE? THAT IS THE QUESTION AS THE MESOLIMBIC DOPAMINE PATHWAY OVERACTIVATION CAN LEAD TO SCHIZOPHRENIA POSITIVE SYMPTOMS EXACERBAT WHILE ANTAGONISING THE MESOCORTICAL DOPAMINE PATHWAY ALAS, CAN WORSEN NEGATIVE SYMPTOMS, STAHL SAY. 19 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT AETIOLOGY: GLUTAMATE HYPOTHESIS Novel hypothesis First novel psychopharmacological agents are based on this hypothesis For revising glutamatergic neurotransmission (synthesis, secretion, neurotransmission, scavenging and reuptake) see Stahl Chapter 4. 20 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT WHAT GLU PATHWAYS? A: Cortico-brainstem Glu projection B Cortico-striatal Glu pathway C Thalamo-cortical Glu pathway D Ventral Hippocampus to Nucleus Accumbens E Cortico-thalamic Glu pathway F Cortico-cortical Glu pathway G Intracortical with GABAergic coordination 21 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT EFFECTS OF KETAMINE AND PHENCYCLIDINE (PCP) ON THE NMDA RECEPTOR Blockade of NMDA-R may prevent Glu-mediated excitation NMDA-R hypofunction has been hypothesized as a mechanism for schizophrenia pathogenesis 22 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT INTRACORTICAL GLUTAMATERGIC NEUROTRANSMISSION IS COORDINATED BY GABAERGIC INTERNEURONS Picrotoxin 100 M 0.5 mV 100 s 23 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT IN TURN: NMDA-R HYPOFUNCTION LEADS TO SCHIZOPHRENIA POSITIVE SYMPTOMS NAc VTA 24 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT IN OTHER TERMS Cortex Subcortical Limbic structures + - + Legend Glutamatergic neurons GABAergic neurons NMDA receptor Dopaminergic neurons 25 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT IN OTHER TERMS Cortex Subcortical Mesolimbic structures + - + Legend Glutamatergic neurons GABAergic neurons NMDA receptor Dopaminergic neurons 26 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT AND NEGATIVE ONES 27 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT IN OTHER TERMS Cortex Subcortical Mesolimbic structures + - + - 28 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT AND NEGATIVE ONES 29 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT NMDA-R HYPOFUNCTION IN PSYCHOSIS MIGHT BE A CONSEQUENCE OF AN AUTOIMMUNE DISORDER 6.3% patients might suffer from a newly described for of psychosis, due to a an autoimmune response against NMDAR- R. https://www.youtube.com/watch?v=Najj0aVLJwU&feature=yout u.be 30 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT AETIOLOGY: SEROTONIN HYPOTHESIS Increased cortical serotoninergic tone, can lead to reduced dopamine secretion, downstream 31 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  SCHIZOPHRENIA SYMPTOMS Symptoms can be divided in positive and negative types: Positive: disinhibited behaviours/thoughts Negative: inhibited/withdrawn behaviours/thoughts. Some can be either positive or negative or have aspects of both. Diagnosis and classification of symptoms is solely psychiatric There are no objective biochemical, metabolic or clinical signs. Symptom types: Thought disorder (+/-) Abnormal beliefs/delusions (+) Abnormal experiences (+) Mood disorder (+/-) Motor alterations (+/-) Changes in social function (-) LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT NEGATIVE SYMPTOMS OF SCHIZOPHRENIA On observation On questioning 33 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT POSITIVE SYMPTOMS OF SCHIZOPHRENIA 34 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CHANGES OF SYMPTOMS WITH TIME Acute psychotic episode typically alerts HCPs and allows patient to enter healthcare system for treatment. Symptoms tend to be initially mild but negative before showing increased positive dominance that steadily trails off into largely negative symptoms in the chronic phase. Stress the fact that 5HT are more effective with negative symptoms 35 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  OUTCOMES ~25% of patients will suffer a single episode, recover and lead a normal life. Prognostic signs for isolated episodes include: No family history Stable premorbid personality Acute onset Emotional responses preserved Early diagnosis and treatment Prognostic signs for persistent (chronic) schizophrenia include: Family history Disturbed premorbid personality Difficulty forming relationships early in life Poor social adjustment/disrupted domestic life Insidious onset Loss of initiative and drive Delayed diagnosis and treatment 36 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT TREATMENTS FOR SCHIZOPHRENIA Control acute attacks (prevent harm to self and others) Resolve contributory social and domestic factors Rehabilitate the patient attacks of psychosis have consequential effects on mood, emotion etc. Begin long-term maintenance therapy if necessary. 37 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT SCHIZOPHRENIA: D2 ANTAGONISTS Psychotherapy does not help in early stages since patients lack insight. Antipsychotic (neuroleptic) drugs e.g. haloperidol, chlorpromazine (1st Generation) Generally only treat positive symptoms Onset slow ~ 30 % of patients do not respond Depot formulation for secondary care – concordance/compliance LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT TREATING SCHIZOPHRENIA: DOPAMINE HYPOTHESIS AND CONVENTIONAL ANTIPSYCHOTICS Reducing mesolimbic dopamine hyperactivity reduces positive symptoms But leads to exacerbated negative symptoms because it also reduces mesocortical dopaminergic tone LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT THERAPEUTIC AND SIDE EFFECTS 40 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT SIDE EFFECTS: EXTRAPYRAMIDAL SYMPTOMS 41 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT EXTRAPYRAMIDAL SYMPTOMS Most common category of side-effect associated with anti- psychotic use. Manifest as movement disorders 42 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT SIDE EFFECTS: PROLACTINAEMIA 43 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT NARROW THERAPEUTIC RANGE 44 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT OTHER ACTIONS OF CONVENTIONAL ANTIPSYCHOTICS E.G. M1 antagonism: what are the side effects 45 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT TREATING SCHIZOPHRENIA: SEROTONIN HYPOTHESIS AND ATYPICAL ANTIPSYCHOTICS Reducing mesolimbic dopamine hyperactivity reduces positive symptoms The 5HT2A antagonism leads to increased DA tone in Nigro-striatal pathways, reducing EPS side-effects LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT BLOCKING 5HT2A IN SCHIZOPHRENIA Blocking Serotonin receptors in the cortex, leads to increased dopamine secretion downstream also reducing EPS and prolactinaemia 47 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT BETTER THERAPEUTIC PROFILE 48 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT BINDING PROPERTIES OF ATYPICAL ANTIPSYCHOTIC (A) Clozapine, olanzapine, and asenapine all bind relatively weakly to the 5HT1B receptor, while quetiapine and asenapine bind to the 5HT1D receptor. (B) Risperidone, paliperidone, ziprasidone, and iloperidone all have some affinity for the 5HT1B and 5HT1D receptors. In particular, ziprasidone binds more potently to the 5HT1B receptor than to the D2 receptor. Lurasidone does not bind to 5HT1B/D. (C) Aripiprazole and brexpiprazole each bind weakly to the 5HT1B receptor; aripiprazole also binds to the 5HT1D receptor; cariprazine does not bind to 5HT1B/D. 49 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT ATYPICAL ANTIPSYCHOTIC SIDE EFFECTS People with schizophrenia smoke more. D2 Antagonists lead to weight gain, diabetes, increased smoking (lowered dopamine neurotransmission in NAc) etc. People with schizophrenia develop metabolic syndrome, especially with atypical new medication (Serotonin antagonism). In the old times people treated with haloperidol were skinny and stiff (parkinsonism). Try reducing smoking, diet. 50 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT METABOLIC SYNDROME 51 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT TREATING SCHIZOPHRENIA: D2 ANTAGONISTS/PARTIAL AGONISTS ATYPICAL ANTIPSYCHOTICS Reducing mesolimbic dopamine hyperactivity reduces positive symptoms: es Aripiprazol The partial agonism towards D2 in the mesocortical pathway, also reduces the negative symptoms LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT D2 ANTAGONISTS/PARTIAL AGONISTS 53 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT SCHIZOPHRENIA DRUGS Anti-psychotics Typical (1st generation) Atypical (2nd generation) Typical Developed in the 1950s and classified by chemical structure chlorpromazine Butyrophenones, phenothiazines or thioxanthenes (see BNF) Atypical Selective (e.g. D2) dopamine antagonists Some with 5HT antagonist effects (subtype specific - 5HT2A, C and 5HT1A) Dopamine partial agonists Treatment tailored to individual patient’s response and tolerance Summary table of drug classes, target symptoms and side effects etc. provided as revision slide at end of lecture. LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT TREATMENT SIDE- EFFECTS Side effects related to dopamine Side effects typically related to side-effects arising from blockade: drug interactions with other (non-dopaminergic) systems Motor (extrapyramidal side Anti-cholinergic effects (EPS)) Anti-histaminic Acute dystonia (involuntary motor Anti-adrenergic Weight gain movement) Diabetic symptoms in African-Carribean populations Akathisia (innner perception of an inability to ‘sit still’) Parkinsonian Tardive dyskinesia (writhing movements of tongue and facial muscles) Hyperprolactinaemia (high blood prolactin levels) >580 mIU/L women; >450 mIU/L men Neuroleptic malignant syndrome Skeletal muscle spasticity Dysfunctional hypothalamic thermal regulation LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT QUIZ: SIDE EFFECTS? Aripiprazole Quetiapine 56 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT HOW TO MANAGE SIDE EFFECTS Your role as pharmacist is to understand the pharmacology, predict and address side effects. Example quetiapine, take it at night because it makes you sleepy + postural hypotension. 57 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  58 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  TREATMENT STRATEGY Treatments maintained for 12-24 months after acute attack ~75% of patients will relapse Poor side effect profiles mean sustained treatment has disadvantages (see also revision table at end of slides for more info) No single best method to deal with relapse: maintain treatment or aggressively treat 59 each acute attack? LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT INTO CANNABIS PSYCHOSIS Psychosis is a symptom in schizophrenia but schizophrenia is not psychosis Acute use (‘one joint’) may be enough to induce a short-term psychotic episode (linked to high THC containing cannabis). anxiety, depression, paranoid ideas, illusions, hallucinations, delusional beliefs (c.f. ‘wanted’ and ‘unwanted’ effects). 10 9 8 7 "HIGH" 6 5 4 3 2 1 0 THC 2 1 0.5 THC ONLY OR THC/CBD RATIO (ORAL) (Karniol et al.,1973) This may be ameliorated by CBD and is NOT the same as cannabis being linked to disorders such as schizophrenia which is where most media confusion lies. LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT CANNABIS AND SCHIZOPHRENIA In the same way as cannabis psychosis has been confused/misrepresented, links between cannabis use and schizophrenia are not clear cut. Facts: Cannabis use and psychosis are associated in general and clinical populations. However, studies are not consistent with cannabis increasing the incidence of schizophrenia. Cannabis may precipitate psychosis in vulnerable individuals or exacerbate symptoms. Psychotics are more likely to become regular users. LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT DRUGS & PSYCHOSIS: CONTEXT Other drugs considered to pose a potentially greater risk in schizophrenia (incidence and complication): Illicit: Prescription: Amphetamines α-adrenoceptor blockers Cocaine Antibiotics MDMA Anticholinergics PCP Antiepileptics Magic mushrooms Antihistamines Alcohol Antimalarials (mefloquine) Mescaline, psylocybin, LSD Digoxin Khat Dopaminergics Solvents H2 receptor antagonists Retinoids SSRIs (e.g. Prozac) LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT SCHIZOPHRENIA – LOSING CONTROL. http://www.bryancharnley.info LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT  REVISION SLIDES 64 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT SUMMARY OF ANTI-PSYCHOTIC DRUG CLASSES 65 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT NEW ANTI-PSYCHOTIC DRUGS: TOLERABILITY 66 LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT