4Psychosis denotes many mental disorders. What is the difference?PSYCHOSISPsychosis is a thought disorder characterized by disturbances of reality and perception, impaired cognitive functioning, and inappropriate or diminished affect (mood).Psychosis denotes many mental disorders.SCHIZOPHRENIASchizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance.
5SchizophreniaSchizophrenia is characterized by profound disruption in cognition and emotion, affecting the most fundamental human attributes: language, thought, perception, affect, and sense of self
6Prevalence of schizophrenia 1.1% population over the age of 1851 mln people worldwide suffer from schizophrenia12 million people in China (a rough estimate based on the population)8.7 million people in India (a rough estimate based on the population)2.2 million people in USA285,000 people in AustraliaOver 280,000 people in CanadaOver 250,000 diagnosed cases in Britain
10Dopamine Theory of Schizophrenia Many lines of evidence point to the aberrant increased activity of the dopaminergic system as being critical in the symptomatology of schizophrenia.
11There are 4 major pathways for the dopaminergic system in the brain: The mesolimbic pathwayfrom substantia nigra to limbic system, functions of memory, emotion, arousal, and pleasureThe mesocortical pathwayfrom substantia nigra to neocortex, cognition, social behavior, planning, problem solving, motivation, and reinforcement in learningThe nigrostriatal pathwayfrom the substantia nigra to the striatum, coordination of involuntary movementThe tuberoinfundibular pathwayfrom the hypothalamus to the pituitary gland, secretion of certain hormones (prolactin)
14Dopamine Synapse Tyrosine Tyrosine L-DOPA DA The synapse and synaptic neurotransmissionDescribe the synapse and the process of chemical neurotransmission. Indicate how vesicles containing a neurotransmitter, such as dopamine (the stars), move toward the presynaptic membrane as an electrical impulse arrives at the terminal. Describe the process of dopamine release (show how the vesicles fuse with the presynaptic membrane). Once inside the synaptic cleft, the dopamine can bind to specific proteins called dopamine receptors (in blue) on the membrane of a neighboring neuron. Introduce the idea that occupation of receptors by neurotransmitters causes various actions in the cell; activation or inhibition of enzymes, entry or exit of certain ions.
15Dopamine receptorsThere are at least five subtypes of receptors:D1, D5 dopamine receptors - cAMP by activation of adenylyl cyclaseD1 – putamen, nucleus acumbensD5 – hypothalamus, hippocampusD2, D3, D4 dopamine receptors - cAMP by inhibition of adenylyl cyclase, inhibits Ca2+ channels and open K+ channelsD2 – caudate–putamen, nucleus acumbensD3 – frontal cortex, medulla, midbrain
16Dopamine and the production of cyclic AMP When dopamine binds to its receptor, another protein called a G-protein (in pink) moves up close to the dopamine receptor. The G-protein signals an enzyme to produce cyclic adenosine monophosphate (cAMP) molecules (in green) inside the cell. [Sometimes the signal can decrease production of cAMP, depending on the kind of dopamine receptor and G-protein present.] Point to the dopamine receptor-G-protein/adenylate cyclase complex, and show how cAMP is generated when dopamine binds to its receptor. Indicate that cAMP (point to the cyclic-looking structures) controls many important functions in the cell including the ability of the cell to generate electrical impulses.
17The dopamine hypothesis (1): Most antipsychotic drugs strongly block postsynaptic D2 receptors in the CNS (meso- limbic system)Drugs that increase dopaminergic activity aggravate schizophrenia and produce psychosis de novoIncreased dopamine receptor density has been found post mortem in brains of schizophrenics
18The dopamine hypothesis (2): PET has shown increased dopamine receptor density in schizophrenicsSuccessful treatment of schizophrenics changes the amount of homovanilinic acid – metabolite of dopamine in cerebrospinal fluid, plasma and urine.
19SCHIZOPHRENIA Dysfunction of DA-ergic system: Hyperactivity of DA system(mesolimbic pathway)Hypo-activity in frontal cortex (mesocortical pathway)Dysfunction of 5-HT, GABA and glutamate –ergic systems
20Onset of schizophrenia Onset - early adulthood, between the ages of 15 and 25.Men tend to develop schizophrenia slightly earlier (16 – 25 years old) than women (25 – 30 years old).The average age of onset is 18 in men and 25 in women
22Early intervention and early use of new medications lead to better medical outcomes for the individualThe earlier someone with schizophrenia is diagnosed and stabilized on treatment, the better the long-term prognosis for their illnessTeen suicide is a growing problem and teens with schizophrenia have approximately a 50% risk of attempted suicideAnti-psychotic medications are the generally recommended treatment for schizophrenia !!!If medication for schizophrenia is discontinued, the relapse rate is about 80 percent within 2 years. With continued drug treatment, only about 40 percent of recovered patients will suffer relapses.
23Outcomes of schizophrenia After 30 years of diagnosed schizophrenia 25% Completely Recover35% Much Improved, relatively independent15% Improved, but require extensive support network10% Hospitalized, unimproved15% Dead (Mostly Suicide)
24Symptoms of schizophrenia (1): Positiveappear to reflect an excess or distortion of normal functions:* delusions (paranoid, reference, somatic, delusions of grandeur)* halucinations (visual, auditory, tactile, olfactory, gustatory)* disorganized speech = „word salad”*disorganized or catatonic behaviorNegativeappear to reflect a diminution or loss of normal functions:* lack of emotion * low energy* affective flattening * low motivation*inappropriate social skills * alogia
25The terms "positive" and "negative" may be confusing The terms "positive" and "negative" may be confusing. They should not be interperated as "good" and "bad" symptoms.
26Symptoms of schizophrenia (2): Cognitivedisorganized thinkingslow thinkingdifficulty in understandingpoor concentrationpoor memorydifficulty with expressing thoughtsdifficulty with integrating thoughts, feelings and behavior
27Symptoms of schizophrenia (3): Disorganized symptoms (?)* thought disorder* confusion* disorientation* memory problemsDisorganized symptoms may reflect an underlying dysfunction common to several psychotic disorders, rather than being unique to schizophrenia.
28Hallucinations and delusions are prominent symptoms SchizophreniaActive phaseHallucinations and delusions are prominent symptomsResidual phase
29U.S. diagnostic criteria for schizophrenia (1) A. Characteristic symptoms: ≥2 during a 1- month period :delusionshalucinationsdisorganized speechdisorganized behaviornegative symptoms
30U.S. diagnostic criteria for schizophrenia (2) Only one Criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person’s behavior or thoughts, or two or more voices conversing with each other.
31U.S. diagnostic criteria for schizophrenia (3) B. Social/occupational dysfunctionworkinterpersonal relationsself-careC. Durationcontinuous signs of the disturbance persist for at least 6 months, including 1 month of symptoms from Criterion A and prodromal symptoms)
32U.S. diagnostic criteria for schizophrenia (4) D. Schizoaffective and mood disorder exclusionno major depressive, manic or mixed episodes have occurred with the active-phase symptomsE. Substance/general medical condition exclusionF. Relationship to a pervasive developmental disorder
38Mechanisms of Action of Antipsychotics conventional antipsychoticsD2 receptor blockade of postsynaptic in the mesolimbic pathwayatypical antipsychoticsD2 receptor blockade of postsynaptic in the mesolimbic pathway to reduce positive symptoms;enhanced dopamine release and 5-HT2A receptor blockade in the mesocortical pathway to reduce negative symptoms;other receptor-binding properties may contribute to efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophrenia
43Actions of neuroleptic drugs (2) Antipsychotic actions:reduce the halucinationsreduce spontaneous physical movementOccur after 4 – 6 weeks of treatmentExtrapyramidal effects:Parkinsonian symptomsakathisiatardive dyskinesia
44Actions of neuroleptic drugs (3) Antiemetic effect (exept thioridazine)Antimuscarinic effect:blurred vision, dry mouth, sedation, confusion, inhibition of GI and urinary smooth muscleOther effects:hypotension, lightheadness
45Neuroleptic drugs are not curative and do not eliminate the fundamental thinking disorder, but often do permit the psychotic patient to function in a supportive environment
46Therapeutic uses Schizophrenia Other psychosis Schizoaffective disordersDeliriumPrevention of severe nausea and vomiting (vertigo, motion sickness, cancer chemo- and radiotherapy)TranquilizersIn combination with narcotic analgesics for treatment of chronic pain with severe anxietyIntractable hiccups
47Pharmacokinetics Neuroleptics are absorbed after oral administration Pass through blood – brain barrierBind well to plasma proteins, highly lipid-solubleAre metabolized in liver by P-450 system
48Adverse effects (1) Neurologic effects due to D2 receptor blockade AcuteAcute dystoniaMedium- termAkathisiaParkinsonismChronicTardive dyskinesiaTardive dystonia
49Fixed muscle postures with spasm: Acute dystoniaIn the beginning of treatmentCommon in young malesTreatment with anticholinergic drugs (procyclidine 5-10mg or benztropine i.m or i.v)Fixed muscle postures with spasm:clenched jaw musclesprotruding tongueopisthotonostorticollisoculogyric crisis(mouth open, head back, eyes staring upwards)
50Akathisia motor restlessness affect lower limb very distressing to the patientTreatment – reduction of the drug dose.
51Parkinsonism induced by blockade of D2 receptors in the striatum !!! appear after a few days to weeksTreatment:anticholinergic drugs (e.g procyclidine)reduction of doseswitching to an atypical antipsychotic
52Tardive dystonia specific movements of the head, neck and trunk. Tardive dyskinesia orofacial dyskinesia -lip smacking and tongue rotating.Tardive dystonia specific movements of the head, neck and trunk.Appear after months to years of drug treatmentClozapine and Risperidone have a low potential for causing extrapyramidal symptoms and lower risk of tardive dyskinesiaThere is no effective treatment !!! They are irreversible.
53Adverse effects (2):Anticholinergic effects due to muscarinic blockade:loss of accomodation, dry mouth, blurred vision, constipation, urinary retentionOrtostatic hypotension due to -adrenergic blockadeNeuroendocrine adverse effects due to D2 blockade in the tuberoinfundibular pathway :Amenorrhoea-galactorrhoeaInfertilityImpotence, Failure to ejaculateDrowsinessWeight gain,Urticaria, dermatitis, rashes, dermal photosensitivity
54Adverse effects of clozapine Bone marrow suppressionCardiovascular side effectsDiabetesAdverse effects of chlopromazineCholestatic jaundice
55Neuroleptic Malignant Syndrome Precise pathophysiology unknown – deranged dopaminergic function ?It is an idiosyncratic reaction that appears from a few days to weeks after beginning treatment, but can occur anytime.The mortality – 20% in untreated (bromocriptine – D1/D2 agonist; dantrolene – sceletal muscle relaxant; supportive treatment)
56Neuroleptic Malignant Syndrome (NMS) HyperthermiaMuscle rigidityAutonomic instabilityFluctuating consciousnessMortality due to renal failure caused by rhabdomyolysis.
59Neuroleptics overdose Rarely fatalDrowsiness proceeds to coma, with intervening period of agitationIncreased muscular excitability may lead to convulsionsDecreased deep tendon reflexesVentricular tachyarrhythmiasGastric lavage !!!
60Dosage of neuroleptic drugs Antipsychotics may be given in divided daily doses initially while effective dosage level is being sought.2 or more episodes of schizophrenia – therapy for 5 yearsFluphenazine and haloperidol i.m. slow release drugs (up to 3 weeks)