Schizophrenia

-If you talk to God, you are praying. If God talks to you, you have schizophrenia.-Thomas S. Szasz

MANY FACES OF SCHIZOPHRENIA

(Clockwise from top left): * Mathematician John Nash* Author Jack Kerouac* Fleetwood Mac guitarist Peter Green* Musician Syd Barrett of Pink Floyd

History

•In Middle Ages people thought as being possessed by witches and devils

•After Modern Medicine in 1911,Emil Kraeplin called it dementia praecox•Firstly it was thought similar to Alzheimer's disease later distinguished because its symptoms begin in late adolescence and early adulthood

•Eugen Bleuler described four major characteristics of this diseaseAmbivalenceAutismLoose Association:Loss of Affect

• FREUD’S WORK: He hypothesized that childhood traumas lead to it, but was proved to be wrong.

• It is not mental inability or fault of the family but is like other diseases.

• It isn't SPLIT PERSONALITY syndrome.• Its treatable but not necessarily curable. Medicines

,rehabilitations ,family and public help matter a lot. • We are at crossroads at the treatment of this disease.

Incidence And Prevalence

•Incidence Expressed in terms of new cases and prevalence total cases.•Meta Analysis has showed variations in incidence rate w.r.t urban city, migration , race and male gender. No variations in prevalence.•Lifetime prevalence of 1.2-4.6 per 1000 in all populations in the world.

•Annual incidence of 0.16 and 0.42 per 1000 population.

Symptoms

Symptoms are divided into three main categories

Positive or Psychotic Negative or Deficit Cognitive Impairment

• Hallucinations : visual, auditory, olfactory, gustatory, tactile.

Auditory Hallucinations : Hearing single or multiple voices of friends ,god, family. These may command the person to do something drastic. The person thinks that the voices belong to the neighbors and they conspire against him.

• Delusions : Paranoid of persecution, grandiosity, external control. The content takes cues from patients life and culture e.g. Americans think CIA is following them. Delusions contain supernatural,E.T and paranormal ideas gleaned from T.V.

• Thought Disorder : Tangential and circumstantial thinking to loosening of associations. Disorganized speech, catatonia. Derailment, neologisms, word salad.

• Video.

Positive or Psychotic

• Alogia: Loss of speech because of slower thinking this subsequently leads to social withdrawal.

• Affective Flattening: Loss of emotions to such an extent that one only feels anxiety and unhappiness

• Avolition: Loss of motivation in pursuing any goal.• Anhedonia: Loss of pleasurable sensations e.g.

smell, taste, sexual pleasure.

Negative or Deficit

• Affects executive function• Attention and Memory deteriorates• General intellectual functioning

Cognitive Impairment

Schizotypy & Creativity

• Highly creative females gave answers to the Rorschach indicative of schizophrenia

• They were not mentally ill • Suggests that creative individuals and

schizophrenics share some thinking patterns• Lowered evidence criterion• May explain increased creativity of

schizotypal individuals• Still these are not completely conclusive .

What do you see?

What do you see?

• Heritability is high and genes contribute up to 80%.• But no Gene is either sufficient nor necessary for illness.• Linkage Analysis and Meta Analysis have been used.• Abnormalities in deletion of 22q11, a balanced reciprocal

translocation of lq42/11q14 and X chromosome.• Microarray analysis demonstrated alteration in expression of

myelination related ,neural transmission, signal transduction genes.

• By Gene association studies NGR1,DTNBP1,DRD1-4 genes are found susceptible.

Genetic View

• Currently genetic view is that it is a heterogeneous ,polygenic disease.

• It results from combined effect of multiple, highly reentrant and individually rare mutations that are very specific.

• Genes DONT code for it per se but other clinical constructs such as psychosis or neuron-cognitive deficits that occur in schizophrenia.

• Analysis lacks precision and has many discrepancies because of the unavailability of samples(linkage) and so

sheer volume(in case of genetic association).

• Biological and Psychological.• Maternal influenza,rubella,toxoplasmosis,fetal hypoxia,

other adverse life events during pregnancy.• Cannabis Use.• Migration, Urban city ,Ethnicity.• Older paternal age due to impaired spermatogenesis.• Season of Birth .

Environmental Factors

Computed tomography and Magnetic resonance imaging have showed gray matter deficit(mainly frontal and temporal lobes ) of brain.

Decreased cortical volume especially in temporal cortex and increased ventricular size(fluid filled spaces) because brain produces more CSF.

Decreased hippocampal and cortical neuron size due to shrinkage in size of dendrites.

Increased dopamine content or metabolism and D2 receptors

Brain Abnormalities.

Enlarged Ventricles

Control Schizophrenic

By PET and CBF studies(in resting state, cognitive tasks, during symptoms) less anterior CBF known as hypofrontality.

Decreased activation of left frontal cortex(during tasks).

Increased left interior frontal CBF(during hallucination) to thalamus, medial temporal cortex and in the striatum.

Reduced activity of limbic/paralimbic regions.Decreased metabolism in temporal language regions.

Whether Neurodegenerative or Neurodevelopmental

Different features of illness may have different explainations, need not be exclusive.

Neurodevelopmental hypothesis of disease include symptoms that were present early in life and later expressed as full disorder such as speech problems, lower educational and test performance.

On the other hand if the brain volume changes are progressive more than the normal pace of increase, it suggests the disease to be neurodegenerative.

However no conclusion is reached as schizophrenia can be the union of both of them as the characters of both the hypothesis have been found in the patients

Theories related with schizophrenia

The DA theory of schizophrenia

According to the DA (dopamine) theory, •schizophrenia is associated with increased activity at dopaminergic receptor sites•antipsychotic drugs exert their clinical effect by reducing increased DA activity. which leads to predictions that: •drugs which increase DA activity should produce schizophrenia •drugs which decrease DA activity should reduce schizophrenia

•This was actually done by examining the effects of amphetamine.

GLUTAMATE theory

Glutamate is an excitatory neurotransmitter, and N-methyl-D-aspartate (NMDA) is a type of glutamate receptor. Phencyclidine (PCP) and its analogues, like ketamine and MK-801, are non-competitive antagonists of the NMDA receptor. That is, when PCP or one of its analogues binds to an NMDA receptor, it inhibits that receptor from responding correctly to glutamate. Since NMDA is a glutamate receptor, and PCP is an NMDA antagonist that induces schizophrenia-like symptoms, it has been hypothesised that schizophrenia is due to glutamatergic underactivity.

GLUTAMATE THEORY

Drugs for schizophrenia

These are : antipsychotics / neuroleptics There are two types of antipsychotic medicine: classic and atypical antipsychotics

Examples of classic antipsychotics: the phenothiazine drugs:

chlorpromazine thioridazine

the butyrophenone drug: haloperidol

the diphenylbutylpiperine drug pimozide

Examples of atypical antipsychotics: clozapine SulpirideRisperidoneRaclopride

Drugs for schizophrenia

Examples of Conventional Neuroleptics-•Perphazine•Trifluoperiazine•Fluphenazine

Drugs for schizophrenia(Atypical antipsychotists)

EFFECT OF CLASSICAL NEUROLEPTICS

SIDE EFFECTS RELATED TO DRUGS

•Acute dystonia - uncontrolled movements of face, neck, tongue •Oculomotor crisis - uncontrollable eye movements •Akathisia - restlessness & agitation •Parkinson's disease - slow movement, shuffle, facial tremor •Tardive dyskinesia - means "late appearing movement disorder". It involves erky movement of the tongue and face, eventually entire body affected.

ANIMAL MODEL FOR SCHIZOPHRENIA

Psychologists use animal models to test biological theories of human behaviour. A model is a simple representation of a complex system. An animal model of schizophrenia is an attempt to capture the essence of the condition, but it does not claim to reproduce the human condition in an animal. The purpose of an animal model is to discover novel medicines that combat the abnormal behaviour in the animal model which could be then be used to alleviate human suffering.

ALTHOUGH AT PRESENT THERE ARE NO ANIMAL MODELS THAT CAN CAPTURE ALL THE FEATURES OF SCHIZOPHRENIA

• Brain imaging and pathological studies.• US $17.3 billion in the United States, £810 million are

spend in U.K every year for treatment of patients.• Narcoleptics in conjunction with psychosocial

rehabilitation have a substantial effect in reducing relapse

• Antipsychotic medications reduce extra pyramidal side effects.

Treatment

• We have not learned much even after mapping of human genome ,the precise mechanism of inheritance still remains obscure.

• Both genetic and environmental factors are responsible but the exact mechanism is not known

• We need to check whether a given factor is a risk modifier or a risk mediator.

• Maybe schizophrenia includes several different diseases whose clinical manifestations are similar.

Conclusion