Prof. Dr. Fareed A. Minhas

Head, Institute of Psychiatry

Rawalpindi General Hospital

Rawalpindi

"Schizophrenia is a cruel disease. The lives of those affected are often chronicles of constricted experiences, muted emotions, missed opportunities, unfulfilled expectations. It leads to a twilight existence, a twentieth-century underground man... It is in fact the single biggest blemish on the face of contemporary medicine and social services; when the social history of our era is written, the plight of persons with schizophrenia will be recorded as having been a national scandal."

- E. Fuller Torrey, M.D., Surviving Schizophrenia

Characterized in general by fundamental and characteristic disorders in thinking and perception, and by inappropriate or blunted affect

Clear consciousness is usually maintained

Intellectual capacity retained though cognitive impairment may set in over time

Disorder of thinking, emotion, volition and perception along with disintegration of personality

Annual incidence between 0.1 and 0.5 per 1000

Onset characteristically between ages 15 & 45

Equal among men and women but mean age of onset is 5 years earlier in men

Lifetime risk between 7.0 and 9.0 per 1000

Prevalence equal in various countries (WHO)

In America alone, 2.2

million people are affected

WHERE DO PEOPLE SUFFERING FROM IT LIVE??

Stigmatization

• Knowledge of the illness lags behind facts ->”discrimination”

• “Fear of violence”

• “Fear of criminal intentions”

• “Fear of unknown and aversion to illness

Impact on the person’s life

• Work limitations such as difficulty performing multiple tasks, interacting with co-workers, accepting criticism or supervision, customer service/contact. Perform inconsistently and may need work space with low stimulation(stress)

• Interpersonal relationships are difficult, mostly live alone or with family

Impact on families

• Sorrow – “We feel like we have lost our child”

• Anxiety – “We are afraid to leave him alone or hurt his feelings”

• Fear – “Will he harm himself or others?”

• Shame and guilt – “Are we to blame? What will people think?”

• Feelings of isolation – “No one can understand”

• Bitterness – “Why did this happen to us?”

• Ambivalence towards the affected person

• Anger and jealousy of siblings

• Depression / Sleeplessness / Weight loss / Social withdrawal

• Total denial of the illness or its severity

• Blaming each other

• Marital discord / Divorce

• Concerns for the future

Community costs

• Schizophrenia costs Canadians more than $2.3 billion in direct health care costs and an additional $2 billion in support costs such as welfare, family benefits and community support services, for a total of $4.3 billion annually. The cost in terms of human suffering is immeasurable...

• People with this disease use nicotine and street drugs excessively

• Suicide rates are high (10 percent – mostly young males)

• Studies show increased prevalence

of various diseases in schizophrenics

such as female breast cancer, MI (s)

Infections, type II diabetes mellitus

• Homelessness

• Accidents

PARANOID SCHIZOPHRENIA

• Commonest type

• Predominant well-organized paranoid delusions

• Thought processes and mood relatively spared

• Disturbance of affect, volition, speech and catatonia mild / absent

SIMPLE SCHIZOPHRENIA

• Insidious development of odd behavior, social withdrawal and declining performance at work

• Clear schizophrenic symptoms might be absent

CATATONIC SCHIZOPHRENIA

• Prominent psychomotor disturbances with alteration between hyperkinesis and stupor, or automatic obedience and negativism

• Posturing / episodes of violent excitement

HEBEPHRENIC SCHIZOPHRENIA

• Affective changes are prominent; delusions and hallucinations fleeting and fragmentary; behavior irresponsible and unpredictable

• Mannerisms are common

• Mood is shallow/inappropriate followed by giggling or self- satisfied/self-absorbed smiling

• Hypochondriacal complaints common

• Thought is disorganized and speech rambling/incoherentOTHER CATEGORIES

• Undifferentiated

• Residual

• Post-schizophrenia depression

• Schizophreniform disorder not otherwise specified

THE ACUTE SYNDROME

• POSITIVE SYMPTOMS (Delusions, Hallucinations)

• NEGATIVE SYMPTOMS (apathy, lack of drive, social withdrawal)

SYMPTOM• Lack of insight into illness

• Auditory hallucinations

• Ideas of reference

• Suspiciousness

• Flatness of affect

• Voices speaking to the patient

• Delusional Mood

• Delusions of persecution

• Thought alienation

• Thoughts spoken aloud

FREQUENCY (%)

97

74

70

66

66

65

64

64

52

50

THE CHRONIC SYNDROME

CHARACTERISTIC• Social withdrawal

• Under activity

• Lack of conversation

• Slowness

• Over activity

• Odd ideas / behavior

• Depression

• Neglect of appearance

• Odd postures and movements

• Threats or violence

• Socially embarrassing behavior

• Suicidal attempts

FREQUENCY %74

56

54

48

41

34

34

30

25

23

8

4

VARIATION OF THE CLINICAL PICTURE

• Different features may predominate within a syndrome eg. In the acute syndrome one may have a predominant paranoid delusion and another may have a thought disorder

• Some may have features of both syndromes

• Depressive symptoms / Water intoxication

FACTORS MODIFYING CLINICAL FEATURES

• Amount of social stimulation of the patient – under stimulated ones have mostly negative symptoms and over stimulated ones positive symptoms

• Social background – previously religious delusions were common

• Intelligence – people of low intelligence exhibit simpler forms

Minimum of one very clear symptom(two or more if less clear) belonging to any one of the groups (a)-(d) or from at least two of the groups (e)-(h) during a period of one month or more

(a) Thought echo/ insertion or withdrawal and broadcasting

(b)Delusions of control,influence,passivity; delusional perception

(c) Hallucinatory voices as a running commentary, third-person or somatic hallucinations

(d)Persistent delusions that are inappropriate and impossible

(e) Persistent hallucinations or over-valued ideas

(f) Breaks/interpolations in train of thought, neologisms

(g)Catatonic behavior such as waxy flexibility/negativism/stupor

(h)Negative symptoms eg. Marked apathy, paucity of speech

(i) Significant consistent change in personal behavior eg idleness

A. CHARACTERISTIC SYMPTOMS OF ACTIVE PHASE (delusions/hallucinations/disorganized speech/catatonia/alogia)

B. SOCIAL/OCCUPATIONAL DYSFUNCTION in at least one major area of functioning such as work, interpersonal relations or self-care

C. DURATION persistent for at least 6 months…with at least one month of symptoms of criterion A

D. SCHIZOAFFECTIVE AND MOOD DISORDER EXCLUSION

E. SUBSTANCE/GENERAL MEDICAL CONDITION EXCLUSION

F. RELATIONSHIP TO A PERVASIVE DEVELOPMENTAL DISORDER

ORGANIC SYNDROMES (drug-induced states, temporal lobe epilepsy, acute brain syndrome of the elderly, dementia)

MOOD DISORDER

PERSONALITY DISORDER

CHILDHOOD AUTISM – ASPERGER’S SYNDROME

Study commenced in 1990 investigating about 20% genomes in large families of history of schizophrenia in east Quebec show association areas on chromosomes

• 11q / 3q / 18q / 6p

•STRONG EVIDENCE FOR SCHIZOPHRENIA SUSCEPTIBILITY GENE 6P22-P24 AND 11Q21-22

Anticipation (increasing severity or early age of onset of disease in successive generations) is found in Schizophrenia

A recent study by molecular biologists at UC Irvine isolated a gene, hSKCa3 located on 22q, which leads to an increased risk to schizophrenia. This isolated gene contains a characteristic CAG repeat American Journal of Genetics(Miziade M et

al)

There is a strong genetic component however only 48% concordance among identical twins says that is not all…

THE DOPAMINE HYPOTHESIS

SHOWS A SIGNIFICANT INCREASED NUMBER OF DOPAMINE RECEPTORS IN A SCHIZOPHRENIC BRAIN

ROLE OF AMINO ACIDS IN SCHIZOPHRENIA

• Glutamate neurotransmitters might have a role – evidence of increased presynaptic/postsynaptic uptake sites for glutamate in orbito-frontal cortex and decreased density of glutamate receptors in the left hippocampus (SEE NEXT SLIDE)

NORMAL

STRUCTURE

People with schizophrenia have smaller and lighter brains

Evidence of enlarged cerebral ventricles

Cytoarchitectural disturbances have been noted

There is evidence of regional cortical loss – volume changes in gray matter 3D profile of gray matter loss in brains of teenagers with early-onset disease.TEMPORAL and FRONTAL areas most affected (red shows maximum effect). These areas are responsible for memory, hearing, motor functions and attention

Frontal composite variability of normal and schizophrenic brains by gender

Shows

Significant structural variability suggestive of changes

Normal vs. Schizophrenia – Composite variability among 15 male subjects

VOLUME OF INTEREST superimposed over three orthogonal slices of the schizophrenic brain – it is simply a sphere of 60 mm radius between midline decussations of ant. And post. commissures

Variability in the sulcal anatomy of the brain between normal and schizophrenic brains is also noted

3D average surface representation and variability maps of the lateral ventricles - highest variability in the posterior horns noted

: MRI imaging showing differences in brain

ventricle size in twins - one schizophrenic, one

not. (image courtesy NIH - Dr. Daniel Weinberger, Clinical Brain Disorders

Branch)

Coronal MR scans from a normal comparison subject (left), and chronic schizophrenic (right). Note increase in CSF in right amygdala-hippocampal complex. (image courtesy of Harvard University Schizophrenia Project

DISARRAY of the hippocampal cytoarchitecture and cingulate gyrus

HYPOFRONTALITY : At rest During card sorting

N

SCZ

“Soft signs” have been reported in many studies – commonly stereognosis, graphaesthesia, balance and proprioception probably due to defects in integration of proprioceptive and other sensory information (Rochford et al-1970/Sanders et al-1992)

Movement disorders common such as dyskinesias and extrapyramidal or parkinsonian signs. Initially the argument was that these are side-effects of anti-psychotic drugs but now a prevalence of 12% of spontaneous dyskinesias has been found in 9 different recent studies of people who never received anti- psychotics. Also 23% prevalence of parkinsonian signs is found in the same category.

Decreased pain perception exact mechanism not know..no studies

EEGs of schizophrenics show increased theta activity, fast activity and paroxysmal activity with scalp electrodes. More abnormal EEGs were seen in patients never treated. Using deep implanted electrodes – spike abnormalities in septal region and secondarily in the hippocampus and amygdala. Also there was abnormality in ‘deep frontal’ and ‘subthalmic’ regions

Evoked potential response (p300) makes use of the person’s ability to identify a target stimulus among irrelevant stimuli and this is lower in schizophrenics and their first-degree relatives

Eye-tracking studies – defective performance by schizophrenics (Freidman et al-1992 and Muir et al-1992)

Cognitive deficits proven by various studies. Studies using subjects who never received anti-psychotics also show significant results.

Main areas of deficit are verbal learning and memory. Less commonly, attention and vigilance as well as visuo-motor processing.

Latest study by Schuepbach et all in 2002 in which 20 patients compared to 21 controls showed significant deficits on the Stroop test for selective attention

Use of comparatively new and technically complex methods – POSITRON EMISSION TOMOGRAPHY (PET) ; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY (SPECT) and FUNCTIONAL MAGNETIC RESONANCE IMAGING (fMRI)

10 studies conducted to date of patients without anti- psychotic treatments. 8 show significant deficits in the dorsolateral prefrontal cortex at the onset on disease

Decreased blood flow in prefrontal and frontal areas

PERINATAL FACTORS : Birth complications, season, influenza

CHILDHOOD DEVELOPMENT/ ANTECEDENTS : Greater hostility towards strangers, reading and speech difficulties

PERSONALITY FACTORS : Asthenic built, schizoid traits

SEX AND AGE OF ONSET : Myelination of frontal and temporal cortex around puberty, sex hormone changes

PSYCHODYNAMIC THEORIES

FAMILY

• Deviant role relationships

• Disordered family communications

CULTURE

OCCUPATION AND SOCIAL CLASS

PLACE OF RESIDENCE

MIGRATION / SOCIAL ISOLATION

PSYCHOSOCIAL STRESSES

According to the BIO-PSYCHO-SOCIAL MODEL

BIOLOGICAL TREATMENT

ANTI-PSYCHOTIC DRUGS

Conventional or Standard Antipsychotics are phenothiazines, butyrophenones, diphenylbutyl pipiredines, thioxanthenes and substituted benzamides. These include: chlorpromazine (Thorazine); fluphenazine (Prolixin); haloperidol (Haldol); thiothixene (Navane); trifluoperazine (Stelazine); perphenazine (Trilafon) and thioridazine (Mellaril).

Atypical Antipsychotics are newer drugs with fewer side effects and include risperidone (Risperdal); clozapine (Clozaril) and olanzapine (Zyprexa).

Side-effects Commonly dry mouth, constipation, blurred vision and drowsiness. Less commonly decreased libido, menstrual changes

Extrapyramidal effects : Parkinsonian tremors, Akathesias, Tardive dyskinesias and dystonias.Watch for ‘Neuroleptic Malignant Syndrome’

Anti-psychotic preparations available

• Oral drugs – Tablets and suspensions

• Injectables – Short acting( Haloperidol, zuclopenthixol acetate) or depot preparations(zuclopenthixol decanoate, fluphenazine)

ECTs

Traditional indications are catatonic stupor and severe depressive symptoms in schizophrenia.

ANTI-DEPRESSANTS AND MOOD STABILIZERS

Depression is a part of the syndrome of schizophrenia. Value of use of anti-depressants is not proven, may be helpful in chronic syndrome but might worsen active psychosis.

Value of lithium in treatment is uncertain. If a schizoaffective case, some benefit might be present.

PSYCHOLOGICAL TREATMENT

INDIVIDUAL PSYCHOTHERAPY

FAMILY EDUCATION

SELF-HELP GROUPS

Good motivation and productivity from patient is essential

WORKING WITH RELATIVES working with emotional expressions within family is most beneficial

BEHAVIORAL TREATMENT include ‘token economies’ and ‘cognitive behavior therapy’ (specially for positive symptoms as they are amenable to structured reasoning)

SOCIAL TREATMENT

REHABILITATION include social and vocational training and improvement of communication skills as the onset of the illness is at a point where they are training for skilled work.

CASE MANAGEMENT (followed in US)

Most consumers with severe or chronic schizophrenia will have a case manager. The role of the case manager is to assist in coordinating all the services that the consumer may need. See figure below as an example of how a case manager can work with other professionals and agencies.

Two different approaches to preventing schizophrenia that are currently being researched:

1. Preventative measures that are taken well prior to any measurable signs of the early phase of schizophrenia (also called the prodromal phase, in medical terms)

2. Preventative measures taken during the prodromal period of schizophrenia. (People typically show some early signs of schizophrenia well before the full development of schizophrenia).

REDUCING THE CHANCE OF GETTING SCHIZOPHRENIA

• Street Drugs increase risk of Schizophrenia particularly cannabis and marijuana

• Enriched Educational, Nutrition and Social Environments Lower Risk of Schizophrenia

• Essential fatty acid (EFA) deficiency and resulting lipid membrane abnormalities may increase risk of schizophrenia

• Antioxidant Intake may reduce risks of schizophrenia and decrease side effects of medications

• Country life (vs. city living) before age 15 is associated with lower rates of schizophrenia

REDUCING THE CHANCE OF GETTING IT AT BIRTH

• Maternal infections during pregnancy are associated with increased risk of schizophrenia mostly flu

• Pregnancy and baby delivery complications are associated with increased risk of schizophrenia

• Season of Birth - Low Sunlight Exposure/Vitamin D is associated with higher risk of schizophrenia

• Older Age of Father increases risk of Schizophrenia due to high levels of DNA damage in sperms of father

• Lead and other Toxic Exposures to Pregnant Women Triples Risk of Schizophrenia for Child

• X-Ray Radiation during Pregnancy may increase risk of schizophrenia for child

Natural course of Schizophrenia as typically described

ICD 10 CLASSIFICATION / DSM IV CLASSIFICATION

-Continuous - Episodic with interepisodic

- Episodic+Progressive deficit residual symptoms

- Episodic+Stable deficit - Episodic with no interepisodic

- Episodic remittent residual symptoms

- Incomplete remission - Continuous(+negative prominence)

- Complete remission - Single episode+partial remission

- Other - Single episode+full remission

Good prognostic factors :

• Sudden onset

• Short episode

• No previous history

• Prominent affective symptoms

• Paranoid type of illness

• Older age of onset

Poor prognostic signs :

• Insidious onset

• Long episode

• Previous psychiatric history

• Negative symptoms

• Enlarged lateral ventricles/Male

• Younger age at onset

• Married

• Good psychosexual adjustment

• Good previous personality

• Good work record

• Good social relationships

• Good compliance• Single/separated/widow/divorced

• Poor psychosexual adjustments

• Abnormal previous personality

• Poor work record

• Social isolation

• Poor compliance

EARLY DETECTION AND INTERVENTION may contribute to lower incidence and prevalence of florid schizophrenia. These programs combine (1) early detection of psychotic features by family practitioners and other primary care providers and (2) close liaison with mental health professionals well trained in psychiatric assessment and treatment strategies effective in reducing the prevalence of established cases of schizophrenia. Long-term monitoring for signs of recurrence of these sub-threshold psychotic episodes, with further intervention as needed, appears essential to maintain these benefits.

Schizophrenia Bulletin, 22(2): 271-282, 1996

Linszen D, Lenoir M, de Haan L, Dingemans P, Gersons B (1998).

British Journal of Psychiatry 172 (Suppl 33): 84-89.

NEWER ANTI-PSYCHOTICS are comparatively safer

In 2001, Thompson's group produced the first time-lapse images revealing a wave of tissue loss rolling across the brains of schizophrenic children at the National Institute of Mental Health. first flicker of the disease -small part of the parietal cortex

Loss of upto 5 percent gray matter per year has been recorded compared to 1 percent per year in normal teenagers.

•In 2002, Desmond Smith of the University of California, Los Angeles and his colleagues developed the technique called "voxelation" to study Parkinson's disease in a mouse model. The problem is that the trouble-making cells behind, schizophrenia, for example, could be a small group of upstarts in the brain's huge collection of specialised cells. And to make the matter worse, only a few of our 30,000 or genes may be misfiring in these cells. Smith is now dissecting brain slices for mapping. In five years, he expects to have a complete genetic map of the healthy human brain composed of 8000 voxels and a 300 voxel map of the healthy mouse brain. At the same time, they will begin developing genetic maps of abnormal brains.

• ADHERENCE TO TREATMENT is a special challenge for both the doctor and the patient as paranoia and lack of insight of the patient often interferes.

• SIDE EFFECTS OF THE DRUGS make a person refuse treatment.

• Long-acting depot preparations are available only for the older anti-psychotics. Future targets include development of intramuscular newer anti-psychotics.

• Development of new drugs that act primarily on receptors other than the dopamine system

• Development of community programmes that aid early detection of psychosis and protection of the rights of the mentally ill

“The schizophrenic experience can be a terrifying journey through a world of madness no one can understand, particularly the person travelling through it. It is a journey through a world that is deranged, empty, and devoid of anchors to reality. You feel very much alone. You find it easier to withdraw than cope with a reality that is incongruent with your fantasy world. You feel tormented by distorted perceptions. You cannot distinguish what is real from what is unreal. Schizophrenia affects all aspects of your life. Your thoughts race and you feel fragmented and so very alone with your “craziness...” (Janice Jordan – an author)

“The worst thing about having schizophrenia is the isolation and the loneliness...”