1. Association Loosening in the Logical Thoughts

Schizophrenia

Schizophrenia is a clinical syndrome of variable but profoundly disruptive psychopathology, which involves thought, perception, emotion, movement, and behavior. The expression of these symptoms varies across patients and over time, but the cumulative effect of the illness is always severe and usually long lasting.

Emil Kraepelin: two major patterns of insanity: manic-depressive psychosis and dementia praecox (or dementia of the young), and under the diagnostic category of dementia precox the previously categories of insanity, such as hebephrenia, paranoia, and catatonia. In differentiating dementia precox from manic-depressive disorder, Kraepelin emphasized what he believed to be the characteristic poor long-term prognosis of dementia precox, as compared to the relatively nondeteriorating course of manic-depressive illness.

In 1911 Eugen Bleuler, recognizing that dementia was not a usual characteristic of dementia precox, suggested the term schizophrenia (splitting of the mind) for the disorder. Bleuler introduced the concept of primary and secondary schizophrenic symptoms; his four primary symptoms (the four As) were:

1. Association loosening in the logical thoughts.

2. Affective blunting or incongruity.

3. Ambivalence: the co- existence of strongly conflicting feelings, attitudes and ideas leading to inconsistent behavior.

4. Autism (withdrawal in thinking and behavior).

Schneider (1957) has defined diagnostic criteria for schizophrenia on the basis of clustering and frequency of symptoms .He designated a group of the most common (so-called first rank) symptoms which in the absence of organic mental diseases signify schizophrenia, these include:

1-Auditory hallucinations taking the form of one of the following:

Thought Echo: Voices repeating the subject's thoughts out loud or anticipating their thoughts.
Third person Hallucination: Two or more hallucinatory voices discussing the subject or arguing about them in the third person.
Voices commenting on the subject's thoughts or behavior, often in the form of a running commentary.

2-Thought Alienation:

A-Thought insertion: The sensation of alien thoughts being put into the subject's mind by some external agency.

B- Thought withdrawal: of their own thoughts being taken away.

C-Thought broadcasting: the sensation that the subject's thinking is no longer confined to their own mind, but is instead shared by, or accessible to, others.

3-Passivity Phenomena :The sensation of feelings, impulses, or acts being experienced or carried out under external control, so that the subject feels as if they were being hypnotized or had become a robot (passivity of affect, impulse, or volition)

4-Somatic passivity:The experience of being a passive and reluctant recipient of bodily sensations imposed by some external agency.

5-Delusional perception (delusional misinterpretation of a normal perception). Refers to the experience of interpreting a normal perception with a delusional meaning.

Limitations of Schneider’s approach:

1. These symptoms carry no prognostic value.

2. Their sensitivity is limited (around 20 % of schizophrenic patients never showed these symptoms).

3. Their specificity is also limited (around 30 % of patients with these symptoms have mood disorders; mania or depression).

EPIDEMIOLOGY

Schizophrenia is a leading public health problem that exacts enormous personal and economic costs worldwide. Schizophrenia affects just under 1 percent of the world's population (approximately 0.85 percent).

Worldwide, 2 million new cases appear each year. The lifetime risk of developing schizophrenia is about 1%.

- Most common between 15 - 35 years. Paranoid type is later onset than other types.

There is no sex difference. Although males tend to have an earlier onset than females (23y vs. 26y) and develop more severe illnesses.

More common in low social class this is generally attributed to the "social drift" phenomenon.

Mortality Suicide is the most common cause of premature death in schizophrenia. It accounts for 10-38% of all deaths in schizophrenia. Risk is probably highest in the year after first presentation

ETIOLOGY

The etiological process or processes by which a causal agent creates the pathophysiology of schizophrenia is not yet known.

All the evidence suggests multi factorial etiology for schizophrenia.

1. Genetic:Family, twin, and adoptive studies documented contribution of genetic factors to the etiology of schizophrenia;however, it is not yet known which genes are involved.

- Incidence in families is higher than in general population.

- Monozygotic twin concordance rate is greater than dizygotic concordance rate (50 %, 15 % respectively)

5 % Parents

10 % Siblings

14 % Child of one schizophrenic parent

46 % Child of two schizophrenic parents

Recent analyses have indicated contributions associated with chromosome 6, 4, 8, 15, and 22.

2. Neurobiological

There are many Biochemical Theories identifies the relation between neurotransmitter and schizophrenia.

A-Dopamine and Schizophrenia The hyperdopaminergic hypothesis of schizophrenia arose from two sets of observations of drug action relating to the dopaminergic system. Drugs that increase dopamine system activity, such as d-amphetamine, cocaine, levodopa (Larodopa), and methylphenidate (Ritalin), can induce a paranoid psychosis that is similar to some aspects of schizophrenia. In contrast, drugs that share the capacity to block postsynaptic dopamine receptors reduce the symptoms of schizophrenia.

Increase in the dopamine or increase in the number or the sensitivity of the dopaminergic receptors lead to schizophrenia.

B-Serotonin hypothesis: abnormal serotonin metabolism in some patients. Evidence includes:

1. Hallucinogens like LSD (serotonin agonist) induce psychosis.

2. Serotonin antagonist, such as clozapine and Risperidone improves psychosis.

B. Glutamate is implicated in schizophrenia; N-methyl-d-aspartate (NMDA) antagonists (e.g., memantine) are useful in treating some of the neurodegenerative symptoms in patients with schizophrenia.

D. Disturbed balance between dopamine and serotonin as supported by the new generation of antipsychotics (dopamine-serotonin antagonists).

3- Psychosocial and Environmental:

A. Life Events: Life stressors, particularly in the three months before onset, can induce schizophrenia in those who are vulnerable.

B. Family Psychodynamic. Precipitation of schizophrenia can be due to:

1. Schizophrenogenic mother: over protective

2. Marital skew (submissive father and dominant mother)

3. Marital schism (contradicting parental messages).

4. Double – bind communication (a parent conveys two conflicting incompatible messages at the time, one is overt and the other is covert).

C. High Expressed Emotions (EE) of the family which include critical comments and emotional over-involvement.

Patients whose families have high expressed emotions have higher relapse rate than those whose families have low expressed emotions.

Other markers of early influences, including gestational and birth complications, exposure to influenza epidemics, Rhesus (Rh) incompatibility, starvation, and winter births ,Marital Status(unmarried), Immigration ,Urbanization and Industrialization:The prevalence of schizophrenia has been reported to be higher in urban environments than in rural areas., Life Stressors ,Infections ,Finally, substance abuse has been identified as a risk factor for developing schizophrenia.

Neuropathology and Neuroimaging :

 CT scan studies: - Cortical atrophy in 10 - 35 % - Enlargement of the lateral and third ventricles in 10 - 50 %.

- Findings correlate more with negative features and with cognitive impairments.

 MRI and PET (Positron Emission Tomography): - Abnormal frontal, parietal and temporal lobe structure and metabolism.

Clinical features:

Prodromal signs:Quite, passive or irritable, fewfriends avoid social activity, day dreams, somaticcomplaints, interest in the occult, religion or philosophy.

Positive symptoms: All types of hallucinations, delusions, bizarre behavior (Clothing, appearance, Social, sexual behavior, Aggressive behavior, Repetitive/stereotyped behavior) and Positive formal thoughtdisorder (Derailment, Tangentiality,Incoherence, Illogicality, Circumstantiality,Pressure of speech, Distractible speech,Clanging.

Negative symptoms: Loss of the normal level of motivation or drive, loss of awareness of socially appropriate behavior, flattening of mood, and difficulty in abstract thinking.

*Affective flattening: Unchanging facial expression, Decreased spontaneous movements, Poor eye contact, Affective non responsivity, inappropriate affect.

*Alogia: Poverty of speech, Poverty of content of speech.

*Avolition-apathy:Grooming and hygiene, Impersistence at work or school, Physical anergia.

*Anhedonia-asociality: limitation in Recreational interests, activities, Sexual interest, activity, Relationship with friends, peers.

*Attention: Social inattentiveness.

Good Prognostic Factors / Bad Prognostic Factors
 Late onset /  Young age at onset
 Acute onset /  Insidious onset
 Obvious precipitating factors /  No precipitating factors
 Good premorbid personality /  Poor premorbid Personality
 Presence of positive symptoms /  Low IQ
 Presence of mood symptoms (especially depression) /  Many relapses
 Good support (married, stable family) /  Poor compliance
 Negative symptoms
 Poor support system
 Family history of schizophrenia
 High Expressed Emotion family

Diagnosis

DSM-IV Diagnostic Criteria for 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):

(1) Delusions

(2) Hallucinations

(3) Disorganized speech (e.g., frequent derailment or incoherence)

(4) Grossly disorganized or catatonic behavior

(5) Negative symptoms, i.e., affective flattening, Alogia, or avolition

Note: 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.

B. Social/occupational dysfunction.

C. Duration: Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated)

D.Schizoaffective and mood disorder exclusion.

E. Substance/general medical condition exclusion:

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ICD-10 schizophrenia

1. At least one of the following:

Thought echo, insertion, withdrawal, or broadcasting.
Delusions of control, influence, or passivity; clearly referred to body or limb movements or specific thoughts, actions, or sensations; and delusional perception.
Hallucinatory voices giving a running commentary on the patient's behavior or discussing him/her between themselves, or other types of hallucinatory voices coming from some part of the body.
Persistent delusions of other kinds that are culturally inappropriate or implausible, (e.g. religious/political identity, superhuman powers and ability).

2. Or, at least two of the following:

Persistent hallucinations in any modality, when accompanied by fleeting or half-formed delusions without clear affective content, persistent over-valued ideas, or occurring every day for weeks or months on end.
Breaks of interpolations in the train of thought, resulting in incoherence or irrelevant speech or neologisms.
Catatonic behavior such as excitement, posturing, or waxy flexibility, negativism, mutism, and stupor.
Negative symptoms such as marked apathy, paucity of speech, and blunting or incongruity of emotional responses.
A significant and consistent change in the overall quality of some aspects of personal behavior, manifest as loss of interest, aimlessness, idleness, a self-absorbed attitude, and social withdrawal.

3. Duration of 1 month.

DIFFERENTIAL DIAGNOSIS OF SCHIZOPHRENIA :

1. Organic Mental Disorders:

 Complex partial seizure (e.g. temporal lobe epilepsy)

 CNS infections

 Substance intoxication (e.g. amphetamine, cocaine …)

 Frontal lobe pathology (e.g. tumor, trauma …)

2. Schizophreniform Disorder: Similar features to those of schizophrenia but last for less than 6 months.

3. Brief Psychotic Disorder: Similar features to those of schizophrenia but last for less than 1 month.

4. Mood Disorders:Manic episode or major depressive episode with psychosis. Note that: hallucination and delusions are mood – congruent and usually develop after the mood disturbance. The course of mood disorders is fluctuating: (repeated episodes of mood disturbance with normal periods in between).

5. Schizoaffective Disorder

Concurrent presence of mood disturbance and schizophrenia features: (there must be delusions or hallucinations, for at least two weeks in the absence ofprominent mood symptoms during some phase of the illness).

6. Delusional Disorders :

 Delusions are systematized and nonbizarre.

 No other features of schizophrenia

 Functioning is much less affected.

7. Personality Disorders: Schizotypal, paranoid, schizoid, and borderline personality disorders may confuse or co-occur with schizophrenia.

DSM-IV Schizophrenia Subtypes

1-Paranoid Type:

Prominent paranoid delusion with frequent auditory hallucinations related to the delusion.
Patient is usually potentially aggressive, angry or fearful, uncooperative and difficult to deal with. No prominent disorganized behavior or mood.
The onset is usually late (compared to other subtypes of schizophrenia).
The prognosis is better than the other subtypes and deterioration in functioning is usually much less.

2-Disorganized Type (Hebephrenic)

Disorganized behavior.
Marked incoherence and loosening of association.
Inappropriate affect.
Grimacing and bizarre mannerism are common.

3-Catatonic Type

Motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor
Excessive motor activity (that is apparently purposeless and not influenced by external stimuli)
Extreme negativism (an apparently motiveless resistance to all instructions or maintenance of a rigid posture against attempts to be moved) or Mutism
Peculiarities of voluntary movement as evidenced by posturing (voluntary assumption of inappropriate or bizarre postures), stereotyped movements, prominent mannerisms, or prominent grimacing
Echolalia or Echopraxia

4-Undifferentiated Type

The criteria are not met for the paranoid, disorganized, or catatonic type.
Prominent delusions and hallucinations.
Prominent disorganization behavior.
Incoherence.

5-Residual Type

Absence of prominent delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior.
There is continuing evidence of the disturbance, as indicated by the presence of negative symptoms or two or more symptoms listed in criterion A for schizophrenia, present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).

MANAGEMENT: Multidisciplinary: Bio, Psycho, Social approach.

Hospitalization is usually indicated in the acute phase in order to:

Clarify diagnosis (rule out possible organic causes).
Control the disturbed behavior.
Protect the patient and / or others (risk of dangerousness or suicide)
Give electroconvulsive therapy (ECT) for Catatonic type, those with concomitant depression and in resistant cases.
Antipsychotic medications

Psychosocial:

Family therapy education and explanation can significantly reduce relapse rate and highEE family interaction can be diminished. Compliance may also be enhanced.
Rehabilitation :

Social skill training (e.g. self-care).

 Illness-management skills (e.g. when to take medication).

 Vocational rehabilitation (for more stable cases).

 Token economy: Useful for institutionalized chronic schizophrenics.

Positive and negative reinforcement are used to alter patient’s unacceptable behavior. It should be part of a behavioral program.

Treatment

Antipsychotics:

 Mechanism of action: Postsynaptic blockade of CNS dopamine receptors type 2 (D2) and will act through three tracts:

 Mesolimbic – Mesocortical tract Therapeutic antipsychotic effect.

 Nigrostriatal tract-Extrapyramidal effects lead to Parkinson like features (side effect).

 Tuberoinfundibular tract Excessive prolactin secretion.

Antipsychotics (Major Tranquilizers – Neuroleptics)

 Phenothiazine:

- Aliphatic class e.g. Chlorpromazine (Largactil) (Low potency): Oral, IM, dose200–600mg/day

 -Piperidine class e.g. Thioridazine (Melleril).Lowpotency:Oral200–600mg/day

Serious Side effects like retinitis pegmantosa and arrhythmia

-Piperazine class e.g. Trifluoperazine (Stelazine).High potency:Oral5–30 up to60mg/day.

 Butyrophenones: Droperidol – Haloperidol (Haldol) high potency: Oral, IM, depot (5–20mg, up to60mg/day oral).

 Thioxanthenes: e.g. Clopenthixol ( Clopixol )

 Substituted benzamide: – Sulpride ( Dogmatil )

 Diphenylbutylpiperidine: Pimozide ( Orap )

 Dibenzodiazepine: Clozapine ( Clozaril - Leponex )

 Benzisoxasol: Risperidone ( Risperdal )

DEPOT (SLOW RELEASE) ANTIPSYCHOTICS: These are esters of antipsychotic drugs, usually in an oily medium, given as deep intramuscular injections to patients who improve with drugs but cannot be relied on to take them regularly by mouth (i.e. poor compliance

 Fluphenazine decanoate (Anatensol – Modecate): e.g. 25 – 75 mg / month.

 Flupenthixol decanoate (Depixol – Fluanxol): e.g. 20 – 100 mg / month.

 Haloperidol decanoate ( haldol ) : 200 – 400 mg. / month.

 Zuclopenthixol decanoate ( Clopixol ) : 200 – 600 mg. /month

-  A test dose is usually given (¼ - ½ the dose) to check patient’s tolerability.

Patients frequently experience the adverse effects of an antipsychotic agent before they experience clinical improvement. Whereas a clinical response may be delayed for days or weeks after drugs are started, adverse effects often begin almost immediately. For low-potency drugs, these adverse effects are likely to include sedation, postural hypotension, and anticholinergic effects, whereas high-potency drugs are likely to cause extrapyramidal side effects.

The therapeutic effect of antipsychotics may take up to 6 weeks to appear.

A-High potency drugs:

 More antidopaminergic effect.

 Less anticholinergic effect.

 EPSE are prominent. e.g. haloperidol, triflouperazine.

B. Low potency drugs:

 More anticholinergic effect.

 Less antidopaminergic effect.

 EPSE are less prominent.

 Postural hypotension and sedation are marked. E.g. chlorpromazine, thioridazine.

Adverse Effects:

(1.) Extra-Pyramidal Side Effects (EPSE)

Acute dystonia:

 Appears within days after antipsychotics.

 Severe painful spasm of neck muscles (toricollis), ocular muscles (oculogric crisis) muscles of the back (opisthotonus) and tongue protrusion.

 Treated with anticholinergic drugs (e.g. procyclidine 5 – 10 mg IM or P.O.).

Parkinsonism:

 Appears within weeks after treatment, its features:

 stooped posture

 akinesia

 muscle rigidity

 masked face

 coarse tremor

Treated with anticholonergic drugs (e.g. procyclidine)

Akathisia (inability to keep still, associated with unpleasant feelings of inner tension)

Usually appears within days – weeks.

 Generally disappears if the dose is reduced.

 Benzodiazepine or beta-blockers may help in the treatment, whereas anticholinergic have no therapeutic effect.

 Tardive Dyskinesia

 occurs in about 10 – 20 % of patients on long-term antipsychotics, Chronic treatment with an antipsychotic—usually for 6 months or morecan result in neuroleptic-induced tardive Dyskinesia

 Chewing, sucking or choreo-athetoid movements of the facial and neck muscles

 may be due to supersensitivity of dopamine receptors resulting from prolonged dopamine blockade

 No specific treatment, the only agreed treatment is to discontinue the antipsychotic drug when the patient’s state allows this.

-Treated by changing to atypical antipsychotic especially clozapine.

(2.) Antidrenergic:

 postural hypotension

 inhibition of ejaculation

(3.) Anticholonergic:

 dry mouth.

 blurred vision.

 constipation.

 urinary retention.

 precipitation of closed – angle glaucoma.

 Poor erection.

(4.) Others:

weight gain, galactorrhoea , amenorrhoea

Toxic Effect : Neuroleptic Malignant Syndrome ( NMS); Muscle rigidity , Fever , High CPK