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Summary Table

Domain	Details
Risk Factors	Family history of schizophrenia (strongest risk factor), perinatal complications (hypoxia, infections), cannabis use during adolescence, urban upbringing, migration, advanced paternal age, childhood adversity
Etiology	Multifactorial: genetic susceptibility + environmental triggers leading to dopaminergic dysregulation (mesolimbic hyperactivity, mesocortical hypoactivity), with contributions from glutamate and serotonin dysfunction
Patient Presentation	A young adult (typically late teens to early 30s) brought by family for bizarre behavior, social withdrawal, declining function at school or work, talking to self, or expressing paranoid beliefs over weeks to months
Classic Physical Exam	Flat or inappropriate affect, poor eye contact, disorganized speech (tangentiality, derailment, neologisms), psychomotor abnormalities, guarded or paranoid demeanor; may show catatonic features. The mental status exam is the examination, not the physical exam.
Key Diagnostic Results	Clinical diagnosis per PPDGJ-III criteria (no confirmatory lab). Labs and imaging are used to rule out organic causes: CBC, metabolic panel, thyroid function, urine toxicology, and brain CT/MRI to exclude structural lesions
Management	Acute: Second-generation (atypical) antipsychotics are first-line (e.g., risperidone, olanzapine, aripiprazole). Treatment-resistant: Clozapine after failure of two adequate antipsychotic trials. Maintenance: Continue antipsychotic at lowest effective dose + psychosocial interventions (CBT, family therapy, social skills training)
Keywords	"Thought insertion," "thought broadcasting," "auditory hallucinations commenting on behavior," "third-person voices," "delusion of control," "bizarre delusions," "flat affect," "social withdrawal," "deterioration in function," "negative symptoms"

1. Pathophysiology

Schizophrenia is a neurodevelopmental disorder with roots that likely begin long before the first psychotic episode. The prevailing model holds that a combination of genetic vulnerability and early environmental insults (prenatal infection, obstetric complications, childhood trauma) leads to aberrant brain development, particularly involving synaptic pruning during adolescence. This aberrant pruning, concentrated in the prefrontal cortex, tips a fragile system into clinical illness during the stress-sensitive period of late adolescence and early adulthood.

The dopamine hypothesis remains the most testable and most tested framework. It is not a single-pathway story but rather a tale of imbalance across four distinct dopaminergic tracts. Hyperactivity of the mesolimbic pathway (projecting from the ventral tegmental area to the nucleus accumbens) is responsible for positive symptoms: hallucinations, delusions, and disorganized thinking. This is the pathway that all antipsychotics target by blocking D2 receptors. Conversely, hypoactivity of the mesocortical pathway (projecting from the ventral tegmental area to the prefrontal cortex) produces negative symptoms (avolition, anhedonia, alogia, flat affect) and cognitive deficits (poor working memory, impaired executive function). This is why D2 blockade alone does not adequately treat negative symptoms, and why second-generation antipsychotics (which also modulate serotonin 5-HT2A receptors to indirectly release dopamine in the cortex) have a theoretical advantage for negative and cognitive symptoms.

Two other dopamine pathways explain the side effects of treatment rather than the disease itself. The nigrostriatal pathway (substantia nigra to caudate/putamen) regulates voluntary movement; blocking D2 receptors here produces extrapyramidal symptoms (EPS) such as dystonia, akathisia, parkinsonism, and tardive dyskinesia. The tuberoinfundibular pathway (hypothalamus to pituitary) tonically inhibits prolactin release; blocking it causes hyperprolactinemia with galactorrhea, amenorrhea, and sexual dysfunction.

Beyond dopamine, the glutamate hypothesis (NMDA receptor hypofunction) helps explain why phencyclidine (PCP) and ketamine, both NMDA antagonists, can produce a full spectrum of schizophrenia-like symptoms including negative and cognitive features, something that pure dopaminergic agents like amphetamine cannot do. Serotonergic dysfunction and GABAergic interneuron deficits also contribute to the final common pathway of cortical-subcortical dopamine imbalance.

Structurally, neuroimaging findings in schizophrenia include enlarged lateral ventricles, decreased cortical gray matter volume (especially in the prefrontal and temporal lobes), and reduced hippocampal volume. These findings are not diagnostic but help explain the clinical picture and are sometimes tested as associations.

2. Classification and Clinical Manifestation

The PPDGJ-III, based on ICD-10, preserves the classical subtypes of schizophrenia. This is an important distinction from the DSM-5, which eliminated subtypes. For exams referencing PPDGJ-III, you must know the subtypes and their hallmark features.

General Diagnostic Criteria (PPDGJ-III for F20)

Before diagnosing any subtype, the general criteria must be met:

Group 1 (at least ONE must be clearly present):

Criterion	Description
(a) Thought alienation	Thought echo, thought insertion, thought withdrawal, or thought broadcasting
(b) Delusions of control/passivity	Delusion of control, delusion of influence, delusion of passivity, or delusional perception
(c) Auditory hallucinations	Running commentary on the patient's behavior, two or more voices discussing the patient in the third person, or voices coming from a body part
(d) Persistent bizarre delusions	Culturally inappropriate and impossible beliefs (e.g., controlling the weather, communicating with aliens)

Group 2 (at least TWO must be present if Group 1 symptoms are absent or unclear):

Criterion	Description
(e) Persistent hallucinations	In any modality, occurring daily for weeks/months, accompanied by fleeting delusions or overvalued ideas
(f) Formal thought disorder	Breaks or interpolations in thinking leading to incoherence, irrelevant speech, or neologisms
(g) Catatonic behavior	Excitement, posturing, waxy flexibility, negativism, mutism, or stupor
(h) Negative symptoms	Apathy, poverty of speech, blunted or incongruent affect leading to social withdrawal (not due to depression or medication)

Duration requirement: Symptoms must be present for at least 1 month.

Additional requirement: There must be a consistent and meaningful change in overall quality of personal behavior (loss of interest, aimlessness, social withdrawal).

Subtypes

Code	Subtype	Key Features	Exam Pearl
F20.0	Paranoid	Prominent delusions (persecutory, grandiose, control) and/or auditory hallucinations. Affect, volition, and speech are relatively preserved. Catatonia is not prominent.	Most common subtype. Best prognosis among subtypes. Look for the patient who is suspicious, guarded, and hears threatening voices.
F20.1	Hebephrenic (Disorganized)	Prominent disorganized behavior and speech, shallow/inappropriate affect (giggling, grimacing). Onset typically 15-25 years. Hallucinations and delusions are present but not prominent. Requires 2-3 months of observation.	Worst prognosis. Premorbid personality often shy and solitary. The vignette patient who laughs inappropriately and has aimless behavior.
F20.2	Catatonic	Dominated by psychomotor disturbances: stupor, mutism, excitement, posturing, negativism, rigidity, waxy flexibility, automatic obedience, or command automatism.	If you see "waxy flexibility" or "posturing" in a vignette, think catatonic. Remember that catatonia can also occur in mood disorders and organic conditions.
F20.3	Undifferentiated	Meets general schizophrenia criteria but does not fit neatly into paranoid, hebephrenic, or catatonic.	Diagnosis of "close but not quite." The patient has mixed features that overlap subtypes.
F20.5	Residual	History of at least one clear psychotic episode. Currently dominated by negative symptoms (psychomotor slowing, blunted affect, passivity, poor self-care). Positive symptoms are minimal. Present for at least 1 year.	This is the "burned-out" schizophrenia vignette. No active hallucinations or delusions, but the patient is apathetic and withdrawn. Must rule out depression and chronic institutionalization.
F20.6	Simple	Insidious, progressive development of negative symptoms and behavioral decline WITHOUT prior overt psychotic episodes. No hallucinations or delusions precede the deterioration.	Hardest to diagnose. The vignette shows a slow decline in function and social engagement without a clear psychotic break. Often a diagnosis of exclusion.

2c. Course Specifiers (Fifth Character)

Code	Course
F20.x0	Continuous
F20.x1	Episodic with progressive deficit
F20.x2	Episodic with stable deficit
F20.x3	Episodic remittent
F20.x4	Incomplete remission
F20.x5	Complete remission
F20.x9	Observation period less than 1 year

3. Diagnostic Workup

Test	Role	What to Look For
Mental Status Examination (MSE)	Best initial and most important "test"	Hallucinations, delusions, thought disorder, negative symptoms, insight, judgment
Urine drug screen	Rule out substance-induced psychosis	Amphetamines, cannabis, PCP, cocaine
Thyroid function tests (TSH, free T4)	Rule out thyroid disorders mimicking psychosis	Hypothyroidism (psychosis), hyperthyroidism (agitation)
CBC with differential	Baseline before starting antipsychotics; rule out infection	Required for clozapine monitoring (ANC)
Basic metabolic panel, liver function	Rule out metabolic encephalopathy; baseline for metabolic monitoring	Electrolytes, glucose, renal function, liver enzymes
Brain CT or MRI	Rule out structural/organic causes (tumor, demyelination)	Not diagnostic for schizophrenia but may show enlarged ventricles or cortical atrophy as associations
EEG	If seizure disorder or delirium suspected	Rule out temporal lobe epilepsy
VDRL/RPR	Rule out neurosyphilis in appropriate clinical context	Tertiary syphilis can mimic psychosis
HIV testing	Rule out HIV-associated psychosis in at-risk patients

The diagnosis of schizophrenia is clinical. There is no blood test, imaging study, or biomarker that confirms it. The PPDGJ-III criteria (the general criteria in Section 2a above) are the gold standard diagnostic tool. Every laboratory and imaging investigation is ordered to exclude organic causes of psychosis, not to confirm schizophrenia.

The workup follows a logical hierarchy. First, obtain a thorough psychiatric history and perform a detailed mental status examination. This is where the diagnosis lives. Look for the characteristic symptoms from Group 1 and Group 2 of the PPDGJ-III criteria, and confirm the duration threshold of at least 1 month.

Second, order a urine drug screen early because substance-induced psychosis (particularly from amphetamines, cannabis, PCP, and cocaine) is the single most important differential to exclude before labeling someone with schizophrenia. A positive drug screen does not automatically exclude schizophrenia (comorbid substance use is common), but the temporal relationship between substance use and symptom onset must be clarified.

Third, obtain basic blood work including a CBC, metabolic panel, thyroid function, and liver function. These serve a dual purpose: ruling out metabolic and endocrine causes of altered mental status, and establishing a baseline before starting antipsychotic medication (particularly for metabolic monitoring of glucose, lipids, and hepatic function).

Fourth, obtain brain imaging (CT or MRI) at least once, particularly in a first episode, to rule out mass lesions, demyelinating disease, or other structural pathology. Do not expect the scan to "diagnose" schizophrenia. The enlarged ventricles and cortical changes seen in chronic schizophrenia are research findings, not clinical diagnostic criteria.

4. Management and Treatment

Phase	Treatment	Key Details
Acute psychosis (first-line)	Second-generation antipsychotic (SGA)	Risperidone 2-6 mg/day, olanzapine 10-20 mg/day, or aripiprazole 10-30 mg/day. Start low and titrate.
Acute psychosis (alternative)	First-generation antipsychotic (FGA)	Haloperidol 5-15 mg/day. Effective for positive symptoms but higher EPS risk.
Acute agitation	IM haloperidol + lorazepam, or IM olanzapine	For emergency behavioral control. Do not combine IM olanzapine and IM benzodiazepines (respiratory depression risk).
Treatment-resistant schizophrenia	Clozapine	After failure of 2 adequate antipsychotic trials (different agents, adequate dose, at least 6 weeks each). Start 12.5 mg/day, titrate to 300-450 mg/day. Target plasma level greater than or equal to 350 ng/mL.
Clozapine monitoring	CBC with ANC	Weekly for the first 6 months, biweekly for months 6-12, then monthly thereafter. Discontinue if ANC falls below 1,000/mm3 (below 1,500 in general population without benign ethnic neutropenia).
Maintenance	Continue effective antipsychotic at lowest effective dose	Minimum 1-2 years after first episode, often lifelong for recurrent episodes. Consider long-acting injectables (LAIs) for adherence issues.
Psychosocial	CBT, family psychoeducation, social skills training, supported employment	Always part of comprehensive management. Reduces relapse and improves function.

Acute Management. When a patient presents with an acute psychotic episode, the immediate priority is to ensure safety (for the patient and for others), establish a therapeutic alliance, and begin pharmacotherapy. Second-generation (atypical) antipsychotics are the recommended first-line agents because they carry a lower risk of extrapyramidal side effects and tardive dyskinesia compared to first-generation agents. Risperidone (starting dose 1-2 mg/day, target 2-6 mg/day), olanzapine (starting dose 5-10 mg/day, target 10-20 mg/day), and aripiprazole (starting dose 10-15 mg/day, target 10-30 mg/day) are common choices. The choice among these agents is largely guided by their side-effect profiles and the patient's comorbidities.

For the acutely agitated patient who is unable to take oral medication, intramuscular (IM) formulations are used. A common regimen is IM haloperidol 5 mg + IM lorazepam 2 mg. Alternatively, IM olanzapine 10 mg may be used. A critical safety point: do not administer IM olanzapine and IM benzodiazepines together due to the risk of severe respiratory depression, hypotension, and bradycardia.

An adequate antipsychotic trial is defined as treatment with a therapeutic dose for at least 4-6 weeks. If the first agent fails, switch to a different antipsychotic (ideally from a different chemical class). If two adequate trials with different antipsychotics have failed, the patient meets criteria for treatment-resistant schizophrenia (TRS), and the next step is clozapine.

Clozapine. This is the only antipsychotic with proven superiority in TRS. It is initiated at 12.5 mg once or twice daily and titrated slowly (typically by 25-50 mg/day every 1-2 days) to a target dose of 300-450 mg/day. The target trough plasma level is $\geq 350\ \text{ng/mL}$. Clozapine is not a first-line agent because of its side-effect profile, which includes:

Agranulocytosis (approximately 1% risk): the most dangerous side effect, requiring mandatory CBC monitoring with absolute neutrophil count (ANC). The monitoring schedule is weekly for the first 6 months, biweekly for months 6-12, and monthly thereafter.
Metabolic syndrome: weight gain, hyperglycemia, dyslipidemia (the most weight-gaining antipsychotic along with olanzapine).
Myocarditis and cardiomyopathy: rare but potentially fatal; monitor troponin and CRP in the early weeks of treatment.
Seizures: dose-dependent, occurring more frequently at doses above 600 mg/day.
Constipation / ileus: can be severe and life-threatening.
Sialorrhea (excessive drooling): paradoxically common despite anticholinergic properties.

Maintenance Therapy. After successful treatment of an acute episode, the antipsychotic should be continued for at least 1-2 years after a first episode and indefinitely (often lifelong) after a second or subsequent episode. Non-adherence is the leading cause of relapse in schizophrenia. For patients with poor adherence, long-acting injectable (LAI) antipsychotics are strongly recommended. Options include paliperidone palmitate (monthly or every 3 months), aripiprazole lauroxil (monthly or every 2 months), and haloperidol decanoate (every 4 weeks).

Psychosocial Interventions. Pharmacotherapy alone is insufficient. Evidence-based psychosocial treatments include cognitive behavioral therapy for psychosis (CBTp), family psychoeducation (which reduces relapse rates by teaching families to reduce expressed emotion), social skills training, and supported employment programs. These should be offered as part of a comprehensive treatment plan.

Contraindications and Cautions:

Olanzapine and clozapine should be used cautiously in patients with diabetes or metabolic syndrome.
Haloperidol and risperidone carry higher EPS and hyperprolactinemia risk.
QTc prolongation is a concern with ziprasidone; avoid in patients with cardiac conduction abnormalities.
In pregnancy, the risk-benefit analysis must consider that untreated psychosis carries its own risks. Haloperidol has the longest safety track record in pregnancy, though atypicals are increasingly used with monitoring.

5. Differential Diagnosis and Distractors

Differential	Why It Looks Similar	Key Discriminator
Brief Psychotic Disorder (F23)	Hallucinations, delusions, disorganized speech/behavior identical to schizophrenia	Duration is less than 1 month with full return to premorbid functioning. PPDGJ-III requires at least 1 month for schizophrenia.
Schizophreniform Disorder	Same symptoms as schizophrenia, same severity	Duration is 1-6 months. If symptoms persist beyond 6 months, the diagnosis is changed to schizophrenia. (Note: PPDGJ-III/ICD-10 does not use "schizophreniform" as a separate code; this is a DSM construct, but the temporal logic is testable.)
Schizoaffective Disorder (F25)	Has clear schizophrenia-like psychotic symptoms AND prominent mood episodes	In schizoaffective disorder, a full mood episode (manic or depressive) is present concurrently with schizophrenia criteria. In schizophrenia, mood symptoms may be present but are not prominent or do not meet full criteria for a mood episode.
Bipolar Disorder with Psychotic Features (F31)	Delusions and hallucinations can occur during manic or depressive episodes	Psychosis is confined to mood episodes. Between episodes, there are no psychotic symptoms. In schizophrenia, psychosis exists independent of mood state.
Substance-Induced Psychotic Disorder (F1x.5)	Amphetamines, cannabis, PCP, cocaine can produce hallucinations and paranoia identical to schizophrenia	Temporal relationship with substance use. Symptoms resolve with abstinence (typically within days to weeks). Urine drug screen is often positive.
Delusional Disorder (F22)	Persistent delusions lasting more than 1 month	Delusions are non-bizarre (plausible situations such as being followed, poisoned, or having a disease). Functioning is relatively preserved outside the delusional system. No prominent hallucinations, no formal thought disorder, no negative symptoms.
Psychotic Disorder Due to a Medical Condition (F06.0-F06.2)	Can present with hallucinations, delusions, catatonia	Evidence of an underlying organic cause (e.g., brain tumor, temporal lobe epilepsy, SLE, neurosyphilis, thyroid disorder, delirium). Onset may be acute. Altered consciousness is a red flag for organic etiology.
Schizotypal Disorder (F21)	Eccentric behavior, odd beliefs, social isolation, unusual perceptual experiences	Symptoms are subthreshold for psychosis. The patient has odd magical thinking and ideas of reference but does not have frank delusions or hallucinations. PPDGJ-III classifies this under F21, NOT as a personality disorder.

6. Traps and High-Yield Pearls

The most common way students get questions on schizophrenia wrong is by failing to enforce the duration criterion. A vignette describing psychotic symptoms for two weeks in an otherwise healthy young adult is not schizophrenia; it is a brief psychotic disorder. The one-month minimum per PPDGJ-III is non-negotiable. The test-writer is specifically checking whether you know this cutoff.

The second major trap involves confusing schizophrenia with schizoaffective disorder or mood disorders with psychotic features. The discriminating question you must ask yourself when reading a vignette is: "Does the mood episode and the psychotic episode exist at the same time, or does the psychosis stand alone?" If a patient has delusions and hallucinations that persist even when their mood is euthymic, that is schizophrenia (or schizoaffective if mood episodes are also prominent and concurrent). If the psychosis vanishes when the mood normalizes, that is a mood disorder with psychotic features.

Third, students frequently select clozapine as a first-line agent because they know it is the "best" antipsychotic. Clozapine is never first-line. It is reserved for treatment-resistant schizophrenia, defined by failure of at least two adequate trials of other antipsychotics. The exam loves to test this sequencing.

Fourth, remember that the PPDGJ-III retains the subtypes of schizophrenia, unlike DSM-5 which dropped them. For Indonesian licensing exams, you must be able to identify the subtype. Hebephrenic (disorganized) schizophrenia has the worst prognosis and the youngest onset. Paranoid schizophrenia is the most common subtype and has the best prognosis among the subtypes. The buzzwords "waxy flexibility" and "posturing" point directly to catatonic schizophrenia.

Fifth, never forget to rule out organic causes before diagnosing schizophrenia. A first psychotic episode in a patient over 40 years old, or psychosis with altered consciousness, seizures, or focal neurological signs, should raise your suspicion for an organic etiology, not primary schizophrenia.

The core competency being tested across all schizophrenia questions is threefold: (1) pattern recognition of the PPDGJ-III symptom groups and their duration threshold, (2) correct sequencing of the pharmacological algorithm from first-line SGAs through clozapine, and (3) disciplined differential diagnosis that hinges on duration, the presence or absence of mood episodes, and exclusion of organic and substance-induced etiologies.

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