Schizophrenia Disorders

1. Overview — What is Schizophrenia?

Schizophrenia is a complex and wide-ranging condition within the group of psychotic disorders, and is considered one of the psychiatric disorders that most profoundly affects daily functioning. It impacts multiple domains at the same time: thinking, perception, decision-making, emotion, behavior, and a person’s social roles. It is not merely “seeing or hearing things” as the general public often imagines, but rather a change in the functioning of multiple interconnected brain systems. This leads to significant disturbances in the ability to distinguish reality from thoughts, and in how one interprets the surrounding world.

By its nature, the illness typically develops gradually. It often begins with subtle symptoms that family members may not recognize as pathological, such as increased social withdrawal, reduced speech, irregular sleep patterns, poor concentration, or the impression that the person is “turning into a different person.” These precede clearer symptoms such as delusions, hallucinations, or markedly abnormal behaviors, which emerge during what is called an acute psychotic episode – the period in which the person begins to lose their ability to “test reality.”

The disorder involves multiple dimensions simultaneously, including:

Perceptual dimension – for example, hearing voices that are not actually there, or misinterpreting real events around them.

Cognitive/thought dimension – for example, believing that someone is following them, controlling them, or sending them special signals.

Emotional and motivational dimension – for example, not wanting to do anything, not feeling pleasure, or showing little emotional expression.

Executive thinking dimension – for example, being unable to plan, having difficulty making decisions, being unable to focus, or working very slowly.

Behavioral dimension – for example, engaging in odd or inappropriate behaviors, or moving in ways that are out of sync with the situation.

These disturbances in thinking and perception have a clear impact on functioning in life roles — such as education, work, or interpersonal relationships. Even though some symptoms improve after treatment, the “traces” of difficulties in motivation, memory, social cognition, or the ability to return to previous levels of functioning may persist for many years after the acute phase has subsided.

The illness does not follow a straight, linear course but tends to have a characteristic pattern consisting of several phases, including:

Premorbid phase – Personality starts to change; academic or work performance declines.
Prodromal phase – Mildly unusual thoughts emerge; anxiety increases; sleep becomes disturbed.
Acute psychosis phase – Prominent delusions, hallucinations, and disorganized thinking.
Recovery phase – Positive symptoms improve, but negative and cognitive symptoms may persist.
Residual phase – The person appears quiet, indifferent, and less engaged with surroundings, but prominent hallucinations are no longer present.
Relapse – Symptoms re-emerge, often triggered by severe stress, stopping medication, or substance use.

Although the public image of schizophrenia is often frightening, in reality many individuals can return to study or work if they receive appropriate treatment. Early intervention, especially starting in the prodromal or first-episode phase, can substantially improve the course of illness and reduce the risk of long-term social disability and severe relapses in the future.

Schizophrenia is not a disorder of “imagining things” or “mental weakness,” as some people believe, but a true brain disorder. This is supported by evidence from research on genetics, neurodevelopment, neurotransmitters (especially dopamine and glutamate), and brain connectivity networks. All of these indicate that the abnormalities arise from changes in biological systems, not from personality or environment alone.

In summary, schizophrenia is a chronic condition that affects multiple levels, from thoughts and perception to overall quality of life. However, it is a condition that can be managed if its nature is understood and if there is continuous care over the long term, including medication, psychotherapy, social support, and rehabilitation of daily living skills.

2. Core Symptoms — Main Symptom Clusters

Schizophrenia is not a disorder with a single isolated symptom; it is a “pattern of multi-dimensional abnormalities” that overlap and interact.

A disturbance in one brain system can impact another. For example:

Disorganized thinking → makes communication difficult → leads to social withdrawal.
Or negative symptoms → reduce work performance → increase stress → trigger a psychotic relapse.

Therefore, the core symptoms of this illness must be described as an “ecosystem of symptoms,” not by looking at any single feature in isolation.

Below is an expanded version of the Positive / Negative / Cognitive / Affective symptom clusters.
Reading it through gives a full picture of the clinical structure.

2.1 Positive Symptoms — Abnormal Experiences that Are “Added”

Positive symptoms are the most prominent during exacerbations (acute episodes).
“Positive” here does not mean “good”; it refers to experiences that are added to the person’s inner world — unusual perceptions, false beliefs, or behaviors that do not fit the context.

1) Delusions — Fixed False Beliefs

A delusion is a belief that arises without evidence and cannot be corrected, even when explained logically.
The person does not think they “believe something wrong”; they are convinced that their belief is “absolutely true.”

Common types include:

Persecutory delusion – believing that someone is trying to harm, follow, or plot against them.

Referential delusion – believing that news, events, or signals in the environment carry a special personal meaning aimed at them.

Grandiose delusion – believing they are special, possess supernatural powers, or have a world-saving mission.

Somatic delusion – believing their body is ruined, infested with animals, or contains foreign objects.

Erotomanic delusion – believing that someone they don’t know (often of higher status) is secretly in love with them, obsessed with them.

Control/passivity phenomena – believing that their thoughts or body movements are being controlled from the outside.

Delusions usually form a structured chain, for example:
“Just a bit suspicious” → “They’re probably spying on me” → “They installed a hidden camera” → “The government is targeting me.”

2) Hallucinations — Perceiving Things That Are Not Really There

Hallucinations in schizophrenia are not usually “dramatic visual ghosts” like in movies. In most cases they are voices (auditory hallucinations) that:

insult or criticize,
comment on the person,
command them to do certain things (command hallucinations),
or talk about them, as if multiple people are conversing inside their head.

Features suggesting psychotic hallucinations include:

The voices seem to have a distinct personality and intention.
The person experiences the voices as coming from outside their mind, not as their own thoughts.
Some individuals may have tactile or visual hallucinations, but these are less common in schizophrenia compared to auditory hallucinations.

3) Disorganized Thinking / Speech

This refers to abnormalities in the form of thought.
When thought cannot be organized, speech becomes fragmented and illogical.

Common patterns include:

Tangentiality – being asked about A but responding about B.
Loose associations – connections between ideas are so loose that the flow of conversation becomes hard to follow.
Derailment – abruptly changing topics without logical reason.
Clanging – speaking based on sound or rhyme rather than meaning.
Neologisms – inventing words that have no meaning to others.
Incoherence / word salad (in severe cases) – no discernible sentence structure at all.

Disorganized thinking is a key indicator that the person is losing the capacity for reality testing.

4) Disorganized Behavior

This is an abnormality in goal-directed behavior — actions are poorly organized or inappropriate to the situation, for example:

Wearing a thick winter coat in very hot weather.
Walking in circles repeatedly.
Suddenly shouting in a quiet place.
Laughing at a funeral.
Arranging objects in strange patterns, such as lining up water bottles in a long straight line for no apparent reason.

This usually occurs because disorganized thinking prevents them from evaluating what is appropriate in a given context.

5) Catatonia

Catatonia does not mean simply “standing still like a statue.” It is a cluster of motor abnormalities, such as:

Immobility – remaining extremely still.
Mutism – not speaking.
Posturing – holding odd positions for a long time.
Negativism – resisting instructions or attempts to be moved without clear reason.
Waxy flexibility – limbs can be moved into positions by someone else and remain there, as if made of wax.
Stereotypy – repetitive movements such as head shaking or lip biting.
Agitation – intense, purposeless excitement without clear cause.

Catatonia can occur in schizophrenia, mood disorders, and medical conditions.

2.2 Negative Symptoms — Things That Are “Missing or Reduced”

Negative symptoms are a major cause of long-term social disability.
They often persist even after positive symptoms improve, and are a key feature of the residual phase.

1) Avolition — Lack of Motivation

This is the feeling of “not wanting to do anything”, which is different from simple laziness.
Life goals become vague; even simple tasks like housework feel overwhelming. The person may not fight, persist, or move forward.
Some individuals struggle even to bathe, despite not being severely depressed.
This reflects dysfunction in motivational circuits, particularly the prefrontal–striatal pathway.

2) Anhedonia — Reduced Capacity to Experience Pleasure

Activities that used to be enjoyable — watching series, gaming, chatting with friends — become meaningless.
We distinguish between:

Anticipatory anhedonia – not expecting that they will enjoy something.
Consummatory anhedonia – actually doing the activity but not feeling pleasure.

Many patients show more anticipatory anhedonia, which leads them to avoid starting new activities.

3) Asociality — Social Withdrawal

This is not simply “disliking people,” but a combination of:

Not feeling the desire to engage.
Not believing that meeting others will be meaningful.
Not initiating conversations.
Not replying to messages.
Being silent in meetings or group settings.

It usually arises from emotional blunting, the high cognitive effort required for social interaction, and social cognition deficits.

4) Alogia — Reduced Speech

This can be divided into:

Poverty of speech – very few words, very short answers.
Poverty of content – speaking at length but conveying little meaningful information.
Thought blocking – thoughts suddenly stop mid-stream and the person becomes silent.

People around them often assume they “just don’t want to talk,” but in reality it reflects impaired thought processing.

5) Blunted / Flat Affect — Overall Flattening of Emotional Expression

This can be observed as:

A blank facial expression.
A monotonous voice without intonation.
Minimal emotional display.
Difficulty laughing.
Appearing indifferent even when facing intense events.

This does not mean there is no inner emotion, but rather that the expressive behavior system is reduced.

2.3 Cognitive Impairments — Thinking Difficulties

These are often the deepest and most chronic symptoms, and they strongly determine quality of life.
They may persist even when positive symptoms have resolved.
They involve the prefrontal cortex, hippocampus, and multiple brain connectivity networks.

1) Working Memory Deficit

This is difficulty “holding short-term information in mind for immediate use,” for example:

Being given three-step instructions but remembering only one.
Reading one page of text but failing to grasp the main idea.
Listening to someone speak but being unable to process what is said in real time.

It arises from reduced functioning of the prefrontal cortex.

2) Executive Dysfunction

This is difficulty “organizing thought and action,” such as:

Inability to plan.
Poor task sequencing.
Slow decision-making.
Getting stuck in repetitive thoughts, being unable to shift away from them.
Difficulty adapting to new situations.

The result is poor performance at school or work, even if overt psychotic symptoms have improved.

3) Attention & Processing Speed Problems

These are key contributors to:

Slow reading.
Difficulty keeping up in conversations or lectures.
Poor performance on tasks that require speed.
Frequent forgetting.

Because processing speed is reduced, all other cognitive skills tend to suffer as well.

4) Social Cognition Deficit

This is misinterpreting “other people’s intentions,” involving emotional perception and theory of mind. For example:

Not reading facial expressions correctly.
Not understanding jokes.
Believing others are angry when they are not.
Making social interactions feel awkward without realizing why.

This domain is crucial because it predicts how well someone can live and interact with others.

2.4 Affective Symptoms — Emotional Features that Often Co-occur

Even though schizophrenia is not classified as a mood disorder, many patients have co-occurring emotional disturbances, which tend to worsen the overall severity.

1) Depressive Symptoms

These are common:

In the early phases of illness.
During recovery phases.
After gaining insight into the illness (so-called “insight-gained depression”).

Symptoms include:

Sadness.
Lack of emotional energy or will.
Pessimism.
Feeling worthless.
Hopelessness about the future.

Depression in schizophrenia significantly increases the risk of self-harm and suicide.

2) Anxiety-related Symptoms

Anxiety in this disorder can arise from:

Abnormal brain mechanisms.
The side effects of hallucinations.
A sense of insecurity.
Confused and disorganized thinking.

Typical features include:

Worrying about being harmed.
Fear of people.
Fear of confined spaces or of leaving home.
Panic attacks.
Hypervigilance (being constantly on edge and watchful).

3) Irritability / Emotional Lability

This is increased emotional reactivity, leading to:

Irritability and being easily annoyed.
Poor emotional control.
Rapid mood shifts.

It is often associated with:

Stress.
Sleep deprivation.
The early stages of relapse (early warning signs).

3. Diagnostic Criteria — DSM-5-TR & ICD-11

This section explains the criteria in detail as if it were a guidebook for content creators and clinicians.
It first describes DSM-5-TR, then ICD-11, with context on how their approaches differ.

3.1 DSM-5-TR — Diagnostic Criteria for Schizophrenia (Detailed Explanation)

DSM-5-TR retains the overall structure of DSM-5 but refines wording and examples for clarity.
The core idea is that there must be:

Psychotic symptoms
Functional decline
Continuity of the illness over time
Exclusion of other causes

A. Core Symptoms (Active Phase): At Least 2 Symptoms for ≥ 1 Month

And at least one of the symptoms must be from 1–3.

The five key symptoms are:

Delusions
Hallucinations
Disorganized speech
Grossly disorganized or catatonic behavior
Negative symptoms (e.g., clearly diminished emotional expression or avolition)

Translating this into plain language:

There must be at least two of these five symptoms that are clearly present and significantly interfere with life.
The “active” symptoms must be present for about one full month or longer.
Among the two (or more) symptoms, at least one must be delusions, hallucinations, or disorganized speech (1–3).
If the person has only negative symptoms plus disorganized behavior, without
delusions/hallucinations/disorganized speech, this is not sufficient for a DSM diagnosis of schizophrenia.

Examples of clinical pictures that meet Criterion A:

A patient with persecutory delusions (believing someone wants to kill them) and auditory hallucinations (hearing voices insulting them) persistently for one month → Symptoms 1 and 2.
A patient with markedly disorganized speech (very tangential, hard to follow) and severe negative symptoms (avolition, flat affect) for one month → Symptoms 3 and 5.
A patient with delusions plus grossly disorganized behavior → Symptoms 1 and 4.

Points to be careful about:

The symptoms must be clinically significant, not just mild odd speech or unusual beliefs that still fall within cultural or religious norms.
It is essential to differentiate from mood episodes with psychotic features (e.g., a depressive episode with mild delusions that are clearly tied to depressive themes).

B. Marked Decline in Functioning in Major Areas of Life

Criterion text in essence:

Since the onset of illness, functioning in at least one major area of life has clearly declined compared to the level before the illness.
Major areas include:

Education.
Work.
Social relationships.
Self-care.

Rephrased:

It is not enough to just “have strange symptoms”; there must be clear impact on real-life roles.

Examples:

A student who used to get good grades starts skipping class, turning in assignments late, and failing multiple courses.
An employee who used to work full-time begins making frequent mistakes, missing work often, and gets put on leave or disciplined.
A person who used to be socially active cuts off friends, stops leaving their room, and avoids conversation.
Self-care deteriorates: not showering, not doing laundry, letting their living space become extremely messy.

If a patient “has psychotic symptoms but still functions well in all areas,” with no clear impairment, clinicians should consider other disorders or other psychotic categories that emphasize shorter duration rather than schizophrenia.

C. Continuous Signs of the Disturbance for ≥ 6 Months

This criterion distinguishes schizophrenia from:

Schizophreniform disorder (1–6 months).
Brief psychotic disorder (< 1 month).

Details:

There must be evidence of some sign of disturbance persisting for at least 6 months.
Within those 6 months, there must be at least approximately one month in which full active-phase criteria (Criterion A) are met.
The remaining time can be:

Prodromal phase: Milder symptoms such as negative symptoms, withdrawal, declining work/school performance, oddities, but not yet clearly psychotic.
Residual phase: Positive symptoms fade, but negative and cognitive symptoms remain.

Example timeline:

Months 1–2: Increasing withdrawal, disturbed sleep, declining performance (prodromal).
Months 3–4: Clear delusions and hallucinations (active episode).
Months 5–6: Delusions fade, but they still cannot return to school/work effectively, and still show flat affect, avolition (residual).

Total = continuous disturbance ≥ 6 months → meets Criterion C.

D–F. Rule Out Other Conditions

DSM-5-TR strongly emphasizes “Do not rush to label it schizophrenia before excluding other causes.”

D. Mood Disorders with Psychotic Features

If psychotic symptoms are present only during full major depressive episodes or manic episodes, the diagnosis is more likely mood disorder with psychotic features.
To diagnose schizophrenia, the pattern must be such that:

Psychotic symptoms are more prominent and longer-lasting than mood episodes; or
Psychosis occurs even when there is no clear mood episode for a significant period.

E. Substance / Medical Condition

We must ensure the symptoms are not due to:

Substances (e.g., amphetamines, cocaine, high-THC cannabis).
Certain medications (e.g., high-dose corticosteroids in some cases).
Medical conditions such as brain tumors, temporal lobe epilepsy, autoimmune encephalitis, delirium, etc.

If psychotic symptoms clearly resolve after discontinuation of the drug/substance for a sufficient period, the diagnosis should be substance/medication-induced psychotic disorder instead.

F. Pre-existing Neurodevelopmental Disorders (e.g., ASD)

If the person already had a diagnosis of Autism Spectrum Disorder or a communication disorder,
Schizophrenia should only be diagnosed if:

There are prominent and continuous delusions or hallucinations for at least one full month.

ASD itself can feature atypical communication, behavior, and social cognition, so we must be careful not to misinterpret these as psychosis without clear delusions/hallucinations.

Practical Overview of DSM-5-TR

A practical summary (but clinically usable) is:

At least two core psychotic symptoms, with at least one being delusions, hallucinations, or disorganized speech, for about one month.
Clear decline in functioning compared to pre-illness.
Continuous signs of illness for at least 6 months (including prodromal and residual phases).
Not just a mood disorder with psychotic features.
Not attributable to substances, medications, or medical conditions.
If ASD is present, there must be clear delusions/hallucinations to diagnose schizophrenia.

This is the “backbone” of schizophrenia diagnosis in DSM-5-TR.

3.2 ICD-11 — Schizophrenia (Code 6A20) in a New Perspective

ICD-11 uses a concept similar to DSM but structures the description somewhat differently.
Its focus is on:

Describing schizophrenia as a “pattern of symptom clusters and mental function impairment” rather than a strict checklist.
Removing the old subtypes (paranoid, hebephrenic, catatonic, etc.).
Introducing “symptom dimensions” and “pattern specifiers” to reflect the reality that the illness exists on a spectrum.

Core Idea of ICD-11 Schizophrenia (6A20)

1) Core Symptom Domains

There must be clear abnormalities across several domains (not just a single spot), such as:

Thought

Delusions.
Thought insertion / withdrawal / broadcasting.
Thought disorder.

Perception

Hallucinations (mostly auditory).

Self-experience

Feeling that thoughts, intentions, or movements are being controlled externally.
Feeling that one’s sense of self is abnormally altered.

Cognition

Attention, memory, social cognition.

Volition

Motivation, intention to engage in activities.

Affect

Appropriateness of emotion, emotional flattening.

Behavior

Odd, disorganized, or catatonic behaviors.

ICD-11 emphasizes that these abnormalities must be “clearly pathological” and result in functional impairment across multiple life domains.

2) Duration

Core symptoms must be clearly present for approximately at least one month.
ICD-11 does not insist on a rigid 6-month total duration like DSM-5-TR, but it still emphasizes continuity and clinically significant chronicity.

3) Functional Impairment

As with DSM, there must be evidence of impact on major life roles.
ICD-11 explicitly states that diagnosis should consider cultural, social, and value-system context.

ICD-11 and the Removal of Old Subtypes

In ICD-10, subtypes included:

Paranoid schizophrenia.
Hebephrenic (disorganized) schizophrenia.
Catatonic schizophrenia.
Residual schizophrenia.
Undifferentiated, etc.

ICD-11 removes all of these because of problems such as:

Low stability over time — people shifted between subtypes.
Limited value for prognosis.
Limited impact on treatment choices.

Instead, ICD-11 adopts a dimensional approach, looking at which symptom clusters are most prominent.

Pattern Specifiers / Symptom Dimensions in ICD-11

ICD-11 suggests using pattern specifiers to describe predominant symptom patterns, such as:

Predominantly positive symptoms

Main features: delusions, hallucinations, thought disorder.
Negative and cognitive symptoms may be present but are not leading.

Predominantly negative symptoms

Main features: avolition, anhedonia, asociality, alogia, blunted affect.
Positive symptoms may be mild or well-controlled by medication.

Mixed presentation

Positive, negative, cognitive, and affective symptoms are all clearly present.

With prominent depression

Depressive symptoms are clearly evident in the overall clinical picture,
but psychosis is not confined solely to depressive episodes.

With catatonia

Prominent catatonic symptoms are present.

These specifiers are not separate subtypes or different diseases, but additional labels that tell clinicians “what the overall pattern looks like right now.”

Philosophical Differences: DSM-5-TR vs ICD-11

DSM-5-TR

Emphasizes a clear checklist (A–F).
More strict about duration (≥ 6 months total course).
Useful for research and legal/insurance communication.

ICD-11

Emphasizes descriptive patterns of symptom clusters.
More flexible about duration while still requiring continuity and chronicity.
Adds pattern specifiers to capture symptom dimensions rather than subtype labels.

Shared core:

Clear psychotic symptoms are required.
Functional impairment is required.
Other causes (mood disorders, substances, medical conditions) must be excluded.
Emphasis on the course of illness, not just a short snapshot.

4. Subtypes or Specifiers

In current academic practice, the old subtypes have been abandoned. Instead, three layers are used:

Symptom Dimensions
Course & Phases
Specifiers (DSM-5-TR & ICD-11)

4.1 Category 1 — Symptom Dimensions

These are usable in both DSM and ICD-11, and are strongly supported by research. UpToDate+2WebMD+2

Positive Symptoms
Delusions / Hallucinations / Disorganized Thinking / Disorganized Behavior / Catatonia
→ Post series: explain real-life examples case by case + underlying brain circuits.

Negative Symptoms
Avolition / Anhedonia / Asociality / Alogia / Blunted Affect
→ Emphasize impact on quality of life and recovery (functional outcome).

Cognitive Impairments
Working memory / Executive function / Attention & Processing speed / Social cognition
→ Link to brain & neurobiology content + cognitive remediation.

Affective Symptoms
Depressive / Anxiety / Irritability
→ Serve as a bridge to comorbidities such as MDD, GAD, and substance use.

4.2 Category 2 — Course & Phases of Illness

floridabhcenter.org+2Resident 360+2

Premorbid Phase
Not yet clearly a disorder, but emerging personality and social patterns: withdrawal, becoming quieter, declining academic performance.

Prodromal Phase
Early mild oddities: suspicious thoughts, poor concentration, insomnia, behavioral changes.
Corresponds to concepts like “Attenuated Psychosis Syndrome / High-risk psychosis.”

Acute / Active Psychotic Episode
Clear delusions + hallucinations + disorganization.

Early Recovery Phase
Positive symptoms begin to improve after treatment, but residual symptoms remain, such as slowed thinking, poor concentration.

Late Recovery / Residual Phase
Negative and cognitive symptoms persist, making return to study/work difficult.

Relapse
Recurrence of symptoms after stopping medication, experiencing severe stress, or using substances.

4.3 Category 3 — Specifiers (DSM-5-TR & ICD-11)

DSM-5-TR Course Specifiers for Schizophrenia Resident 360+1

First Episode, Acute
First Episode, Partial Remission
First Episode, Full Remission
Multiple Episodes (Acute)
Multiple Episodes (Partial Remission)
Multiple Episodes (Full Remission)
Continuous
With Catatonia
Current Severity Specifier (uses a 0–4 rating for each symptom dimension)

ICD-11 Pattern Specifiers (Examples) FindACode+1

Predominantly Positive Symptoms
Predominantly Negative Symptoms
Mixed Presentation
With Prominent Depression
With Catatonia

This entire block is content at a meta level: “Why subtypes died and specifiers took over.”

4.4 Category 4 — Related & Overlapping Conditions (Schizophrenia Spectrum)

Empendium+1

Schizoaffective Disorder
Schizophreniform Disorder
Brief Psychotic Disorder
Delusional Disorder
Substance-Induced Psychosis (e.g., Cannabis-Induced Psychosis)
Psychosis due to Medical Conditions
Attenuated Psychosis Syndrome (APS) / High-Risk Psychosis

5. Brain & Neurobiology — Key Neural Mechanisms in Schizophrenia

Today, the research field views schizophrenia not as simply a “dopamine disorder,” but as a:

multisystem brain disorder involving abnormal brain networks and multiple interacting neurotransmitter systems—glutamate → GABA → dopamine—plus abnormal synaptic pruning, neuroinflammation, and disrupted resting-state networks.

The eight sections below represent the “core pillars” used by neuroscientists and psychiatrists to model the disorder today.

5.1 Dopamine Hypothesis 2.0 — Hyper/Hypo Activity in Distinct Neural Pathways

The original dopamine hypothesis stated, simply:

“Positive symptoms arise from excessive dopamine.”

The evidence: nearly all antipsychotics block dopamine D2 receptors, and drugs that strongly increase dopamine (e.g., high-dose amphetamines) can induce psychosis resembling schizophrenia.

The modern version (Dopamine Hypothesis 2.0) is more complex:

Mesolimbic Pathway – Hyperdopaminergia

Pathway: midbrain → ventral striatum (especially nucleus accumbens)

PET/SPECT studies show that people with psychosis have increased dopamine synthesis and release in the striatum.

Excess dopamine disrupts the salience attribution system, making ordinary stimuli appear highly meaningful → leading to delusions and hallucinations.

Mesocortical Pathway – Hypodopaminergia

Pathway: midbrain → dorsolateral prefrontal cortex (DLPFC)

Models suggest dopamine is too low in the PFC → resulting in:

impaired working memory
executive dysfunction (planning, decision-making, cognitive control)
prominent negative symptoms: avolition, alogia, blunted affect

Summary

Limbic system = high dopamine → positive symptoms
Prefrontal cortex = low dopamine → negative + cognitive symptoms

Today’s view: dopamine imbalance is a downstream effect of upstream abnormalities involving glutamate, GABA, synaptic pruning, hippocampal hyperactivity, etc.

5.2 Glutamate & NMDA Hypofunction — The “Upstream” Driver of Dopamine Abnormalities

Glutamate is the brain’s major excitatory neurotransmitter.
NMDA receptors are crucial for learning, plasticity, and circuit stability.

The NMDA hypofunction model proposes:

In schizophrenia:

NMDAR function is reduced in key prefrontal–hippocampal circuits.

PCP and ketamine—NMDA antagonists—can produce a syndrome in healthy individuals resembling schizophrenia including delusions, hallucinations, and cognitive deficits.

Circuit mechanism:

Most NMDARs in cortex sit on GABAergic interneurons.

If NMDARs on interneurons underperform →
interneurons cannot inhibit pyramidal neurons →
pyramidal neurons overfire and lose synchrony →
this dysregulated cortical output dysregulates midbrain dopamine →
producing mesolimbic hyperdopaminergia downstream.

Thus, glutamate/NMDA hypofunction is a plausible upstream cause of dopamine abnormalities.

5.3 GABAergic Dysfunction — Interneuron Failure → Network Desynchronization

GABA is the main inhibitory neurotransmitter.
Parvalbumin-positive (PV) interneurons regulate gamma oscillations (30–80 Hz) essential for:

perception
working memory
binding information across brain regions

Research finds:

reduced PV interneurons
reduced GAD67 expression
abnormal gamma oscillations in PFC and other networks

Functional impact:

The brain fails to synchronize its networks → connectivity becomes “loose” → resulting in:

working memory deficits
attention impairments
executive dysfunction

Modern models propose:

NMDA hypofunction on PV interneurons → GABAergic dysfunction → network synchrony failure → cognitive impairment → dopamine dysregulation.

This explains why GABA-targeted treatments are being explored for cognitive symptoms.

5.4 Synaptic Pruning Abnormalities — Excessive Pruning During Adolescence

During adolescence, the brain “prunes” unused synapses to refine networks.

Genetic studies show:

The complement gene C4 is strongly linked to schizophrenia risk.
Overexpression of C4A → excessive tagging of synapses for elimination.

Complement proteins + microglia “tag and remove” synapses.

If overactive → excessive synaptic pruning →
leading to reduced synapse density and cortical thinning in schizophrenia.

Functional impact:

Reduced prefrontal and associative cortex connectivity →
persistent cognitive impairment + negative symptoms.

This forms a bridge:

genetics (C4) → neurodevelopment (pruning) → anatomy (thinning) → symptoms (cognitive/negative).

5.5 Abnormal Connectivity & Hypofrontality — Underactive Prefrontal Cortex

The PFC (especially DLPFC) governs:

working memory
planning
decision making
cognitive control
social cognition

Findings in schizophrenia:

reduced PFC activity (“hypofrontality”)
reduced blood flow/metabolism
abnormal connectivity with thalamus, striatum, hippocampus

These contribute to:

negative symptoms
cognitive deficits

Dysconnectivity in prefrontal–subcortical networks may also relate to long-term antipsychotic effects and gradual gray matter loss.

5.6 Hippocampal Hyperactivity — Overactive Hippocampus Drives Dopamine

The hippocampus regulates:

episodic memory
context processing
outputs to amygdala, hypothalamus, striatum

Findings in schizophrenia:

reduced hippocampal volume
abnormally high resting activity (hyperactivity)
especially in the anterior hippocampus/subiculum

Circuit model:

Hippocampal hyperactivity → overstimulation of ventral striatum →
ventral striatum pushes midbrain dopamine neurons →
mesolimbic hyperdopaminergia → positive symptoms.

In high-risk/prodromal groups, hippocampal hyperactivity often appears before full psychosis.

5.7 Default Mode Network (DMN) Dysfunction — Abnormal “Self-Processing” Network

DMN includes:

medial prefrontal cortex
posterior cingulate/precuneus
inferior parietal lobule

Functions:

self-referential thinking
mind-wandering
internal narrative

In schizophrenia:

DMN hyperactivation
abnormal connectivity within DMN and between DMN & control/visual networks

Clinical consequences:

intrusive self-focused thoughts
difficulty shifting attention outward
increased self-referential delusions
hallucinations with self-critical content
disorganized thoughts

Different DMN patterns correlate with:

positive-symptom-dominant cases
disorganization-dominant cases
treatment-resistant psychosis

5.8 Neuroinflammation & Microglia — Micro-Level Brain Inflammation

Evidence includes:

altered cytokines (IL-6, IL-1β, TNF-α, IL-17, IL-23)
microglial activation on PET imaging
Th17 pathway involvement
blood–brain-barrier instability

Possible roles:

During development:

Maternal infection → cytokine surge → altered neural proliferation, migration, synapse formation.

During adolescence:

Overactive immune tagging → excessive synaptic pruning (C4 model).

During adulthood:

Chronic low-grade inflammation → dysregulated dopamine/glutamate → treatment resistance and cognitive decline in some individuals.

Overall, schizophrenia increasingly appears to involve immune–synaptic–neurotransmitter–network interactions, not a single pathology.

5.9 Summary: Molecules → Cells → Circuits → Symptoms

Putting all eight together:

Genetics / Neurodevelopment

C4, NMDAR, GABA, dopamine genes → abnormal pruning + NMDAR hypofunction

Cellular / Neurotransmitters

NMDAR dysfunction on interneurons → GABA failure → network oscillation abnormalities
Hippocampal hyperactivity → striatal dopamine excess
Mesocortical dopamine deficit → hypofrontality

Network-Level

DMN hyperactivity → self-referential delusions
Prefrontal–thalamic–striatal dysconnectivity → executive/motivation deficits

Immune / Inflammation

Cytokines, microglia, complement → long-term shaping of neural circuits

Clinical Outcome

Positive symptoms
Negative symptoms
Cognitive impairments
Affective symptoms

6. Causes & Risk Factors — Why Are Some People More Vulnerable?

6.0 Big Picture: No Single Cause — Only Interacting Systems

Schizophrenia arises from:

genes + neurodevelopment + environment + immune/inflammatory factors

Each factor adds risk, not destiny.
The more vulnerabilities + life stressors → the higher the probability of psychosis.

This is captured in:

Stress–Vulnerability Model
Diathesis–Stress Model
Sociodevelopmental Model

Risk = Vulnerability × Stress

6.1 Genetic Factors — Unequal Vulnerability From Birth

Heritability

Twin studies: heritability ~70–80%.

Risk levels:

General population: ~1%
One parent with schizophrenia: ~10%
Both parents: ~40%
Identical twins: high concordance but not 100% → environment matters.

Polygenic Risk

No single gene causes schizophrenia.
Hundreds of small-effect variants across:

synaptic genes
dopamine/glutamate-related genes
immune/complement genes

Complement C4

C4A overexpression → excessive synaptic pruning → cortical thinning.

Rare Variants / CNVs

E.g., 22q11.2 deletion → dramatically increased psychosis risk.

Genetics = baseline vulnerability.

6.2 Obstetric Complications — Pregnancy & Birth Factors

Examples:

prolonged labor
perinatal hypoxia
preterm birth
low birth weight
maternal complications (preeclampsia)

These affect neural proliferation, migration, and early wiring.

Combined with genetic vulnerability → risk increases.

6.3 Prenatal Infection / Inflammation

Maternal infection (influenza, rubella) and elevated cytokines (IL-6, IL-8, CRP) correlate with increased schizophrenia risk.

Mechanism:
Maternal immune activation → cytokines reach fetus → alter neural development → increase vulnerability emerging in adolescence.

6.4 Childhood Trauma

Strong evidence links:

physical abuse
sexual abuse
emotional neglect
chronic family chaos
severe bullying

with elevated psychosis risk (dose–response relationship).

Mechanisms:

HPA-axis dysregulation
epigenetic changes
stress sensitization

Trauma does not cause psychosis alone, but magnifies risk in already vulnerable individuals.

6.5 Urbanicity — Growing Up in Cities Raises Risk

Meta-analyses: urban upbringing → ~2× risk of schizophrenia.

Factors include:

social fragmentation
isolation
pollution
noise + environmental stress
inequality + chronic social comparison
community disconnection

6.6 Migration & Minority Stress

Migrants and ethnic minorities show significantly higher psychosis rates.

Not due to “ethnic genetics,” but due to:

discrimination
racism
social defeat
chronic stress
lack of belonging

This chronic psychosocial stress disrupts dopaminergic and threat-detection circuits.

6.7 Cannabis / Substance Use

Evidence is consistent:

Cannabis risk increases with:

early onset of use
frequent use
high-THC strains

In high-genetic-risk individuals, cannabis is a strong trigger.

Other substances (amphetamine/meth/cocaine) can directly produce psychosis.

6.8 Stress–Vulnerability & Sociodevelopmental Model

Vulnerability

genetics (polygenic, CNVs, C4)
obstetric/neurodevelopmental insults
early neuroinflammation

Stress Load

trauma
urbanicity
migration/minority stress
substance use
chronic life stress

Neurobiological Response

HPA overactivation
inflammation
dopamine/glutamate imbalance
abnormal pruning
dysconnectivity

Threshold

When cumulative stress exceeds a person’s vulnerability threshold → psychosis emerges.

Protective Factors

supportive family
safe community
early intervention
avoidance of substances
healthy coping skills

Genes set the stage; environment writes the script.

6.9 Summary

Schizophrenia emerges from multilayered interactions:

Genetics → baseline vulnerability
Neurodevelopment → altered wiring
Environment → chronic stressors
Immune/Inflammation → circuit shaping
Substances → triggers

7. Treatment & Management

7.1 Antipsychotic Medications

First-Generation Antipsychotics (FGAs)

haloperidol, chlorpromazine
strong D2 blockade
effective for positive symptoms
higher EPS & tardive dyskinesia risk

Second-Generation Antipsychotics (SGAs)

risperidone, olanzapine, quetiapine, aripiprazole
fewer EPS, but more metabolic effects

Clozapine for Treatment-Resistant Schizophrenia

most effective for TRS
reduces suicidal risk
requires close monitoring (agranulocytosis/metabolic)

Long-Acting Injectables (LAIs)

useful for adherence
reduce relapse

7.2 Psychosocial & Cognitive Interventions

CBT for Psychosis

Helps patients reinterpret delusions/hallucinations, reduce distress.

Family Psychoeducation

Reduces high expressed emotion → lowers relapse.

Cognitive Remediation

Trains memory, attention, executive skills → improves functioning.

Social Skills Training

Improves conversation skills, social cues, role-playing.

Supported Employment/Education

IPS model → helps patients work/learn with real-world support.

Early Intervention in Psychosis (EIP)

Comprehensive team care during first-episode → best long-term outcomes.

8. Notes — Real-Life Functioning, Comorbidity & Social Challenges

8.1 Comorbidity & Special Problems

Depression

Very common during early psychosis and residual phases.

Anxiety

GAD, panic, social anxiety may overlap.

Suicide Risk

Highest during:

first episode
post-hospital discharge
after gaining insight into illness

Substance Use

Worsens symptoms and relapse rates.

Metabolic Syndrome

Monitor weight, BMI, glucose, lipids.

Cognitive Decline vs Negative Symptoms

Differentiate “can’t do” (cognitive) vs “don’t feel like doing” (negative).

8.2 Functional & Social Topics

Social functioning: forming & maintaining relationships
Occupational functioning: returning to work/school
Insight deficits: not recognizing illness → treatment refusal
Stigma: affects family, work, community
Family burden: emotional, financial, time costs
Independent living skills: money, home, appointments

📚 References

Diagnostic & Criteria

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR). Washington, DC.
World Health Organization. International Classification of Diseases, 11th Revision (ICD-11): Schizophrenia and other primary psychotic disorders.
Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet. 2016;388(10039):86–97.
Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia “just the facts” series. Schizophrenia Research.

Symptom Dimensions & Course

Insel TR. Rethinking schizophrenia. Nature. 2010;468:187–193.
van Os J, Kapur S. Psychosis: a comprehensive perspective.
McCutcheon R, et al. The psychosis continuum: mechanisms and clinical implications.
Addington J, et al. Prodromal symptoms and early course of schizophrenia.

Neurobiology (Dopamine/Glutamate/GABA/Connectivity)

Howes OD & Kapur S. The dopamine hypothesis of schizophrenia: version III. Schizophrenia Bulletin.
Coyle JT. NMDA receptor and glutamate hypotheses of schizophrenia.
Lewis DA, et al. GABAergic interneuron dysfunction in schizophrenia.
Grace AA. Hippocampal dysregulation of dopamine system function.
Stephan KE, et al. Dysconnectivity hypothesis of schizophrenia.
Whitfield-Gabrieli S, et al. Default Mode Network abnormalities in schizophrenia.

Genetics & Synaptic Pruning

Sekar A, et al. Schizophrenia risk from increased complement C4A expression. Nature 2016.
Ripke S, et al. Genome-wide association studies (GWAS) of schizophrenia.
Purcell SM, et al. Common polygenic variation contributes to schizophrenia.
Kirov G. CNVs and schizophrenia.

Risk Factors & Environmental Influences

van Os J, Kenis G, Rutten BPF. The environment and schizophrenia. Nature.
Vassos E, et al. Urbanicity as a risk factor for schizophrenia: meta-analysis.
Arseneault L. Childhood trauma and risk for psychosis.
Cantor-Graae E, Selten JP. Migration and schizophrenia risk.
Moore THM, et al. Cannabis use and psychosis risk.

Treatment & Management

Kane JM, et al. Clozapine for treatment-resistant schizophrenia.
Leucht S, et al. Comparative efficacy of antipsychotics.
Wykes T, et al. Cognitive remediation in schizophrenia.
Dixon LB, et al. Psychosocial interventions in schizophrenia.

Neuroinflammation / Immune Pathways

Müller N. Inflammation and schizophrenia.
Khandaker GM, et al. Immune system and psychosis.

Schizophrenia, Psychotic Disorders, Positive Symptoms, Negative Symptoms, Cognitive Impairments, Delusions, Hallucinations, Disorganized Thinking, Catatonia, Prodromal Phase, First Episode Psychosis, Neurobiology, Dopamine Hypothesis, NMDA Hypofunction, GABA Dysfunction, Synaptic Pruning, Microglia, Neuroinflammation, Genetic Risk, Environmental Risk Factors, Cannabis and Psychosis, Urbanicity, Childhood Trauma, Brain Connectivity, Schizophrenia Treatment, Antipsychotics, Clozapine, CBT for Psychosis

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