Attenuated Psychosis Syndrome (APS) / High-Risk Psychosis

1) Overview — What is Attenuated Psychosis Syndrome (APS) / High-Risk Psychosis?

Attenuated Psychosis Syndrome (APS) is a condition in which a person begins to develop mild (subthreshold) psychotic or schizophrenia-like symptoms — not full-blown psychosis, but an early warning sign that the brain’s reality-processing system is “starting to wobble” in some respects. 

For example, they may start to hear faint sounds but cannot tell where they come from, begin to feel that someone is watching them but still hesitate whether this is real or just thoughts in their own head, or begin to speak in a slightly disorganized way while still being able to maintain a conversation to some degree. These abnormalities are therefore classified as mild positive symptoms or attenuated positive symptoms, which are the direct hallmark of this condition.

In DSM-5, APS is placed in Section III: Conditions for Further Study, meaning that even though it has a clear symptom pattern and is indeed seen in real-world clinical practice, it has not yet been elevated to a “full official medical diagnosis.” This is because more empirical data are still needed — regarding the stability of diagnostic criteria, treatment outcomes, and the long-term course in these patients. However, this “still under study” status does not mean APS is unimportant — on the contrary, it is one of the topics the early psychosis field is most interested in, because it represents a critical window in which early intervention can dramatically reduce long-term impact.

DSM-5-TR sharpens the criteria for APS by removing the phrase “relatively intact reality testing” and shifting the emphasis to the severity level of symptoms, specifying that they must be attenuated forms of delusions, hallucinations, and disorganized speech in particular. This change reflects the fact that, although individuals with APS may still retain some degree of insight, research has shown that insight in early psychosis can change very rapidly. Therefore, the criteria must rely on features that can be measured and are more stable.

In early psychosis research and clinical services, broader terms are used, such as Clinical High Risk for Psychosis (CHR-P), Ultra High Risk (UHR), and At-Risk Mental State (ARMS), which refer to people at high risk of progressing to full-blown psychosis, usually via one of the following pathways:

• Having mild positive symptoms (attenuated positive symptoms)

• Having had a brief, acute psychotic episode that remitted back to baseline (Brief Intermittent Psychotic Symptoms – BIPS)

• Having high genetic risk combined with deterioration in academic or occupational functioning (Genetic Risk and Deterioration – GRD)

The CHR-P group is typically adolescents or young adults, a period during which the brain is undergoing intense neurodevelopment, especially synaptic pruning and rebalancing of the dopamine–glutamate–GABA circuits. This makes it the most sensitive developmental window for the emergence of psychosis-spectrum symptoms. Many people in this group present to clinicians because they start to feel that “something is not quite right,” such as finding it harder to distinguish their thoughts from reality, experiencing subtle perceptual distortions, or starting to interpret events in over-connected, overly meaningful ways. All of these are early warning phenomena, not full psychosis.

A crucial point to emphasize is that APS does not mean that a person is destined to become psychotic. Large meta-analyses worldwide show that the probability of transition from CHR-P to full psychosis within 2–3 years is only about 20–25%. In other words, more than 75% do not develop psychosis, even though they have mild psychosis-like symptoms. However, those who do not transition still have an elevated risk of other mental health problems, such as depression, anxiety, PTSD, mild negative symptoms, or chronic functional impairment.

Therefore, APS is a neuropsychiatric warning sign that the reality-perception system is losing balance, but we are still within a time window where psychological care and non-pharmacological interventions (e.g., CBT-CHR, family intervention, stress reduction, sleep regulation) can genuinely alter the long-term trajectory — both by reducing distress and lowering the chance of developing severe psychosis.

APS is thus viewed as an opportunity window in psychosis prevention and is central to early psychosis programs that aim to help individuals return to a stable life, free from unnecessary stigma and free from the side effects of unnecessary treatments such as premature antipsychotic use at stages where they may not yet be appropriate.

If we compress it to the shortest form: APS is an early sign of a treatable disturbance in reality perception, with a high chance of improvement, and understanding it early is a key to preventing future psychosis.

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2) Core Symptoms — The Central Features of APS / High-Risk Psychosis

The core of APS / CHR-P is:

“Mild psychotic symptoms (attenuated positive symptoms) + a certain degree of life disruption.”

It is not just about whether there are hallucinations or delusional thoughts; we also look at “how mild they are” and “how much they actually affect real life.”

We’ll go through each symptom cluster:

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2.1 Attenuated Delusions — “Halfway” Delusional Beliefs

Full delusion = a belief that is clearly false, held with strong conviction, and not changed even in the face of clear contradictory evidence. For example, believing that the CIA has installed cameras in one’s house even though there is no evidence whatsoever and refusing to accept any alternative explanation.

An attenuated delusion in APS looks similar in content but is “dialed down” roughly as follows:

• There is still inner hesitation, such as:
• “I feel like people in the office are talking about me all the time… but I’m not sure if I’m just overthinking it.”
• “It’s like the news on TV is sending me some kind of message… I don’t know if it’s really true or I’m just too sensitive.”

• Patients often speak in terms like “I feel like…,” “Maybe…,” “I’m not sure…”, rather than asserting things 100% like in a full delusion.

• When confronted with contrary evidence, such as friends saying no one is talking about them, they may still respond:
• “Yeah, maybe you’re right… but I still feel weird about it.”

Key points:

• The content really resembles delusions, such as:
• Persecutory (“They probably don’t like me,” “It feels like they’re watching me.”)
• Referential (“This song in the shop feels like it’s being played just for me.”)
• Mild grandiose ideas (“I feel like I was born for something very special, but I can’t explain it yet.”)

• But the level of conviction is not 100% — they can still argue with themselves, still doubt themselves.

• The symptoms cause real distress, such as stress, insomnia, reluctance to go to work because of fear of being watched.

• They affect life, for example:
• Starting to avoid people
• Being afraid to speak up in meetings
• Being afraid to use social media

Clear clinical examples:

• A university student who begins to avoid their friend group because:
• “I feel like they’re sending hidden signals to each other in the chat, but I don’t know if I’m imagining it.”

• An office worker who feels that

• their boss is “playing mind games” with them, yet still says:

• “Maybe it’s just me overthinking it, but it really doesn’t feel okay.”

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2.2 Attenuated Hallucinations — Perceptions That Feel Almost Real, But Not Quite

Full-blown hallucination = perceiving something that does not actually exist in the external world, created entirely by the brain, with “100% realism.” For example, clearly hearing a voice insulting them when nobody is there.

In APS / CHR-P, this shows up in a softer, more ambiguous form:

• Hearing faint sounds or whispers and not being sure where they come from, such as:
• Feeling like someone is calling their name from behind, but when they turn around there is no one.
• Hearing something that sounds like whispers, but the content is unclear.
• Seeing human-like shadows or dark shapes out of the corner of the eye; when they turn to look, nothing is there.

• When asked “What do you think it is?” they often answer:
• “I really don’t know if I’m just imagining it, or if there’s something wrong with my ears, or what exactly is going on.”

How this differs from full hallucinations:

• The vividness is lower:
• The sound may not be as clear as an actual person’s voice.
• The image might just be a silhouette or outline, not a clearly formed person.

• The degree of belief in its reality is not 100%:
• There is still mental space for, “Am I just going crazy?” or “Is this just my imagination?”

• They often occur under conditions of fatigue, stress, or sleep deprivation, but with a high enough frequency to be noticeable:
• For example, occurring every week, at least several times per month.

If this continues without addressing risk factors / stress / substance use / sleep, these phenomena can gradually solidify into full-blown hallucinations in a subset of people.

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2.3 Attenuated Disorganized Speech / Thinking — Thought Processes Start to “Come Loose,” But Not Completely Fall Apart

In full psychosis, disorganized thinking can reach the point where sentences lack structure, are incomprehensible, and topics change without any logical connection.

In APS / CHR-P, we usually see a “downgraded” version, such as:

• The person can tell a story, but loses the main point very easily.

• When they talk, it often becomes long-winded, tangential, overly detailed with a lot of unnecessary information.

• The listener has to repeatedly “pull them back,” saying things like:
• “You were just talking about A, right? How is that related to B again?”

• The person themselves may feel that:
• “Lately I feel like my thoughts aren’t very organized. When I speak, I can’t really grasp my own main point.”

Real-life examples:

• Answering a simple question but taking a long detour with multiple loops, leaving the listener confused.

• Switching topics quickly with no connecting sentences, such as:
• Starting with talking about work → jumping to climate change → to politics → then back to complaining about a co-worker, while the listener cannot detect a clear pattern.

In early psychosis clinics, tools like SIPS / CAARMS are used to rate:

• The continuity of thought (goal-directedness)

• Levels of tangentiality, derailment, loosening of associations

• The ability to return to the original topic

The key point: this is not yet at the level of “word salad” or “completely incomprehensible answers,” but after interviewing for a while, you clearly sense that the person’s thought process is becoming “looser” than that of the general population.

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2.4 Negative Symptoms & Functional Decline — The “Baseline” of Life Starts to Drop

Although the term APS focuses primarily on positive symptoms, in real life:

• This group often also has negative symptoms plus functional decline.

Common negative symptoms:

• Asociality
• Not really wanting to talk to anyone
• Avoiding friends / social activities, even though they used to be okay with them

• Avolition
• Lacking the internal “starter motor”
• “I know I should do it, but I just don’t have the drive to start.”

• Anhedonia
• Activities that used to be fun → now feel flat or indifferent

• Blunted affect
• Facial expressions, eye contact, and tone of voice become more flat
• People around might say: “You don’t look as lively as before.”

Functional decline = extremely important in CHR-P:

• Grades clearly dropping over the past 6–12 months
• Increased absenteeism from work or school
• Work performance drops enough that supervisors comment
• Relationships with family, friends, or partners become more distant

Some cases may not have prominent positive symptoms but show this pattern:

“In the past, they had good grades, friends, and hobbies. Now, their grades are down, they don’t want to meet anyone, and all they can say is: ‘I feel like my brain isn’t the same anymore.’”

Within the CHR-P framework, where the criteria Genetic Risk + Deterioration (GRD) are used, this functional decline is precisely what is used as a “risk filter” alongside genetic vulnerability.

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2.5 Insight Is Still Present — And This Is Why They Can Come for Help

Unlike full-blown psychosis where patients often “believe without question” that what they perceive is 100% real:

• In APS / CHR-P, most people still retain some degree of insight.

• They might say things like:
• “I’m afraid I’m going crazy.”
• “I’m not sure if what I’m seeing is real or just in my head.”

This feeling of “being afraid of losing their mind” is often what pushes them to go to the hospital or see a psychiatrist.

This level of insight matters in two major ways:

• It is evidence that the symptoms are still in the attenuated zone.

• It opens the door to psychological interventions working well, such as CBT-CHR (because if there is no insight at all, therapy becomes much harder).

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3) Diagnostic Criteria — How Are APS / High-Risk States Diagnosed?

This section can be split into two major frameworks:

• DSM-5 / DSM-5-TR: Attenuated Psychosis Syndrome (APS)

• CHR-P / UHR criteria used in research and specialized early psychosis clinics

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3.1 DSM-5 / DSM-5-TR: Attenuated Psychosis Syndrome (APS)

APS is in Section III: Conditions for Further Study — it is not yet part of the “main diagnostic chapter,” but is a condition DSM is proposing for the medical field to monitor and study further.

Core elements of the criteria:

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A) Presence of at least one “attenuated” psychotic symptom

Three symptom groups to consider:

• Delusions (attenuated)
• Hallucinations (attenuated)
• Disorganized speech (attenuated)

The term attenuated here does not just mean “a bit milder” but includes:

• Severity: lower than full-blown psychosis
• Frequency: not yet chronic-level
• Impact: not yet causing reality testing to completely collapse, but already affecting real life

It does not mean “just overthinking.”
They must be symptoms that a clinician can clearly see as “fitting the psychotic phenomena framework, but milder than full-blown.”

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B) Symptom frequency — Not just a one-off blip

APS does not apply to cases like:

• Hearing a voice once after 3 nights without sleep
• Seeing a “ghost” once while acutely stressed and never again

The criteria specify that:

• Symptoms must occur at least once a week,
• Continually for approximately the past month or more.

Reason:

• To capture people whose symptoms are “forming a base” in daily life
• To exclude “noise” — transient phenomena from acute stress or a single substance use episode that disappears completely.

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C) Onset / Worsening — It must be a recent change, not something lifelong

The criteria look for:

• Symptoms that have newly emerged

or

• Symptoms that were already there in some form but have clearly worsened in the past 1 year.

Clinicians will be interested in questions like:

• “Before this past year, have you ever had such unusual thoughts or perceptions?”
• “Over the last year, what has changed? How much worse has it become?”

Reason:

• To capture the “prodromal period”
• To differentiate from people who have always had unusual traits but remain stable over a lifetime (e.g., schizotypal personality).

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D) Distress / Impairment — Not just having symptoms, but life actually deteriorates

APS is not only about “Are there symptoms?” but also about:

“To what degree are these symptoms ruining your life?”

There must be at least one of:

• Clear subjective distress, such as severe anxiety, stress, insomnia, feeling hopeless.

• Decline in study performance, work performance, or relationships, for example:
• Frequently missing school or work because they are afraid to leave the house due to feeling watched.
• Inability to finish tasks because their concentration is hijacked by the idea that someone is spying on them.

This principle is crucial:

• DSM wants APS to apply to cases that “actually warrant clinical attention,”
• Not to label people who merely have unusual experiences but no negative impact on life.

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E) Exclusion — Rule out other disorders and causes

APS is a diagnosis that should only be used after the following have been “cleared”:

• Mood disorder with psychotic features
• If psychotic symptoms occur only during severe depression or mania → it may be a mood disorder, not APS.

• OCD, PTSD, ASD, and other conditions that make thoughts/perceptions seem odd but are not true psychosis, such as:
• Intrusive thoughts in OCD
• Flashbacks in PTSD

• Substance / medical condition
• Drugs, steroids, delirium, epilepsy, etc.

And importantly:

• The person must never have previously met criteria for a full psychotic disorder (e.g., Schizophrenia, Schizoaffective, Brief Psychotic Disorder, etc.).

APS = the zone before entering a psychotic disorder.
It is not a label for people who have already had full-blown psychosis.

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Status of APS in DSM

To remember it easily:

• It is in Section III = Conditions for Further Study

This means:

• DSM is essentially saying:
• “We have reasons to believe this syndrome exists and is clinically important,”

• But we are not yet ready to declare it a full disorder because:

• We still need to prove how accurate the current criteria are in predicting long-term outcomes,
• And we need to be careful that labeling does not create more fear or stigma than benefit.

In practice:

• Some early psychosis clinics use the APS / CHR-P concept to design care.

• But they may not use “APS” as an official diagnosis in the medical record (depending on country/system/professional guidelines).

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3.2 Clinical High Risk for Psychosis (CHR-P) / UHR Criteria

For research and specialized early psychosis clinics, the terms CHR-P / UHR are even more important than APS because:

• They are used to select study cohorts,
• And to design monitoring and prevention programs for psychosis.

Main tools:

• SIPS (Structured Interview for Psychosis-Risk Syndromes)
• CAARMS (Comprehensive Assessment of At-Risk Mental States)
• Newer harmonized standard: PSYCHS, which attempts to unify these two approaches.

Both SIPS and CAARMS assess in great detail:

• Unusualness of thoughts
• Unusualness of perceptions
• Duration and frequency of symptoms
• Level of conviction / distress / functional impact
• Family history of psychosis and degree of functional decline

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CHR-P / UHR divides people into three main groups

1) Attenuated Positive Symptom Syndrome (APSS)

• This group is the closest to APS as described in DSM.

Summary of key features:

• They have attenuated positive symptoms (delusion-like, hallucination-like, disorganized speech that is not yet full).

• Symptoms began within the past year, or clearly worsened during the past year.

• Frequency and severity reach the threshold defined by the rating scales (e.g., scores ≥ threshold in SIPS/CAARMS).

• They cause distress or functional impairment.

This is the “classic” high-risk psychosis group in modern psychiatric imagery.

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2) Brief Intermittent Psychotic Symptoms (BIPS)

• This group has previously had full psychotic symptoms, such as:
• Clear hallucinations
• Clear delusions

• But the pattern is:
• Very short duration (e.g., only a few days),
• And they remit on their own (spontaneous remission).
• They do not yet meet the duration requirement for a full psychotic disorder (such as Schizophreniform Disorder, which requires ≥ 1 month).

You can think of BIPS as:

“Having briefly touched psychosis” and then stepping back, but because they’ve “touched it” once, they are considered a very high-risk group and must be closely monitored.

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3) Genetic Risk and Deterioration Syndrome (GRD)

Used for people who:

• Have high genetic risk, for example, a parent or first-degree sibling with Schizophrenia / Schizoaffective / Psychotic Bipolar disorder,

• And have at least ~30% functional decline in academic, occupational, or social functioning within the past year.

Examples:

• A previously high-achieving student whose grades suddenly drop sharply without a clear external reason (no major life event to explain it).

• Someone who can no longer meet work standards even though their skills are the same.

• Starting to withdraw, rarely leaving their room, even though they used to be active.

Even though some GRD individuals do not yet have clear positive symptoms, when combined with genetic risk they are considered to be on a trajectory that warrants serious monitoring.

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Why do we need three “entry routes” into CHR-P?

Because each group represents a different “pathway to psychosis”:

• Some people start with mild positive symptoms → APSS.
• Some have a short psychotic episode and then remit → BIPS.
• Some are heavily loaded genetically and their functioning slowly deteriorates → GRD.

This classification helps:

• Design targeted monitoring / intensive care strategies.

• Analyze in research:
• “Which group has the highest risk of transition?”
• “Which group transitions the fastest?”
• “Which type of intervention works best for which subgroup?”

If we want a short schematic summary:

Core Symptoms =

• Attenuated positive symptoms (delusion / hallucination / disorganized speech)
• Plus negative symptoms & functional decline
• With some degree of preserved insight

Diagnostic Criteria =

• DSM: APS (Section III) → focuses on attenuated symptoms + frequency + onset within 1 year + distress/impairment + exclusion.

• Research/Clinic: CHR-P/UHR → uses SIPS/CAARMS → classifies into APSS, BIPS, GRD.

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4) Subtypes / Specifiers — How Can APS / High-Risk Groups Be Subdivided?

APS / CHR-P does not have official subtypes the way “old” Schizophrenia did (paranoid, disorganized, etc.), but research has started to identify patterns such as:

By leading symptom profile (Symptom-dominant patterns)

• Positive-symptom-dominant APS
• Clear attenuated delusions / hallucinations, but negative symptoms are not yet prominent.

• Negative/Functional-deterioration dominant
• Withdrawal, avolition, cognitive decline are more prominent than positive symptoms.

• Basic-symptom-dominant / cognitive-perceptive
• A group with “basic symptoms,” such as an abnormal experience of one’s own thinking and internal loose associations, without clear delusions/hallucinations yet.
• Criteria like COGDIS / COPER can predict psychosis well, especially over the long term. Wikipedia+1

By pathway to psychosis (Trajectory-based)

• Converters = individuals who progress to a full psychotic disorder within 2–3 years.

• Non-converters but persistently ill = do not become psychotic but continue to suffer from depression, anxiety, PTSD, and functional impairment.

• Remitters = attenuated symptoms improve markedly, and they return to near-normal functioning. PMC+2 Frontiers+2

By assessment instrument (Instrument-defined subgroups)

• SIPS vs CAARMS vs basic symptom criteria (COGDIS/COPER).

• Meta-analyses show that both UHR criteria and basic symptom criteria have similar predictive power for psychosis within ≤ 2 years, and basic symptoms may be more accurate for long-term follow-up. Wikipedia+1

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5) Brain & Neurobiology — What Is Happening in the Brains of People at High Risk for Psychosis?

Big picture first:
APS / CHR-P is not viewed as “just a dopamine disease,” but rather as:

• A disorder of brain networks,
• Involving multiple neurotransmitter systems (dopamine, glutamate, GABA),
• Combined with adolescent brain development where synaptic pruning may be excessive,
• Plus dysregulation of stress systems and inflammation.

It is the “opening scene” of the psychosis circuit: certain networks start to lose balance but the system has not yet collapsed as in full-blown Schizophrenia.

We’ll break it down into several axes:

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5.1 Dopamine Dysregulation — From “Reward Balance” to “Delusional Salience”

The classic dopamine theory of psychosis says that patients with Schizophrenia have:

• Excess dopamine release (hyperdopaminergia) in the striatum → related to delusions / hallucinations.

• Concurrently, possibly reduced dopamine in the prefrontal cortex → related to negative symptoms and cognitive deficits.

In individuals with Clinical High Risk for Psychosis (CHR-P), they are not yet frankly psychotic, but many PET / SPECT studies have found a pattern that is starting to tilt in the same direction, namely:

• Dopamine synthesis capacity in the striatum is higher than in healthy controls, but not as high as in patients with established psychosis. PMC+1

• This abnormality is associated with the severity of attenuated positive symptoms, and in some studies can predict who has a higher likelihood of transitioning to psychosis.

This ties into the “aberrant salience” theory:

Under normal conditions, dopamine helps us determine “what is important and worth paying attention to.”
When dopamine in the striatum is dysregulated, the brain starts to “assign importance to the wrong things” — everyday stimuli.

Example:

• People laughing on the bus → normally: “They’re just talking among themselves.”

• In a dysregulated dopamine system → the brain interprets it as “They’re laughing at me” or “They’re sending some kind of signal to me.”

In APS/CHR-P, this process is still “halfway”:

• The person does not fully believe 100% that someone is tailing them.

• But they “feel” that everything around them has some special meaning directed at them → this manifests as high suspiciousness / referential thinking.

This is the biological foundation of attenuated delusions that we see clinically.

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5.2 Glutamate & GABA Circuitry — Deep-Level Neuronal Circuit Breakdown

If earlier decades emphasized the “dopamine hypothesis,” the current era is more about the “dopamine + glutamate + GABA network hypothesis.”

Key idea:

• Glutamate (especially via the NMDA receptor) on GABA interneurons is the pacemaker that sets the rhythm of network firing.

• If NMDA function on interneurons is impaired → GABA cannot control the circuit properly → downstream networks such as dopamine become dysregulated.

In high-risk individuals:

• MRS (magnetic resonance spectroscopy) studies show abnormalities in glutamate / glutamine in regions such as:
• Anterior cingulate cortex (ACC)
• Hippocampus
• Dorsolateral prefrontal cortex (DLPFC)

• Some studies report elevated glutamate (hyperglutamatergic) states in the ACC and hippocampus in UHR/CHR-P individuals and early-stage patients compared to healthy controls. PMC+2 Canadian Science Publishing+2

A widely discussed model is:

Hippocampal glutamatergic hyperactivity → drives dopaminergic hyperactivity in the striatum → generates psychosis.

In simpler terms, the hippocampus is firing too strongly, which then overactivates the striatum’s dopamine system beyond what is appropriate. Nature+1

In APS / CHR-P, we are likely seeing a “milder version” of this process:

• Those with abnormal glutamate in ACC/hippocampus + rising striatal dopamine + psychotic-like experiences = individuals whose circuits are “entering aberrant salience mode” but have not yet locked into a full delusional loop.

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5.3 Synaptic Pruning & Neurodevelopment — Adolescence: When the Brain “Cleans House” Aggressively

The age range with the highest incidence of APS / CHR-P is roughly 15–25 years, which corresponds to:

• A period of intense synaptic pruning,
• When the brain is “clearing redundant wiring” to make networks more efficient.

Main hypothesis:

• In those at risk for Schizophrenia / Psychosis, there may be “excessive pruning” — too many synapses are eliminated, especially in key circuits (fronto-temporal, fronto-parietal), leading to network imbalance.

As a result:

• Sensory and associative circuits for processing information lose their balance.
• The ability to filter stimuli and prioritize information deteriorates.
• This leads to perceptual aberrations, unusual experiences, and loosely associated thinking, as seen in the high-risk group.

Evidence:

• Neuroimaging in high-risk individuals or children/adolescents with psychotic-like experiences shows structural brain abnormalities, such as faster-than-normal thinning of grey matter in certain regions. This fits the excessive pruning model of Schizophrenia, but at a lighter level. PubMed+1

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5.4 Network Connectivity & Resting-State — When Brain Networks “Talk Out of Sync”

The brain is not one solid block; it is a set of networks that constantly communicate, especially:

• Default Mode Network (DMN) → active during internal mentation, daydreaming, self-reflection.
• Salience Network → detects “what is important or salient” in the environment.
• Frontoparietal Control Network → supports cognitive control, decision-making, shifting focus.

In Schizophrenia, there is strong evidence that:

• DMN, Salience, and Frontoparietal networks show abnormal functional connectivity (both hyper- and hypoconnectivity in various nodes).

• This leads to “mode-switching errors” in the brain:
• DMN is overactive when the person should be externally focused.
• The salience network makes ordinary stimuli feel overly important.
• The control network fails to regulate these misfires.

In CHR-P / high-risk:

• Resting-state fMRI studies show that certain patterns of connectivity abnormalities are similar to those in Schizophrenia, but milder.

• Especially abnormal connectivity among hippocampus – striatum – midbrain – DMN/salience networks that can predict which individuals will have a higher transition risk in follow-up. Nature+1

Intuitively:

Networks that should be helping to “filter, decide what matters, and mute background noise” start to fall out of sync.
As a result, the brain starts interpreting the world as “full of strange, special meanings,” while the top-down control system cannot fully keep things in check.

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5.5 Stress, HPA Axis & Inflammation — The Brain in a State of “Chronic Threat”

Individuals in the APS / CHR-P group often have histories of:

• Childhood trauma, bullying, abuse, rejection/oppression, discrimination, migration/minority status, etc.

These are linked to the social defeat hypothesis — being repeatedly “defeated” or subordinated in social contexts keeps the brain in a state resembling a “chronically defeated animal,” increasing long-term risk for psychosis. rpm.psikologi.ui.ac.id+3 ScienceDirect+3 ResearchGate+3

Relevant biological mechanisms:

• HPA Axis (Hypothalamic-Pituitary-Adrenal)
• Chronic stress → repeated HPA activation → abnormal cortisol patterns.
• Everyday minor stressors trigger disproportionately strong responses.
• Some studies show that early-life HPA dysregulation is associated with psychotic-like experiences and psychosis risk in adolescence/adulthood. DNB Portal+1

• Inflammation / Immune system
• Some high-risk studies find elevated inflammatory markers (e.g., CRP, cytokines) compared to controls.
• The brain is no longer conceptualized as separate from immunity — we now think in terms of “immune–brain cross-talk.”
• Chronic inflammation can affect neurodevelopment, synaptic pruning, and neurotransmitter regulation.

• Stress × Dopamine × Glutamate
• Chronic stress → increases dopamine release in the striatum.
• Combined with a pre-existing glutamate dysregulation → the aberrant salience circuit becomes even stronger.

In summary:

The brain of a high-risk individual is not only running on “miswired dopamine–glutamate circuits”
but is also in a chronic alert mode due to life experiences of threat, making the whole system more vulnerable to sliding into psychosis.

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5.6 Overall Picture: The “Glutamate ↔ GABA ↔ Dopamine + Network + Stress” Model

Putting it all together, we get something like:

• Genetic liability + Neurodevelopmental factors
  → Make glutamate–GABA circuits in the hippocampus / cortex more fragile.

• Adolescence = intense synaptic pruning
  → If pruning is “excessive” or “abnormally patterned,” control and perceptual networks become imbalanced.

• Glutamatergic circuits in hippocampus / ACC become dysrhythmic
  → They send abnormal signals to upregulate dopamine in the striatum.

• Striatal dopamine rises to a subclinical level
  → Produces aberrant salience = perceiving “special meaning” in ordinary things.
  → Misinterpreting the world → psychotic-like experiences, attenuated delusions/hallucinations.

• DMN–Salience–Control networks sync poorly
  → Thought processes go off-track, become overly imaginative, with impaired focus.

• All of this is amplified by chronic stress, trauma, social defeat, inflammation, and some substances.

In APS / CHR-P, all of the above is still happening at the “upstream / subthreshold” level — and that is exactly why early intervention still has a chance to “pull the circuit back” before it becomes a rigid, full-blown psychotic disorder in a portion of these individuals. DNB Portal+4 PMC+4 PubMed+4

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6) Causes & Risk Factors — What Pushes Some People into the High-Risk Zone?

This section uses a full biopsychosocial model:
Genetics + brain development + environment + substances + personality/psychology + social structure.

Important: There is no single factor that guarantees, “You must become psychotic.”
Most factors are “probability boosters” that, when layered together, make it easier for someone to slide into APS / CHR-P.

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6.1 Genetics (Genetic Liability)

If a person has first-degree relatives (parents / siblings) with:

• Schizophrenia
• Schizoaffective disorder
• Bipolar disorder with psychotic features

→ Their overall lifetime risk of a psychotic disorder is significantly elevated.

In the CHR-P framework:

• Genetic Risk + Deterioration (GRD) is one of the “entry routes” into the high-risk group:
• Having first-degree family history plus
• At least ~30% decline in functioning (school/work/social) over the last year. PubMed+1

At the molecular level:

• Studies on polygenic risk scores (PRS) show that people with higher PRS for Schizophrenia have a greater chance of:
• Psychotic-like experiences,
• Being in UHR/CHR-P groups, or
• Transitioning to psychosis compared to those with lower PRS. PubMed+1

However, PRS is not used alone in clinical settings yet, because risk remains heavily intertwined with environmental factors.

In short: genetics are not a “sentence,” but a stage that makes the brain more vulnerable to other factors.

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6.2 Neurodevelopmental Factors — Risks Before Birth and in Early Childhood

Pregnancy–birth–early childhood is a period in which the brain is creating its basic structure.

Commonly discussed risk factors:

• Intrauterine infections (e.g., influenza, toxoplasma in some studies).

• Perinatal hypoxia (lack of oxygen at birth).

• Low birth weight, birth complications.

• Early developmental problems, such as:
• Delayed speech
• Motor delay
• Odd social communication (but not meeting full ASD criteria).

These do not form a “recipe that guarantees psychosis,” but:

• They make certain brain systems develop in a “more fragile” manner than usual.

• Once the person enters adolescence (pruning and restructuring years), their brain is more likely to “tilt” toward a psychosis trajectory than the general population. PubMed+1

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6.3 Environmental and Social Factors — Social Defeat, Urbanicity, Trauma

These are highly tangible risk factors with strong narratives, connecting research with real life.

• Urbanicity (growing up in large cities)
• Growing up in big cities repeatedly correlates with higher psychosis risk.

• Underlying factors may include:

• Social isolation (even when surrounded by people)
• Inequality
• Stress from competition / lack of community cohesion

• Migration & Minority Status
• Migrants or ethnic/religious minorities in a given society have clearly higher psychosis risk.

• Not because of “race,” but due to:

• Exclusion
• Discrimination
• Constantly feeling like they “don’t belong.”

• Bullying, Ostracism, Discrimination
• Many studies link childhood/adolescent bullying to psychotic-like experiences and later psychosis.
• Repeated social defeat (being bullied, excluded, discriminated) becomes both psychological trauma and a stress signal to brain systems. rpm.psikologi.ui.ac.id+3 ScienceDirect+3 OUP Academic+3

Social Defeat Hypothesis in simple terms:

Living in a chronic state of “losing / being inferior / being oppressed”
forces stress and dopamine systems to adapt in maladaptive ways → creating fertile ground for the neurobiology of psychosis.

In those with existing genetic liability, social defeat acts like an “ignition source” that helps push the brain further into APS / CHR-P.

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6.4 Substance Use — Especially High-THC Cannabis and Stimulants

Substances do not “create psychosis out of thin air” in everyone.
But in a brain that is already vulnerable, they are powerful accelerants.

Cannabis:

• Large meta-analyses show that:
• Heavy cannabis users have several-fold higher odds of psychosis than non-users (with odds ratios around ~3–4 in some studies). PubMed+2 PMC+2
• High-THC potency cannabis (modern potent strains) → much higher risk than older, weaker forms.

• European and UK data show:
• Regular use of high-potency cannabis in adolescence / early adulthood is significantly associated with first-episode psychosis. The Lancet+2 psychiatryadvisor.com+2

In CHR-P populations:

• Recent evidence maps conclude that cannabis use does not necessarily increase the chance of being in CHR-P in the first place in all cases, but among those already in CHR-P, heavy cannabis use is often associated with worse outcomes, such as relapse, symptom exacerbation, and slower recovery. ScienceDirect+2 cmaj.ca+2

Other substances:

• Stimulants (amphetamine, methamphetamine, cocaine)
• Strongly boost dopamine → can directly induce substance-induced psychosis.
• In a high-risk brain, they can accelerate the jump from APS → full psychosis.

• LSD / other hallucinogens
• Affect serotonin and glutamate systems → can generate psychosis-like experiences.
• In vulnerable individuals, they can be a trigger for the first psychotic episode.

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6.5 Psychological and Personality Factors — Schizotypy, Magical Thinking, Anxiety/Depression

• Schizotypal/High-Schizotypy Personality

Features include:

• Magical thinking
• Strong belief in the supernatural, omens, hidden energies
• Odd experiences such as intermittently feeling that others can “read their mind”

High schizotypy does not mean “you must become psychotic,” but it is a baseline cognitive-perceptive style that is closer to psychotic-like phenomena than average.

• Anxiety & Depression

Severe anxiety and depression are not direct causes of psychosis, but they:

• Increase distress from psychotic-like experiences.
• Make interpretations more negative, thereby setting the stage for delusional content to turn persecutory, guilt-based, or worthlessness-based.

In many CHR-P cohorts, the most common comorbidities are actually depression & anxiety, more so than the psychotic features themselves. PubMed+2 sonar.ch+2

• Coping Style & Cognitive Biases

People who tend to:

• “Jump to conclusions”
• Be sensitive to threat or rejection

are more likely to exhibit cognitive biases found in those with psychotic-like experiences and CHR-P, potentially forming a bridge from “odd experiences” to “firmly held delusional beliefs.”

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6.6 Protective Factors — Why Do Some People Not Transition?

Despite all the talk about risk, large datasets tell us:

In CHR-P groups, most do not transition to full psychotic disorders.

Because there are protective factors and balancing mechanisms:

• Supportive family/community
• Having people to talk to genuinely
• Receiving help early, without stigma

• Early access to treatment / counseling
• Entering early psychosis clinics as soon as attenuated symptoms begin
• Receiving CBT-CHR, psychoeducation, and lifestyle interventions (sleep, substance, stress)

• Clear life goals + engagement with school/work
• Having meaningful roles in daily life is a key buffer for the illness trajectory.

• Avoiding substances + minimizing cumulative stress

When combined, the picture becomes:

• Risk factors = push the brain toward psychosis.

• Protective factors = pull it back toward functional stability.

APS / CHR-P is the stage where “pushing vs. pulling forces” are in direct conflict — this is precisely where early intervention has the highest value.

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6.7 Narrative Summary

If we tell it as a story in an article:

Some people are born onto a stage where their brain wiring is slightly more fragile than others (genetics + neurodevelopment).
They grow up in a hard and lonely city, bullied and made to feel small (social defeat).
They escape the stress with cannabis or stimulants, and a brain that once only trembled slightly now truly loses its rhythm (dopamine–glutamate network).
In the years when the brain is pruning circuits heavily, the networks that should help distinguish “what matters/what doesn’t” start to malfunction.
Ordinary things become special signals. The world feels filled with hidden meanings, but deep down they still sense that maybe this is just their brain misfiring.
That moment is what we call Attenuated Psychosis Syndrome / Clinical High Risk for Psychosis —
not a curse, but a warning light on the dashboard that if we take care of it now, there is still a very high chance we can prevent the engine from blowing up in the future.

ScienceDirect+4 PMC+4 PubMed+4

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7) Treatment & Management — How Do We Care for the High-Risk Group (According to the Latest Evidence)?

The central concept now = “Early, least harmful, function-focused, and stepped care”
= intervene as early as possible, starting with the least risky methods, and step up only if necessary.

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7.1 General Principles Most Guidelines Agree On

From EPA guidance, Australian Early Psychosis Guidelines, 2024 CHR-P summary guidelines, and 2025 meta-analyses on prevention, the overall picture is: Headspace+4 Europsy+4 Orygen+4

• Psychoeducation + careful communication about “risk”

Explain that:

• They have certain symptoms that place them in a “high-risk zone.”
• But overall probability numbers ≈ about 1 in 4 within 3 years, not 100%.

Emphasize that the goals are to:

• Reduce distress,
• Improve quality of life,
• Monitor closely.

Avoid labeling them as “definitely going to get Schizophrenia,” as this only increases stigma and anxiety unnecessarily.

• Psychosocial Interventions as first-line

• CBT for Psychosis / CBT-CHR
  

  Goals: reduce distress from attenuated symptoms, reframe beliefs about unusual experiences, and build coping skills.
  Large RCTs show that CBT may not dramatically reduce transition rates in all samples, but it clearly improves symptoms, functioning, and quality of life. Nature+2 Iris+2

• Family psychoeducation / multi-family groups
  

  Helps reduce expressed emotion, teaches families how to handle symptoms and reduce household stress. Europsy+2 Orygen+2

• Resilience-focused therapy & functional recovery
  

  Focuses on restoring educational/work and social roles, co-creating life goals — not just symptom reduction.

• Management of comorbid conditions
  

  Depression, anxiety, PTSD, and substance use disorders should be treated fully, following standard guidelines.
  Very often, the main source of suffering in CHR-P is mood/anxiety, more than psychosis per se. Zenodo+1

• Pharmacological treatment — the most debated area

7.1.1 Antipsychotics

Meta-analyses and recent guidelines converge on:

• Antipsychotics should not be used as first-line in CHR-P / APS.

Several RCTs show that antipsychotics do not significantly reduce transition risk compared to placebo/psychosocial controls over 6–12 months, and they carry substantial side effects. Nature+2 Lippincott Journals+2

They may be considered short-term at low dose if:

• Positive symptoms are extremely severe, close to full psychosis,
• There is risk to self/others,
• Or distress from symptoms is so high that functioning is severely impaired.

But this should be done within an early psychosis service / specialist team, with close monitoring.

7.1.2 Omega-3 fatty acids, minocycline, etc.

There was a period when omega-3 was hyped as potentially preventing psychosis in UHR groups.

Recent meta-analyses (including more RCTs) show omega-3 is not clearly superior to placebo in reducing conversion rates. Nature+1

Other agents (minocycline, cognitive enhancers, TMS, etc.) currently lack sufficient evidence to be recommended as standard.

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7.2 Monitoring and Duration of Untreated Psychosis (DUP)

• Long-term monitoring (at least 2–3 years)
  

  Because transition risk is highest in the first 2–3 years after CHR-P status is identified. PubMed+2 PMC+2
  
  Follow-up should include:

• Positive/negative symptoms
• Mood/anxiety
• Functioning (school/work)
• Substance use

• Reducing Duration of Untreated Psychosis (DUP)
  

  Early psychosis guidelines emphasize: if/when full psychosis does emerge, the earlier the treatment, the better the long-term outcome. Wikipedia
  
  Thus, being in a CHR-P program means:
• The team can detect changes quickly.
• It reduces the chance that someone will “drop out of the system” and remain untreated for a long time.

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8) Notes — Key Points / Pitfalls / Cautions

• APS / CHR-P ≠ a curse that “you will definitely get Schizophrenia.”

Current data: about 1 in 4 within 3 years will transition → meaning most will not develop a full psychotic disorder but still need serious mental health care. Cambridge University Press & Assessment+1

• Risk of over-diagnosis / over-pathologizing
  

  Many people in the general population have mild “psychotic-like experiences,” such as hearing a voice once or twice when extremely exhausted or being half-awake/dreaming.
  
  This does not automatically mean APS or high-risk status. Papeles del Psicólogo+1
  Terms like APS / CHR-P should be used by teams trained to apply SIPS/CAARMS systematically.

• Stigma & self-stigma
  Telling someone “you are at risk for psychosis” without good explanation may:
• Generate self-stigma, depression, and social withdrawal.
• Lead some to stop studying or planning their future unnecessarily.

• Research is ongoing (an active field)
  DSM is explicit that APS is in “conditions for further study” because many important questions remain, such as:
• How accurately can we distinguish people who are truly at high risk from those with benign psychotic-like experiences?
• Does labeling APS/CHR-P do more good than harm in real-world settings? Wikipedia+2 PMC+2

• All of this information = general knowledge, not a tool for self-diagnosis
  

  If someone begins to experience persistent hearing voices/seeing things, feelings of being controlled, intense paranoia, or marked decline in functioning,
  → they need a full assessment by a psychiatrist / early psychosis team, not self-diagnosis.

Read Schizophrenia

📚 Reference 

1) DSM & Criteria Framework

• American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5 & DSM-5-TR). Section III: Attenuated Psychosis Syndrome.
• Tsuang MT, et al. “Attenuated Psychosis Syndrome in DSM-5: Rationale and Empirical Evidence.” Schizophrenia Research, 2013.
• Fusar-Poli P. “The Clinical High Risk State for Psychosis (CHR-P): Recent Advances.” Psychological Medicine, 2017–2023 series.

2) Transition Risk & Meta-Analyses

• Fusar-Poli P, et al. “Probability of Transition to Psychosis in Individuals at Clinical High Risk: A Meta-Analysis.” JAMA Psychiatry, 2020–2021.
• de Pablo GS, et al. “Risk of Psychosis in Clinical High-Risk Populations: Updated Systematic Review.” World Psychiatry, 2021.
• Fusar-Poli P. “Mapping the Onset of Psychosis: Meta-analytical Evidence.” Biological Psychiatry, 2020–2024.

3) Neurobiology — Dopamine, Glutamate, GABA

• McCutcheon R, Abi-Dargham A, Howes OD. “Dopamine and Glutamate in Schizophrenia: Biology, Symptoms, and Treatment.” Molecular Psychiatry, 2020.
• Grace AA. “Dysregulation of the Dopamine System in Psychosis.” Cell Tissue Research, 2016–2023.
• Howes OD, et al. “Dopamine Synthesis Capacity Elevated Prior to Psychosis Onset.” Schizophrenia Bulletin, 2011–2020.
• Poels EMP, et al. “Glutamatergic Abnormalities in Clinical High Risk for Psychosis.” Neuroscience & Biobehavioral Reviews, 2014–2020.

4) Brain Structure, Connectivity, Development

• Pantelis C, et al. “Neurodevelopment and Psychosis: Excessive Synaptic Pruning Model.” Lancet Psychiatry, 2016.
• Kambeitz J, et al. “Altered Resting-State Connectivity in Clinical High-Risk for Psychosis.” Biological Psychiatry, 2016–2024.
• Allen P, et al. “Hippocampal Abnormalities and Psychosis Risk.” Neuropsychopharmacology, 2016–2023.

5) Stress, Trauma, Social Defeat

• Selten JP, Cantor-Graae E. “Social Defeat Hypothesis of Schizophrenia.” Psychological Medicine, 2005–2022.
• Trotta A, et al. “Childhood Trauma and Transition to Psychosis.” Schizophrenia Research, 2015–2023.
• Bloomfield MAP, et al. “Stress, HPA Axis and Psychosis Risk.” Neurobiology of Stress, 2019.

6) Substance Use (Cannabis & Stimulants)

• Di Forti M, et al. “High-Potency Cannabis and First-Episode Psychosis.” Lancet Psychiatry, 2015–2023.
• Murray RM, et al. “Cannabis and Psychosis: The Strongest Environmental Risk Factor.” Nature Reviews Neuroscience, 2016–2023.
• Foti DJ, et al. “Cannabis Use and Psychotic-Like Experiences.” Biological Psychiatry, 2018.

7) Early Intervention & Treatment Guidelines

• EPA (European Psychiatric Association). “Guidance on Early Detection of Clinical High Risk States.” 2015, 2023 update.
• NICE Guidelines (UK). “Psychosis and Schizophrenia in Adults: Early Interventions.”
• Orygen Early Psychosis Guidelines (Australia).
• Fusar-Poli P, et al. “Treatment of Clinical High Risk for Psychosis: Evidence Map and Recommendations.” World Psychiatry, 2024.

8) Cognitive Bias & Psychological Mechanisms

• Garety P, Freeman D. “Cognitive Processes in Psychosis.” Psychological Medicine, 2013–2023.
• van der Gaag M. “Jumping to Conclusions Bias in Psychosis Risk.” Schizophrenia Bulletin, 2012–2021.

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🔑 

Attenuated Psychosis Syndrome • APS • Clinical High Risk for Psychosis • CHR-P • Ultra High Risk • UHR • At-Risk Mental State • ARMS • Prodromal Psychosis • Psychosis Risk Syndrome • Attenuated Positive Symptoms • APSS • BIPS • GRD • Delusion-like Ideas • Hallucination-like Experiences • Disorganized Thinking • Negative Symptoms • Functional Decline • Aberrant Salience • Dopamine Dysregulation • Striatal Dopamine • Hippocampal Hyperactivity • Glutamate Dysfunction • NMDA Hypofunction • GABA Interneuron • Synaptic Pruning • Neurodevelopmental Vulnerability • Resting-State Connectivity • Salience Network • Default Mode Network • Stress Vulnerability Model • HPA Axis • Social Defeat • Childhood Trauma • Urbanicity • Cannabis High Potency • Substance-Induced Risk • Early Intervention • CBT-CHR • Omega-3 Psychosis Prevention • Antipsychotic Debate • Transition to Psychosis • Meta-analysis Psychosis Risk