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Psychosis due to Medical Conditions

Nerdyssey December 09, 2025


1) Overview — What is Psychosis due to Medical Conditions?

“Psychosis due to Medical Conditions,” or in full DSM-5-TR terminology, Psychotic Disorder Due to Another Medical Condition, and in ICD-11 it is called Secondary Psychotic Syndrome (6E61), is a cluster of psychotic symptoms that does not arise from “the brain malfunctioning on its own like schizophrenia,” but rather from a medical illness that directly affects the central nervous system to the point that it produces prominent delusions or hallucinations.

The key point is that “the medical illness is the root cause” — not a substance, not a medication, and not a primary psychiatric disorder such as schizophrenia, schizoaffective disorder, or bipolar disorder with psychosis.

Therefore, this is not psychosis as a flare of a primary psychiatric condition, but psychosis that is “triggered by a physical illness”, such as stroke, brain tumor, thyroid dysfunction, autoimmune encephalitis, kidney or liver failure, infections of the central nervous system (CNS), or severe metabolic disturbances.

In other words, the brain is not losing neurochemical balance because neurotransmitters are dysregulated in the typical way seen in schizophrenia, but is instead being attacked by bodily disease, such as inflammation (neuroinflammation), suppression of neurotransmitter function, structural damage to brain tissue, hormonal deficiency, toxicity from metabolic waste accumulating in the body, or even the immune system directly attacking the brain.

The DSM-5-TR emphasizes that clinicians must demonstrate physiological evidence that the psychotic symptoms are “directly related” to a medical condition — through history, physical examination, blood tests, brain imaging (CT/MRI), or cerebrospinal fluid (CSF) studies — which is different from other psychotic disorders that are often diagnosed primarily from behavior and symptoms alone.

The ICD-11 chooses the term Secondary psychotic syndrome because it wants to make it explicit that psychosis is the outcome, not the primary disease — this pushes psychiatrists to think in terms of “the body sending abnormal signals” rather than viewing the problem as purely psychiatric.

From an epidemiological standpoint, even though the number of patients with secondary psychosis is not large — roughly 3–9% of all psychotic cases — this group is very important because some causes can be life-threatening, such as neuroinfections, encephalitis, metabolic failure, or brain tumors that have not yet been diagnosed.

Interestingly, older adults and those with multiple chronic medical conditions (multimorbidity) are at higher risk of developing this kind of psychosis, because the brain is more vulnerable to metabolic disturbances and neurodegenerative changes.

Psychiatrists and neurologists often use this topic as a “warning signal” for the whole team not to rush into diagnosing schizophrenia, especially in cases where symptoms start between ages 40–70, which clearly deviates from the usual pattern of schizophrenia.

In summary:

Psychosis due to Medical Conditions is psychosis that arises because “there is a real physical disease actively affecting the brain,” not because the brain’s own systems have lost balance in the way seen in schizophrenia.
The correct treatment is therefore not simply increasing antipsychotic dosage, but “treating the underlying medical condition” as quickly as possible.

This explains why this topic is one of the key categories in differential diagnosis for any patient presenting with psychosis — because some underlying diseases, if treated in time, can allow near-full recovery, but if missed, can cause permanent and severe brain damage.

2) Core Symptoms — Central Symptom Dimensions

When we talk about psychosis from medical conditions, the main pillars are similar to general psychosis:

But the context and certain patterns are significantly different from “pure” schizophrenia.

2.1 Primary Psychotic Symptoms

2.1.1 Delusions

Re-defining the concept in more detail:

A delusion is “a belief that is clearly false and inconsistent with reality, but the person holds onto it so firmly that even strong contradictory evidence can hardly shake it.”

It is not just an ordinary misunderstanding, nor a personal or cultural/religious belief (for example, belief in spirits in South East Asia culture that many people share).

Key features of delusions:

  • Strongly deviate from objective reality
  • Do not change even when challenged with reason or evidence
  • Occupy cognitive space and behavior to the point of clearly impairing functioning in daily life

Common themes in secondary psychosis include:

Persecutory delusions (belief of being harmed / followed / targeted)

  • Believing someone is planning to harm them, secretly installing cameras, wiretapping, or monitoring them.
  • This can be extended to ideas of being poisoned, hypnotized, or followed by mysterious organizations.

  • In medically induced psychosis, this theme is sometimes linked to bodily symptoms, for example:
    • Believing that hospital staff are intentionally making them sicker.
    • Believing that doctors are putting something harmful into their IV line.

Somatic delusions (delusional beliefs about the body)

  • Believing the body has a bizarre disease, something crawling inside, insects in the bloodstream, or certain organs rotting — even though physical examination finds nothing.
  • In secondary psychosis, this pattern is very common because the brain is “receiving strange input from the body” and misinterpreting it, such as:
    • Patients with thyroid disease, metabolic disorders, or neuropathy may experience abnormal numbness or pain → interpreted as having a chip implanted, energy being sucked out, etc.

Religious / grandiose delusions

  • Religious: Believing they have been chosen by God, having a special mission, or receiving secret messages through various signals.
  • Grandiose: Believing they have special powers, superhuman abilities, are a world-class genius, or an important figure watched by the entire world.

In secondary psychosis, a key difference is that these themes may emerge acutely, along with clear signs of physical illness, for example:

  • Someone who has never talked about religion suddenly begins to speak of a “mission from God” at the same time as they develop severe hyperthyroidism, extreme insomnia, weight loss, palpitations, etc.

Mixed / atypical delusions

  • Having persecutory + somatic + religious themes mixed together.
  • In many cases of autoimmune encephalitis, SLE, or metabolic encephalopathy, delusional patterns are quite chaotic and mixed, more so than classic schizophrenia patterns.

Links to medical conditions (not a strict one-disease-one-pattern, but trend-level associations):

  • Thyroid disease (hypo-/hyperthyroidism)
    • Severe hypothyroidism (myxedema psychosis) → typically the patient appears slow, lethargic, cold-intolerant, gains weight, has dry skin, slow speech, but internally has clear persecutory/somatic delusions and paranoia.
  • Neurodegenerative diseases (such as Parkinson’s disease, Lewy body dementia)
    • Often have intermittent psychosis characterized by misperception of images, seeing people/animals in the home, or believing strangers are living with them, etc.

For writing/content purposes:
You can present a “hypothetical case” of a person with severe hypothyroidism who starts to believe someone is poisoning their food because they feel fatigue, chills, and mental fog. All of this helps readers understand that “the brain is misinterpreting bodily signals.”

2.1.2 Hallucinations

Clear definition:

A hallucination is a perception that is genuinely experienced by the person, but there is no external stimulus at all.

It is a full perception, not imagination or thinking in one’s head.

Examples:

  • Hearing a person speaking clearly as if standing right next to the ear.
  • Seeing a person walking in the room when no one is actually there.

Hallucinations can affect all sensory modalities, including:

  • Auditory (hearing)
  • Visual (seeing)
  • Olfactory (smelling)
  • Gustatory (tasting)
  • Tactile (touch; feeling something crawl, electric shocks, etc.)

Key patterns in secondary psychosis that differ from schizophrenia:

In classic schizophrenia:

  • Auditory hallucinations (voices talking, commenting, commanding) are the main feature.

In medically induced psychosis:

  • Visual, olfactory, and tactile hallucinations are more frequent and/or particularly prominent, often occurring together.

Examples:

Olfactory hallucinations (smelling things that are not there)

  • Smelling burning, rotting, gas, or strange odors.
  • Common in temporal lobe epilepsy, temporal lobe brain tumors, and lesions around the olfactory cortex.
  • Patients will often report suddenly smelling intense burning when no one else does → this is a major neurological clue.

Visual hallucinations

  • Can range from seeing a vague “shadow passing by” to very vivid images of people, animals, or beings in the room.
  • In Lewy body dementia and Parkinson’s disease psychosis, visual hallucinations are often of “small people or animals” in the house, vivid enough that the patient can talk to them.
  • Sometimes these hallucinations occur in the evening or dim light conditions, causing family members to misinterpret them as “spirit/ghost beliefs,” when in fact they are due to neurodegeneration.

Tactile hallucinations

  • Feeling insects crawling under the skin, something moving on the body, even though nothing is visible.
  • Seen in both substance-induced states (such as cocaine or amphetamine) and in some medical conditions such as neuropathy plus psychosis.

Multimodal hallucinations

  • Some patients experience a combination of sounds + visuals + smells together.
  • In autoimmune encephalitis or metabolic encephalopathy, hallucinations can come as a “large package,” along with confusion, seizures, and bizarre behaviors.

What makes these hallucinations a physical red flag?

  • They often begin quite acutely, over days to weeks.
  • They are frequently accompanied by “physical symptoms” or “neurological symptoms”, such as severe headache, seizures, unsteady gait, altered consciousness, fever, etc.

  • Sometimes the content of the hallucinations is not consistent with the person’s prior life story, for example:
    • A person who never believed in the supernatural suddenly sees a person walking in the house very clearly, worsens at night, and at the same time has short-term memory problems and abnormal movements → this should prompt evaluation for dementia, Parkinson’s disease, or encephalitis rather than being written off as a typical psychotic disorder.

2.1.3 Associated Abnormal Thinking/Behavior

Although the primary diagnostic criteria focus on delusions + hallucinations, in real life we often see other symptoms:

Disorganized thinking

  • Speech is tangential, rapidly changing topics, and failing to maintain a coherent thread.
  • The structure of sentences becomes illogical, such as following one sentence with a completely unrelated thought.
  • In secondary psychosis, this often co-occurs with delirium or encephalopathy, meaning consciousness and attention are impaired as well.

Disorganized behavior

  • Inability to follow steps or finish tasks.
  • Acting in ways that are not appropriate to the situation, such as going out onto the street in pajamas.
  • Getting lost in familiar places.

Catatonic features

  • Abnormal stillness, not speaking, not moving (stupor).
  • Or, on the other extreme, agitation, repeating the same movements (e.g., swinging arms, performing stereotyped actions).
  • Seen in many forms of psychosis, including autoimmune encephalitis and certain medical conditions.

Mood symptoms

  • Depressive symptoms
  • Manic or hypomanic symptoms
  • Irritability
  • Severe anxiety

If mood symptoms are very prominent and dominate the picture, clinicians must differentiate mood disorder with psychotic features and should not quickly label it as secondary psychosis.

2.2 Features Suggesting “Secondary” Rather Than Schizophrenia

This section is the “clinical instinct filter” used to decide whether:

This case is likely psychosis from a medical condition (secondary)
or a primary psychiatric disorder like schizophrenia.

2.2.1 Age of Onset

True schizophrenia usually begins in late adolescence to early adulthood (around 15–35 years old, especially 18–30).

If someone who has never had any psychiatric illness in their life suddenly develops psychosis for the first time at age 45, 55, or 70+, we must first suspect a medical cause.

Especially if accompanied by:

  • Worsening balance
  • Coexisting short-term memory problems
  • Marked weight loss or gain
  • Or a history of chronic physical illness

2.2.2 Clear Neurological Signs

Examples:

  • Seizures
    • Especially focal seizures or temporal lobe epilepsy
    • Post-ictal psychosis (psychosis after a seizure) is a classic entity.
  • Hemiparesis/weakness, numbness, slurred speech, facial droop
    • Suggests stroke, brain tumor, or other lesions in the brain.
  • Altered level of consciousness
    • Apathy, excessive drowsiness, slow response, or fluctuating consciousness throughout the day.
    • If symptoms fluctuate dramatically over a day + there is inattention → think delirium.
  • Visual disturbances
    • Double vision, unusual visual distortions, loss of part of the visual field.

If psychosis appears together with neurological signs like these, it is almost a “neuro emergency” — we must promptly look for lesions or medical causes in the brain, rather than simply prescribing antipsychotics and sending the patient home.

2.2.3 Clear Physical Symptoms Before or Along with Psychosis

For example:

  • Marked weight loss over a short period, poor appetite, or abnormal fatigue.
  • Chronic fever, joint pain, rash, lymph node enlargement → think autoimmune or chronic infections.
  • Jaundice (yellow skin, yellow eyes) → liver disease.
  • Thyroid symptoms: palpitations, excessive sweating, heat intolerance; or, conversely, sensitivity to cold, sluggishness, edema.
  • Markedly reduced urination, swelling, itching → kidney disease.

A pattern that is suspicious:

  • Before psychosis, the patient had “physical” illness for some time (e.g., easy fatigue, weight loss, low-grade fevers for months) but had not been diagnosed.
  • Once the medical illness reaches a severe level, the brain begins to be affected → psychosis shows up as the “final stage.”

2.2.4 Relationship Between Severity of Medical Illness and Psychotic Symptoms

One of the most important signals:

  • Medical condition worsens → psychosis worsens
  • Medical condition is controlled/treated well → psychosis improves significantly

Examples to illustrate:

  • A patient with chronic kidney disease who receives dialysis inconsistently:
    • When metabolic parameters (urea, electrolytes) are severely abnormal → visual hallucinations, agitation, confusion.
    • After receiving dialysis and returning metabolic values closer to normal → psychosis markedly improves.
  • A patient with autoimmune encephalitis:
    • During periods of intense inflammation (CSF studies and antibodies clearly positive) → hallucinations + agitation + catatonia.
    • After steroid / IVIG / plasmapheresis → psychiatric symptoms gradually improve in parallel with reduction of inflammation.

If the picture looks like this, we become more confident that:

Psychosis = a “marker” that the medical illness is currently impacting the brain.

3) Diagnostic Criteria — DSM-5-TR / ICD-11

The core of this section is to answer three questions:

  1. Is there true psychosis? (clear delusions / hallucinations)
  2. Is this psychosis directly “tied” to a medical condition?
  3. Is there another psychiatric disorder or delirium that explains it better?

3.1 DSM-5-TR: Psychotic Disorder Due to Another Medical Condition

DSM-5-TR arranges the criteria as follows (summarized in accessible language):

Criterion A — Prominent hallucinations or delusions

There must be at least one of the two:

And it must be at a level that is “clinically significant,” not just mild or trivial.

Examples:

  • Firm delusional beliefs causing major conflict at home or at work.
  • Hallucinations that cause intense fear, inability to sleep, or significant distress.

Note: DSM-5-TR distinguishes Psychotic Disorder Due to Another Medical Condition from delirium or major neurocognitive disorder where only mild perceptual disturbances occur.

Criterion B — Evidence that the psychosis is the direct result of a medical condition

This is the core of calling it “due to another medical condition.”

There must be at least one of:

  • From history
    • For example, before psychosis, there was stroke, brain injury, CNS infection, encephalitis, thyroid disease, etc.
    • Psychosis begins after a medical event within a time frame that makes sense biologically.
  • From physical examination
    • Signs of physical disease such as unilateral paralysis, signs of meningeal irritation, neck stiffness, endocrine signs, etc.
  • From labs or imaging
    • Severe electrolyte disturbances
    • Liver or kidney failure
    • Markedly abnormal thyroid function
    • MRI/CT shows a brain lesion such as tumor, infarct, hemorrhage
    • CSF reveals inflammation, autoantibodies, or evidence of infection

The key point is that the clinician must be able to link by biological reasoning that:

This medical condition can cause psychosis,
and no other mental disorder explains it better.

Criterion C — Not better explained by another primary psychiatric disorder

This criterion is about excluding other diagnoses, such as:

A rough way of thinking:

  • If psychosis began long before the medical illness, or followed a chronic course consistent with schizophrenia → it is unlikely to be “due to another medical condition.”
  • If mood symptoms (severe depression or mania) are very prominent and psychosis always appears in the context of mood episodes → think mood disorder with psychotic features instead.

Criterion D — Does not occur exclusively during delirium

If all psychotic symptoms occur in the context of delirium (with characteristic features such as):

  • Fluctuating level of consciousness
  • Poor attention and concentration
  • Severely disturbed sleep-wake cycle

→ DSM will primarily diagnose Delirium Due to Another Medical Condition, not Psychotic Disorder Due to a Medical Condition.

At most, psychosis in delirium will be recorded as a feature of delirium, not as a separate disorder.

Criterion E — Causes significant distress or impairment

As with most disorders in DSM:

  • It must cause significant distress to the patient, or
  • Significantly impair functioning at work, in education, self-care, or relationships.

If psychotic symptoms are very mild, barely affect life, and are short-lived, they may be considered subclinical or included in “other specified/unspecified” categories.

3.2 Specifiers in DSM-5-TR

DSM-5-TR has main specifiers such as:

  • With delusions (F06.2 / 293.81)

    Delusions are the predominant symptom (hallucinations may be present but not as prominent).

  • With hallucinations (F06.0 / 293.82)

    Hallucinations predominate (especially visual/olfactory/tactile hallucinations, which are particularly suggestive of secondary psychosis).

In terms of writing/academic style, you can use these as tags in articles, such as:

  • Psychotic Disorder Due to Hypothyroidism, With Delusions
  • Psychotic Disorder Due to Temporal Lobe Epilepsy, With Hallucinations

This helps clarify what the main feature is and also connects well with other posts in a series (like a secondary psychosis map).

3.3 ICD-11: Secondary Psychotic Syndrome (6E61)

The ICD-11 uses a similar conceptual framework but with different wording.

The core of the ICD-11 definition is:

A “psychotic syndrome due to a health condition not classified under mental and behavioural disorders.”

That is, the primary illness lies in another chapter (e.g., neurological disorders, endocrine diseases, infections, autoimmune conditions), and psychosis appears as “secondary.”

Main requirements in ICD-11:

  • Clinical evidence that these symptoms:
    • Are a direct result of a medical condition.
    • Are not primarily due to substances (drugs/medications).
  • Cannot be better explained by:
    • Primary psychotic disorders.
    • Mood disorders with psychotic features.
    • Delirium.
    • Dementia or major neurocognitive disorder alone.

ICD-11 often recommends specifying the medical illness, for example:

  • 6E61.0 Secondary psychotic syndrome due to epilepsy
  • 6E61.1 Secondary psychotic syndrome due to endocrine disease

For your writing/website, this is a golden opportunity to build sub-series such as:

  • Secondary Psychosis from Endocrine Disorders
  • Secondary Psychosis in Autoimmune Diseases
  • Epilepsy-Related Psychosis

Each can be developed into a full mega-post.

3.4 Big-Picture Summary of Diagnostic Criteria (for an infographic/box)

You can summarize it in a bullet box on the website like this:

Diagnose Psychotic Disorder Due to Another Medical Condition when…

  • ✅ There are clear delusions and/or hallucinations.
  • ✅ There is evidence that these symptoms originate from a medical illness (from history, physical exam, labs, imaging, etc.).
  • ✅ It is not better accounted for by schizophrenia, schizoaffective disorder, or mood disorder with psychotic features.
  • ✅ It is not just delirium (with fluctuating consciousness throughout the day).
  • ✅ It significantly disrupts life, functioning, relationships, or causes substantial distress.

If all are met → think of “secondary psychosis” before labeling it as “schizophrenia.”

4) Subtypes or Specifiers — Subgrouping / Specifiers

In DSM-5-TR, there are main specifiers such as (as collected from sources like Psych Central, etc.):

  • With delusions (F06.2 / 293.81)

  • With hallucinations (F06.0 / 293.82)

Beyond DSM labels, in terms of conceptual organization, you can also classify patterns by the type of underlying medical condition, for example:

Neurological causes

  • Temporal lobe epilepsy
  • Brain tumor
  • Stroke
  • Parkinson’s disease
  • Huntington’s disease
  • Multiple sclerosis
  • Autoimmune encephalitis (e.g., anti-NMDA receptor encephalitis)
  • Etc.

Endocrine / metabolic causes

  • Hyperthyroidism / hypothyroidism (thyrotoxicosis, myxedema psychosis)
  • Cushing’s syndrome
  • Adrenal disorders
  • Hepatic/uremic encephalopathy
  • Electrolyte disturbances
  • Hypoglycemia/hyperglycemia
  • Etc.

Autoimmune / inflammatory / infectious causes

  • SLE
  • Hashimoto encephalopathy
  • Autoimmune encephalitis
  • HIV
  • Syphilis
  • CNS infections
  • Etc.

Systemic or genetic/metabolic diseases

  • Wilson’s disease
  • Porphyria
  • Some leukodystrophies
  • Inborn errors of metabolism
  • Etc.

In ICD-11, some places also further sub-code depending on whether hallucinations vs delusions are predominant, or explicitly specify the associated medical illness, for example:

  • Secondary psychotic syndrome due to systemic lupus erythematosus

5) Brain & Neurobiology — Key Brain Mechanisms in Psychosis Due to Medical Conditions

First, the big picture:

  • Schizophrenia is often described as a “dopamine disorder” (dopamine hypothesis) plus abnormalities of fronto-temporal-limbic circuits.
  • Psychosis from medical conditions = the brain being attacked all at once by:
    • Structural damage (lesions)
    • Neurochemical disruption (neurotransmitters)
    • Inflammation/autoimmune processes
    • Metabolic instability/toxin accumulation
    • Neurodegeneration

Therefore, it is not a single pattern, but rather “many medical diseases → many pathways through which the brain is affected → ending in psychosis.”

5.1 Structural Brain Abnormalities (Structural Lesions)

Main focus: the presence of a “mass or lesion” in the brain → disrupts circuits involved in perception, thinking, and emotion → results in psychosis.

Examples of lesions:

  • Brain tumor
  • Stroke (infarct / hemorrhage)
  • Focal cortical dysplasia
  • Traumatic brain injury (TBI)
  • Aneurysm / AVM with hemorrhage

Brain regions that, if affected, carry higher risk of psychosis:

Temporal lobe (especially medial/limbic regions)

  • Involved in auditory processing, memory, and emotion.
  • Lesions in the temporal lobe can cause:
    • Auditory hallucinations (hearing voices, commands).
    • Olfactory hallucinations (smelling burning, rot).
    • Strange déjà vu or jamais vu experiences.
    • Increased religious/mystical delusions.
  • Classic example: Temporal lobe epilepsy with psychosis before or after seizures.

Limbic system (hippocampus, amygdala, parahippocampal gyrus)

  • Central to emotion, fear, and episodic memory.
  • If affected:
    • Fear and paranoia can spike disproportionately to environmental triggers.
    • Ordinary stimuli may be misinterpreted as highly significant (misattribution of salience) → delusions.

Frontal lobe (especially prefrontal cortex)

  • Responsible for executive functions, reality testing, and impulse control.
  • Lesions in dorsolateral or orbitofrontal regions can result in:
    • Poor reality testing.
    • Greater susceptibility to bizarre or false beliefs because the brain area that “monitors and corrects itself” is impaired.
    • Impulsive behavior, disinhibition, and poor insight into abnormality.

Parietal/occipital/other association cortices

  • Lesions here may lead to visual hallucinations or visuospatial distortions.
  • Particularly relevant in certain stroke or tumor locations.

Network-level mechanism

Even if a lesion is localized, the brain functions as an interconnected network.

⇒ A focal lesion can disrupt an entire circuit (diaschisis). For example:

  • A lesion in the temporal lobe may disrupt connections to the prefrontal cortex → causing both delusional thinking and hallucinations.
  • A frontal lesion may reduce top-down control over limbic activity → allowing delusional content to “break through” more strongly.

A simple way to phrase this on your website:

“If a shard of glass cuts through the main power line, the whole house’s electricity can go haywire.
In the same way, a lesion in the temporal–limbic–frontal network can cause global disruption of the brain’s ‘thought–emotion–perception’ system, resulting in psychosis.”

5.2 Neurotransmitter Imbalance

Many medical illnesses cause rapid or severe changes in brain chemistry, such as:

  • Hormonal disorders (thyrotoxicosis, Cushing’s syndrome)
  • Liver or kidney failure → toxin accumulation
  • CNS infections or severe systemic infections
  • Autoimmune encephalitis

Key players:

Dopamine

  • Involved in reward, motivation, and salience (what the brain decides to focus on).
  • If dopamine is excessive in the mesolimbic pathway, the brain may interpret neutral stimuli as highly meaningful → delusions and hallucinations.
  • Some medical conditions (e.g., endocrine disorders, hepatic encephalopathy) and certain medications (dopaminergic agents) can disturb dopamine balance.
  • This differs from schizophrenia, where dopaminergic disturbance tends to be chronic + linked to genetic/early neurodevelopmental factors.

Glutamate

  • The main excitatory neurotransmitter.
  • Conditions such as anti-NMDA receptor encephalitis:
    • Autoantibodies attack NMDA receptors.
    • This leads to dysregulation in fronto-temporal-limbic circuits → psychosis, catatonia, seizures.
  • Many models of psychosis propose that “NMDA hypofunction” leads to secondary dysregulation of dopaminergic systems.

GABA

  • The main inhibitory neurotransmitter.
  • If GABAergic tone is reduced (e.g., due to metabolic failure or post-seizure changes), the brain becomes more easily overexcited → hallucinations, agitation, psychosis.

Serotonin & Acetylcholine

  • Serotonin: involved in mood, perception, and complex cognition.
  • Acetylcholine (ACh): crucial for attention and memory.
  • In Lewy body dementia and Parkinson’s disease, cholinergic deficits combined with dopaminergic dysregulation lead to prominent visual hallucinations and misperceptions.

Overall:

Medical diseases = disruptors of homeostasis across multiple neurotransmitter systems simultaneously, not just a single linear pathway.

5.3 Neuroinflammation and Autoimmune Mechanisms

This area is now very prominent in neuropsychiatry, as it explains why some people:

  • Previously completely healthy,
  • Suddenly develop severe psychosis/catatonia/mania,
  • And respond much better to immunosuppressive treatment (steroids, IVIG, rituximab) than to antipsychotics.

Examples of diseases:

  • Autoimmune encephalitis (e.g., anti-NMDAR, anti-LGI1, anti-GABA-B)
  • SLE with CNS involvement
  • Hashimoto encephalopathy

Mechanisms:

Autoantibodies

The body produces antibodies that bind to:

  • Receptors (e.g., NMDAR)
  • Ion channels (e.g., VGKC complex)
  • Or neuronal/glial proteins

→ directly disrupting synaptic transmission.

Blood–Brain Barrier (BBB) breakdown
  • Normally, the BBB is a barrier between blood and brain.
  • During inflammation, immune cells, cytokines, and complement can infiltrate the CNS more easily.
  • This leads to interference with neural circuits.

Microglial activation

  • Microglia, the brain’s immune cells, become activated.
  • They release cytokines and may cause excessive synaptic pruning.
  • This leads to network dysconnectivity, like network cables being chewed apart in sections.

Clinical consequences:

  • Patients exhibit a combination of psychosis, disorganized behavior, catatonia, seizures, and abnormal movements.
  • Initially, symptoms may appear purely psychiatric (and be misdiagnosed as schizophrenia or bipolar disorder).
  • Over time, seizures, dyskinesias, and cognitive changes emerge.

When treated with steroids, IVIG, plasmapheresis, or other immunotherapies, psychotic symptoms often improve clearly, reinforcing that:

The fundamental cause is immune-mediated.

5.4 Metabolic / Toxic Encephalopathy

This category is like the brain “floating in toxic fluid” from the body, such as:

  • Liver failure (hepatic encephalopathy)
  • Kidney failure (uremic encephalopathy)
  • Hypoxia (lack of oxygen)
  • Severe electrolyte disturbances (Na+, Ca2+, Mg2+, etc.)
  • Marked abnormalities in glucose (hypoglycemia/hyperglycemia)
  • Severe sepsis

Key mechanisms:

Toxins build-up

  • Ammonia in hepatic failure, uremic toxins in renal failure, etc.
  • Cause swelling of neurons and astrocytes, disruption of ion gradients, and abnormal network firing.

Energy failure

  • Lack of oxygen or glucose → the brain lacks energy.
  • Repair processes fail → signaling becomes unstable.

Global network dysfunction

  • Not a single focal lesion, but a global lack of coordination in brain function.
  • Result = delirium + fluctuating psychotic symptoms throughout the day.

Important point:

  • In such cases, the primary diagnosis is often Delirium Due to Another Medical Condition.
  • Psychotic symptoms are considered features of delirium, not a separate psychotic disorder.
  • However, in some cases where consciousness recovers but delusions/hallucinations persist, clinicians may consider evolution into secondary psychosis.

5.5 Neurodegeneration

Neurodegenerative diseases that frequently have associated psychosis include:

  • Parkinson’s disease
  • Dementia with Lewy bodies (DLB)
  • Huntington’s disease (HD)
  • Frontotemporal dementia (FTD)
  • Alzheimer’s disease (especially in later stages)

Main mechanisms:

Basal ganglia–cortical circuit disruption

  • Conditions like PD, DLB, HD involve pathology in basal ganglia and brainstem.
  • This affects circuits projecting to the prefrontal cortex and limbic system.
  • Result = motor symptoms plus psychosis (e.g., “tremor + seeing hallucinated figures”).

Dopaminergic dysregulation

  • PD itself involves dopamine deficiency in motor circuits.
  • Dopaminergic medications used to treat PD, if excess, can push patients into psychosis by overstimulating mesolimbic pathways.
  • DLB includes a combination of cholinergic deficits and dopaminergic dysregulation → prominent visual hallucinations.

Cortical atrophy and network disintegration

  • In dementias, association cortices gradually atrophy.
  • Reality testing and memory deteriorate.

  • Patients misinterpret situations, for example:
    • Believing family members are impostors (misidentification delusions).
    • Believing people are stealing their belongings when they themselves have misplaced them.

What makes these fit into secondary psychosis:

  • Psychosis arises against a background of clearly detectable neurodegenerative illness.
  • The more advanced the disease, the more prominent the psychotic symptoms.
  • Often with characteristic patterns: visual hallucinations more than auditory, misidentification, fluctuations over time.

5.6 Summary of Brain & Neurobiology

You can present it to readers as:

Psychosis from medical conditions does not arise from “one neurotransmitter going wrong.”
It is a cocktail of:

  • Structural brain damage → major circuit failures
  • Neurotransmitter chaos → signals amplified in the wrong places
  • Immune and inflammatory damage → synapses destroyed / receptors attacked
  • Metabolic failure → the brain bathed in toxic waste
  • Gradual neurodegeneration → reality testing falling apart

Mix all this together and you get delusions and hallucinations that look like schizophrenia, but with different roots and different treatment strategies.

6) Causes & Risk Factors — Causes and Risk Factors

This section is perfect for building a Mega Map of “Secondary Psychosis”, grouped by underlying medical illness, plus risk factors that make some individuals more vulnerable.

6.1 Medical Causes (Groups of Physical Illnesses Commonly Implicated)

Think in terms of broad categories, then each can be expanded into separate posts:

6.1.1 Neurological Causes

Epilepsy (especially temporal lobe epilepsy)

There can be:

  • Ictal psychosis (during seizures)
  • Post-ictal psychosis (1–2 days after the seizure)

Possible symptoms:

  • Auditory/olfactory hallucinations
  • Paranoia
  • Prominent religious/mystical experiences

Mechanism: repeated overexcitation of the temporal–limbic–frontal network → long-term synaptic changes.

Brain tumors

  • Tumors in frontal/temporal regions → personality changes, psychosis, seizures.
  • Sometimes patients are labeled as having depression or psychosis for a long time before anyone considers CT/MRI.

Stroke (Ischemic / Hemorrhagic)

  • If lesions affect right parietal, temporal, or frontal regions →
    • Visual hallucinations
    • Neglect + delusional misinterpretation (e.g., ignoring half the world and creating bizarre explanations).
Autoimmune encephalitis
  • Examples: anti-NMDAR, anti-LGI1, anti-GABA-B, etc.
  • Presentation: psychosis, dyskinesia, seizures, autonomic instability.
  • If medical causes are not sought, it is easy to mislabel these as fulminant schizophrenia.

Neurodegenerative diseases

  • Parkinson’s disease, DLB, HD, FTD, etc.
  • Psychosis is due to combined chemical and structural factors: degeneration + medication effects.

6.1.2 Endocrine / Metabolic Causes

Hypothyroidism (Myxedema Psychosis)

Patients may show:

  • Cold intolerance, weight gain, dry skin, slowed movements, drowsiness.
  • Yet internally: paranoia, somatic delusions, depressive symptoms, psychosis.

Many cases are labeled “psychotic disorder” before extremely elevated TSH is discovered.

Hyperthyroidism / Thyrotoxicosis

  • Palpitations, sweating, weight loss, insomnia, irritability.
  • Along with agitation, anxiety, psychosis.

Cushing’s syndrome / other adrenal axis disorders

  • Chronically elevated cortisol → depression, irritability, psychosis.

Severe hepatic failure

  • Hepatic encephalopathy → confusion, delirium, hallucinations.
  • With characteristic breath odor, asterixis, and abnormal LFTs.

Renal failure (uremic encephalopathy)

  • Alternating drowsiness and agitation, delirium, hallucinations.
  • Often improves after dialysis when toxins decrease.

Electrolyte disorders (Na+, Ca2+, Mg2+, etc.)

  • Severe hypo- or hypernatremia.
  • Hypocalcemia/hypercalcemia.
  • Both can disrupt neuronal firing → confusion and psychosis.

Glucose dysregulation (hypo-/hyperglycemia)

  • Hypoglycemia: altered consciousness, seizures, bizarre behavior, hallucinations in some cases.
  • Hyperglycemic crisis: delirium + hallucinations.

6.1.3 Systemic / Autoimmune / Infectious Causes

Systemic Lupus Erythematosus (SLE)

  • With CNS involvement → psychosis, seizures, cognitive dysfunction.
  • Often alongside:
    • Rash
    • Joint inflammation
    • Proteinuria
    • Positive ANA/anti-dsDNA

Hashimoto encephalopathy

  • Patients have high anti-thyroid antibody titers.
  • Present with psychiatric symptoms (psychosis, mood, cognitive) + seizures.
  • Often respond very well to steroids.

CNS vasculitis / systemic vasculitis

  • Inflammation of small cerebral vessels → patchy ischemia throughout the brain → psychosis + neurologic deficits.

HIV-related psychosis

  • May arise from HIV-associated neurocognitive disorder, opportunistic CNS infections, or medication effects.
  • Often characterized by cognitive decline + psychosis.

Neurosyphilis

  • Can cause a wide range of psychiatric symptoms, including psychosis.
  • If clinicians are not cautious, it may be entirely overlooked in adults with unusual psychiatric symptoms.

Other CNS infections

  • Viral encephalitis, bacterial meningitis/encephalitis, TB meningitis, etc.
  • Psychosis usually appears along with fever, headache, neck stiffness, and altered level of consciousness.

Other systemic inflammatory / autoimmune illnesses

  • For example, sarcoidosis, Behçet’s disease, Sjögren’s syndrome, if they have CNS involvement.

6.1.4 Genetic / Metabolic / Other Rare Causes

Wilson’s disease

  • Copper accumulation in liver and brain.
  • Symptoms: movement disorders, personality change, psychosis, Kayser–Fleischer rings in the cornea.

Acute intermittent porphyria and other porphyrias

  • Abdominal pain + psychiatric symptoms (anxiety, depression, psychosis).

Inborn errors of metabolism / leukodystrophies

  • Rare but critical in children and adolescents.

Nutritional deficiencies

  • Vitamin B12 deficiency → neuropathy, cognitive changes, psychosis in some cases.
  • Niacin deficiency (pellagra) → the “3 Ds”: dermatitis, diarrhea, dementia (can include psychosis).

Toxic exposures

  • Heavy metals (lead, mercury), carbon monoxide poisoning, solvent exposure, etc.

Even though these are rare, for deep-dive content like Nerdyssey, this group is “gold”, as it makes the article more comprehensive and useful as a reference.

6.2 Individual & Environmental Risk Factors

1. Age

  • Older adults (≥ 65 years) have higher risk of secondary psychosis because:
    • They have more chronic illnesses.
    • Their brains are more vulnerable to even subtle metabolic changes.
    • They often take multiple medications (polypharmacy).

2. Multimorbidity (having multiple chronic conditions)

  • For example, having diabetes + chronic kidney disease + heart disease + thyroid disease.
  • Each condition affects the brain in its own way, and the medications can interact → overall increased risk of psychosis.

3. Polypharmacy and brain-acting medications

  • Steroids (e.g., high-dose prednisolone) → steroid-induced psychosis.
  • Anticholinergics → confusion and psychotic features, especially in the elderly.
  • Opioids, benzodiazepines, and sedatives.

4. Immune dysregulation / autoimmunity

  • Individuals with multiple autoimmune diseases (SLE, autoimmune thyroiditis, type 1 diabetes, etc.)
  • May have a slightly higher risk of autoimmune encephalitis or CNS autoimmune involvement.

5. Genetic factors and family history

  • A family history of psychotic disorders or some neurodegenerative diseases can make the brain more vulnerable to stressors from medical illness.
  • Combined with environmental stress (infection, trauma, surgery), this may push the brain into psychosis more easily.

6. Acute medical stressors

  • Major surgery, sepsis, major trauma, ICU stays.
  • In some people, after such events, delirium followed by psychosis or secondary psychosis may develop.

7. Substance use + coexisting medical illness

  • Alcohol, stimulants, cannabis, etc., when present in the picture together with medical illness:
    • Make case interpretation more complex.
    • Increase the overall risk of neurotoxicity.

6.3 Red Flags — When to Seriously Look for a Medical Cause

You can highlight this in a red box in your article:

If you see psychosis like this, do not rush to call it schizophrenia.
Always look for a medical cause first:

  • Very rapid onset
    • Psychotic symptoms worsen over days–weeks, not slowly over months–years.
  • Prominent visual / olfactory hallucinations
    • Especially strange smells, highly detailed visual hallucinations.
    • Auditory hallucinations alone are not enough, but if visual/olfactory hallucinations appear as well → think medical.
  • Fever, severe headache, neck stiffness, seizures, focal neurological signs
    • Such as weakness in one limb, slurred speech, unsteady gait.
    • These are true “neuro red flags.”
  • Age of onset is atypical
    • Sudden first-episode psychosis at age 40–70.
    • With no prior psychiatric history.
  • Unusual physical symptoms for a long time before psychosis
    • Significant weight loss, fatigue, abnormal heat/cold intolerance, chronic diarrhea/constipation, urination changes or edema, etc.
  • Strange response to antipsychotics
    • No improvement at all, or a dramatic worsening (e.g., neuroleptic sensitivity in Lewy body dementia).
    • Or very severe side effects at relatively low doses.

7) Treatment & Management — Treatment and Clinical Management

The core principle is:

“Treat the medical illness accurately + manage psychosis safely + work as a multidisciplinary team.”

7.1 Initial Assessment (Workup)

Detailed history:

  • Onset and course of psychosis.
  • Past and current medical illnesses, family history.
  • All medications/herbs/supplements being taken.

Physical and neurological examination:

  • General physical exam.
  • Detailed neurological exam.

Basic labs:

  • CBC
  • Electrolytes
  • Renal and liver function tests
  • Glucose
  • Thyroid function
  • B12/folate
  • Inflammatory markers
  • Autoimmune panels as indicated
  • Infectious workup (HIV, syphilis, etc.)

Neuroimaging:

  • Brain CT/MRI when lesions or neuroinflammatory disease are suspected.

EEG:

  • If epilepsy or encephalopathy is suspected.

CSF analysis:

  • If infection or autoimmune encephalitis is suspected.

7.2 Treatment Principles

Treat the underlying medical condition

  • Adjust thyroid hormone in myxedema psychosis / thyrotoxicosis.
  • Provide immunosuppressants or immunotherapy in autoimmune encephalitis (steroids, IVIG, plasmapheresis, rituximab, etc.).
  • Treat infections, correct metabolic abnormalities, and manage brain tumors or stroke according to standard guidelines in each specialty.

In many cases, psychosis improves dramatically once the medical condition is properly controlled.

Direct management of psychotic symptoms

  • Use antipsychotics at low to moderate doses, cautiously.
  • Choose type and dose based on comorbidities:

    • For Parkinson’s / Lewy body dementia:

    • Avoid strong D2 blockers; 
      • often use low-dose quetiapine or clozapine (following guidelines).
  • For elderly:
    • “Start low & go slow,” closely monitoring for side effects.
  • If catatonia is present → consider benzodiazepines (e.g., lorazepam) and, in some cases, ECT.

Managing safety and the environment

  • Assess risk of self-harm or harm to others.
  • Adjust environmental stimuli (light, noise, routine, sleep schedule) to reduce agitation and confusion.
  • Educate family members that delusions/hallucinations are consequences of medical illness, not the patient “going crazy for no reason.”

Long-term follow-up

  • Monitor whether psychosis resolves in parallel with the medical illness or persists/recurs.
  • In some cases (e.g., focal brain injury, chronic epilepsy), psychosis may become chronic and require follow-up similar to first-episode psychosis.

  • Assess:
    • Cognitive function
    • Functional status
    • Quality of life
  • Provide psychosocial support (rehabilitation, occupational therapy, etc.).

8) Notes — Key Points / Cautions

  • Do not rush to call every psychotic presentation “schizophrenia”
    • Especially when the age of onset is not in adolescence/early adulthood, or when clear physical signs coexist.
  • Delirium vs. Psychotic Disorder Due to Medical Condition
    • If there is clear fluctuating consciousness and marked inattention → diagnose delirium first.
    • Psychotic Disorder Due to Another Medical Condition is used when there is no delirium dominance and psychotic symptoms are central.
  • Substances/medications
    • If there is a history of substance use or medications that can cause psychosis (stimulants, steroids, dopaminergic agents, etc.) → consider Substance/Medication-Induced Psychotic Disorder instead, or in combination if both medical illness and substances are present.
  • Autoimmune psychosis is an emerging and very important field.
    • Autoimmune encephalitis can present initially with purely psychiatric symptoms (mania, psychosis, catatonia).
    • Early recognition, timely testing for autoantibodies/CSF abnormalities, and appropriate immunotherapy can dramatically change the patient’s long-term outcome.
  • Prevalence is not high, but impact is severe.
    • Even though secondary psychosis comprises a minority of psychosis cases overall, many of these illnesses (such as SLE, Wilson’s disease, endocrine crises) can lead to death or permanent disability if not recognized and treated promptly.

For content creation:

The power of this topic lies in reminding readers that “not every psychosis is schizophrenia, and sometimes psychosis is a warning sign that the body is seriously ill.”


Read Schizophrenia

✅ Reference

  • American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR). 2022. — Section: Psychotic Disorder Due to Another Medical Condition.
  • World Health Organization (WHO). International Classification of Diseases 11th Revision (ICD-11). 2019. — Code: 6E61 Secondary Psychotic Syndrome.
  • Keshavan MS, Kaneko Y. Secondary psychoses: an update. World Psychiatry. 2013;12(1):4–15.
    — A classic review summarizing medical causes such as endocrine, infectious, autoimmune, and neurologic factors.
  • Pollak TA, Rogers JP, Nagele RG, Peakman M, Stone JM, David AS.
    Autoimmune psychosis: an international consensus on an approach to the diagnosis and management. The Lancet Psychiatry. 2020.
    — A landmark paper that formalizes the concept of “autoimmune psychosis” as a distinct entity.
  • Dalmau J, Graus F.
    Antibody-mediated encephalitis. New England Journal of Medicine. 2018.
    — Explains the mechanisms of anti-NMDAR, GABA-B, LGI1, etc., which are major causes of psychosis from medical conditions.
  • Hansen N. Autoimmune encephalitis and psychosis. Frontiers in Psychiatry. 2021.
    — Summarizes how neuroinflammation can lead to psychosis.
  • MSD Manual (Professional Edition). Psychotic Disorders Due to Medical Conditions. Updated 2024.
    — Explains diagnosis, workup, and red flags in a format that is easy to adapt for public education.
  • Zarranz JJ. Neurology. 2018.
    — Contains sections on psychosis in Parkinson’s disease and dementia with Lewy bodies.

  • Wijdicks EF. Metabolic encephalopathies. Continuum (Minneap Minn). 2017.
    — Summarizes hepatic, renal, and electrolyte disturbances and how they lead to hallucinations, delirium, and psychosis.

  • Friedman JI. Neuropsychiatric manifestations of thyroid disease. Psychosomatics. 2002.
    — A key source on myxedema psychosis and thyrotoxic psychosis.
  • UpToDate. Evaluation of psychosis in adults (2024 Edition).
    — Describes algorithms for evaluating psychosis due to medical conditions and identifying red flags.
  • BMJ Best Practice. Psychosis – Assessment and Management.
    — A practical reference for management and choosing antipsychotics in patients with comorbid medical illnesses.

✅ 

Psychosis due to medical conditions, Secondary psychosis, Medical causes of psychosis, Psychotic disorder due to another medical condition, ICD-11 6E61, DSM-5-TR psychosis, Autoimmune psychosis, Autoimmune encephalitis, Anti-NMDAR psychosis, Myxedema psychosis, Thyrotoxic psychosis, Epilepsy psychosis, Post-ictal psychosis, Brain tumor psychosis, Stroke psychosis, Neuroinflammation, Metabolic encephalopathy, Hepatic encephalopathy, Uremic psychosis, Visual hallucinations medical causes, Olfactory hallucinations medical causes, Delirium vs psychosis, Neuropsychiatry, NeuroNerdSociety, Nerdyssey psychosis series


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