Psychosis

• 1. Introduction

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  Psychosis is the inability to distinguish what is or is not real. Hippocrates wrote about it in the 4th century BCE, and descriptions of something resembling it appear in the Ebers Papyrus dating as far back as 1500 BCE. Yet for most of recorded history, its victims were thought to be possessed by demons, afflicted by imbalanced bodily fluids, or simply mad. In the United States today, about 3% of people experience psychosis at some point in their lives. It is not a single disease. It is a state, a set of symptoms that can arise from schizophrenia, bipolar disorder, brain damage, severe stress, certain medications, and even a brief stint in a completely dark and silent room. The word itself was introduced to the psychiatric literature in 1841, and yet the field is still working out what it means at the level of neurons and neurotransmitters. What are the symptoms that define it? Why does a person in Ghana describe hearing voices very differently than a person in the United States? And how did medicine go from bloodletting and lobotomies to the antipsychotic drugs used today?

• 2. The Symptoms

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  Auditory hallucinations, particularly hearing voices, are the most common and often prominent feature of psychosis. Up to 15% of the general population may experience auditory hallucinations at some point, though not all of those are due to psychosis. In patients with schizophrenia, the prevalence is generally estimated around 70%. When voices are present, the average number has been put at three. People who hear those voices can frequently identify where they seem to originate, how loud they are, and may even assign identities to them. During the early 20th century, auditory hallucinations were actually second to visual hallucinations in frequency; the order has since reversed, at least in clinical schizophrenia populations.

  Visual hallucinations occur in roughly a third of people with schizophrenia, though some studies show rates higher than 60%. Content commonly involves animate objects, but can also include changes in lighting, shading, or the sensation that the ground is tilting. A rarer and more disorienting phenomenon is the cenesthetic hallucination, sometimes called a visceral hallucination, in which a person experiences sensations like burning or the rearrangement of internal organs without any physical cause.

  Delusions are a second major category. A delusion is a fixed, false belief that does not change even when a person is presented with clear evidence to the contrary. Prevalence of delusions in schizophrenia is generally put at around 80-90%, according to Columbia University. The most common type is the persecutory delusion, in which a person believes an entity is trying to harm them. Others include the belief that one's thoughts are audible to others, which is called thought broadcasting, or that one's thoughts are not even one's own, which is called thought insertion. Two rarer examples are Cotard's syndrome, the belief that one is partly or wholly dead, and clinical lycanthropy, the belief that one has transformed into an animal.

  The thematic content of delusions has shifted visibly over time. In the early 1900s in the United States, syphilis was a common subject of delusional content. During the Second World War, Germany became a frequent focus. In the Cold War era, communists appeared often. Now, technology is a common subject.

  Disorganized speech and thought round out the core symptom picture. These include derailment, where a person rapidly switches topics; tangential thinking, where topics shift to unrelated ones; and incoherence, sometimes described as a word salad. Catatonia, a profoundly agitated state that can manifest either as complete stillness and waxy flexibility or as excessive, purposeless movement, was once a prominent feature of psychosis but is rarely seen today. Whether that change reflects the use of modern treatments or some other shift is not known.

  Negative symptoms are often overlooked. These include reduced emotional expression, decreased motivation called avolition, reduced spontaneous speech called alogia, and anhedonia, the inability to feel pleasure. Researchers Nev Jones and Mona Shattell have noted that there is less curiosity in clinical practice toward the richness of psychotic experience, both the difficult and the positive, than toward the more dramatic symptoms.

• 3. What Causes It

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  Childhood trauma is a specific and measurable risk factor. Individuals with psychotic symptoms are three times more likely to have experienced childhood trauma, including physical or sexual abuse or emotional neglect, than people in the general population. The relationship between traumatic events and psychotic symptoms appears to be dose-dependent: multiple traumatic life events accumulate, compounding both the frequency and severity of symptoms. Even acute stressors can trigger brief episodes. Sensory deprivation offers a stark demonstration: a healthy person placed in an empty room with no light and no sound can develop psychosis in about 15 minutes.

  Neuroticism, a personality trait associated with vulnerability to stress, is an independent predictor of psychosis development, separate from trauma history.

  Substance use adds a distinct and well-documented pathway. Methamphetamine induces psychosis in 26%-46% of heavy users, and some develop a long-lasting psychosis that can persist for longer than six months. People who experienced a short-lived methamphetamine-induced episode can relapse into psychosis years later after a stressful event, even without returning to the drug. Cannabis use before age 15 may increase the risk of developing psychosis in adulthood, and the frequency of use correlates with risk. The two active compounds in cannabis appear to have opposite effects: THC can induce psychotic symptoms in healthy individuals, while limited evidence suggests CBD may have antipsychotic effects. Approximately 3% of people with alcoholism experience psychosis during acute intoxication or withdrawal, potentially through a kindling mechanism.

  A 2024 meta-analysis of psychedelic-induced psychosis found an incidence of 0.002% in population studies and 0.6% in randomized controlled trials. The same research found that psychedelic use interacted with family history: those with a family history of bipolar disorder showed an increase in psychotic symptoms with psychedelic use, while those with a personal history of psychosis but no family history of psychotic disorders showed a decrease.

  Beyond psychiatry and substances, a very large number of medical conditions can cause secondary psychosis. These include autoimmune disorders such as anti-NMDA-receptor encephalitis and systemic lupus erythematosus, neurodegenerative diseases like Parkinson's and Alzheimer's, vitamin B12 deficiency, thyroid disorders, and a range of electrolyte disturbances. A review also found an association between a first episode of psychosis and prediabetes.

• 4. The Brain Beneath

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  The first brain image of a person with psychosis was taken in 1935 using a technique called pneumoencephalography, a painful and now obsolete procedure in which cerebrospinal fluid was drained and replaced with air to reveal brain structures on an X-ray. Since then, neuroimaging has built up a detailed but still incomplete picture of what distinguishes a psychotic brain.

  Both first-episode psychosis and high-risk status are associated with reductions in grey matter volume. Studies during active hallucinations show increased activity in the left middle temporal gyrus, left superior temporal gyrus, and left inferior frontal gyrus, which is the region known as Broca's area. One proposed model suggests that hallucinations arise from a failure of feedforward networks from sensory cortices to the inferior frontal cortex; normally these networks cancel out sensory activity generated internally, and when they fail, the brain cannot distinguish its own internally generated speech from something heard externally.

  Psychosis has traditionally been linked to overactivity of the neurotransmitter dopamine, specifically in the mesolimbic pathway running from the ventral tegmental area to the ventral striatum. Two pieces of evidence support this: dopamine receptor D2-blocking drugs, which are antipsychotics, reduce psychotic symptoms; and drugs that increase dopamine, such as amphetamines and cocaine, can trigger psychosis in some people. But dopaminergic overactivity does not fully explain the picture. Psychosis commonly occurs in Parkinson's disease, a condition involving reduced rather than increased dopaminergic activity. Soyka and colleagues found no evidence of dopaminergic dysfunction in people with alcohol-induced psychosis. And newer antipsychotics block slightly less dopamine than older ones while also blocking 5-HT2A receptors, suggesting the original dopamine hypothesis was oversimplified.

  NMDA receptor dysfunction is a competing and complementary model. Dissociative NMDA receptor antagonists such as ketamine and PCP induce a psychotic state that mirrors schizophrenia, including negative symptoms. NMDA antagonism also mimics neurophysiological features such as reductions in the amplitude of P50, P300, and MMN evoked potentials. The endocannabinoid system is also implicated, given that CB1 receptor agonists like THC can trigger psychotic symptoms and CB1 antagonists like CBD appear to ameliorate them.

  Recent pharmacological thinking has refined how dopamine fits in. Rather than simply suppressing psychotic symptoms, antipsychotics may work by attenuating the reward mechanisms involved in delusional thinking, specifically the tendency to connect unrelated stimuli and assign them significance. One research paper summarizing this model acknowledged directly that the model is based on incomplete knowledge and will need to evolve as more is learned.

• 5. Culture Shapes the Experience

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  Cross-cultural studies have found that individual experiences of hearing voices vary substantially depending on where a person lives and the frameworks their culture provides for understanding unusual perceptions. In the United States, where a biomedical understanding of mind and mental health predominates, subjects have been found to describe their hallucinations as having violent content and often self-described themselves as crazy. In Accra, Ghana, the same experiences were more often described as having spiritual meaning and were frequently reported as positive. In Chennai, India, subjects described their hallucinations as kin, family members, or close friends who offered guidance.

  Researchers attribute these differences to a concept called social kindling, by which a person's social context shapes how they interpret and experience unusual sensations. This aligns with cognitive theories around reality modelling, and recent research supports it: individuals with psychosis can be taught to attend to their hallucinations differently, which in turn alters the character of the hallucinations themselves.

  In Cambodia, hallucinations are linked with spirit visitation, described there as cultural kindling. In Muslim majority countries, psychosis and schizophrenia are often attributed to jinn, or spirits. India and Cambodia share alternative knowledge systems that draw connections between mind, body, culture, nature, and society. These are not merely folk beliefs operating outside the medical system; they shape the lived texture of the illness and may open or close pathways for treatment that purely pharmacological approaches do not reach.

  A study of outpatients in psychiatric clinics found that 30% of religious patients attributed the cause of their psychotic symptoms to evil spirits, and many underwent exorcistic healing rituals that they largely reported as positive experiences. The rituals had no measured effect on symptoms. However, coercive forms of exorcism that excluded medical treatment were associated with a significant worsening of psychotic symptoms.

• 6. From Bloodletting to Antipsychotics

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  The medical teachings of Hippocrates of Cos, writing in the 4th century BCE, proposed that madness had natural rather than supernatural causes, and that the brain was its seat. His humoralist theory held that psychotic symptoms were caused by an excess of both blood and yellow bile, which led directly to his recommended treatment: bloodletting. That recommendation persisted for centuries.

  Benjamin Rush, an 18th-century physician widely considered the founder of American psychiatry and whose image appears on the official seal of the American Psychiatric Association, also prescribed bloodletting as a first-line treatment for psychosis. Rush believed active purging and bleeding corrected disruptions in the circulatory system, which he considered the primary cause of insanity.

  Early 20th-century treatments shifted toward shock therapies, including insulin shock therapy, cardiazol shock therapy, and electroconvulsive therapy. Despite considerable risk, these were considered highly efficacious. They paved the way for more invasive interventions. In 1888, Swiss psychiatrist Gottlieb Burckhardt performed the first medically sanctioned psychosurgery, excising portions of the cerebral cortex. Some patients showed symptom improvement, but one died and several developed aphasia or seizure disorders. Burckhardt published his clinical outcomes but was largely ignored by the medical community.

  In the late 1930s, Egas Moniz conceived the leucotomy, also called the prefrontal lobotomy, after watching a 1935 demonstration by neuroscientists John Fulton and Carlyle in which two chimpanzees were given leucotomies and their pre- and post-surgical behavior was compared. Before the procedure the chimps engaged in typical behavior including throwing feces and fighting; afterward, both were pacified. During the question-and-answer session, Moniz asked whether the procedure could be extended to humans, a question Fulton later described as startling. Moniz received the Nobel Prize in 1949 for extending the procedure to humans with various psychotic disorders. Between the late 1930s and early 1970s, leucotomy was widely practiced, often in non-sterile environments including small outpatient clinics and patient homes.

  The era of psychosurgery ended with the first clinical trial of antipsychotics in 1952. Chlorpromazine, sold under the brand name Thorazine, became the first antipsychotic approved for both acute and chronic psychosis. Its mechanism of action was not understood until 1963. The side effects of this first generation were severe and often irreversible, including Parkinsonian symptoms such as tardive dyskinesia. Atypical antipsychotics, or second-generation antipsychotics, arrived with a comparable response rate but a different side-effect profile: lower risk of Parkinsonian symptoms but higher risk of cardiovascular disease and metabolic syndrome, most pronounced with olanzapine. Psychiatrist David Healy has criticized pharmaceutical companies for promoting oversimplified biological theories of mental illness that downplay the social and developmental factors known to influence the etiology of psychosis.

• 7. Diagnosis and Treatment Today

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  Diagnosing psychosis correctly requires ruling out a wide range of other conditions first. Blood tests can check thyroid-stimulating hormone, vitamin B12 levels, electrolytes, and serology for syphilis and HIV. An EEG can exclude epilepsy. MRI or CT scans can rule out brain lesions. Toxicology screening can exclude substance- and medication-induced psychosis with a high degree of certainty. Because dietary supplements can also induce psychosis or mania but cannot be detected by standard lab tests, clinicians are advised to ask a patient's family or friends whether any supplements are being taken.

  Common diagnostic mistakes include not properly excluding delirium, missing a toxic psychosis by failing to screen for substances, and premature diagnostic closure. The Brief Psychiatric Rating Scale assesses 18 symptom constructs including hostility, suspicion, hallucination, and grandiosity, based on a clinical interview and observations of the patient's behavior over the previous 2-3 days. The 30-item Positive and Negative Syndrome Scale, or PANSS, is used to assess both positive and negative symptoms during initial assessment and follow-up.

  For many psychotic disorders, antipsychotic medication remains the first-line treatment and can reduce positive symptoms in about 7 to 14 days. About 40-50% of people show a good response, 30-40% a partial response, and 20% show treatment resistance, defined as failure to respond satisfactorily after six weeks across two or three different antipsychotics. Clozapine is effective for treatment-resistant cases but carries a risk of agranulocytosis, a dangerous drop in white blood cell count, in less than 4% of people.

  Psychological treatments increasingly complement medication. Acceptance and commitment therapy may help people function in line with their values despite persistent symptoms. Metacognitive training is associated with reduced delusions, hallucinations, and negative symptoms, as well as improved self-esteem, in people with schizophrenia spectrum disorders. A randomized controlled trial of a web-based cognitive behavioral therapy program called Coping With Voices found promise for increasing access to therapy and improving the management of distressing psychotic symptoms. A separate study suggested that combining cognitive behavioral therapy with SlowMo, an application designed to help people notice unhelpful quick-thinking patterns, may be more effective for treating paranoia than standard CBT alone. In 2014, the UK National Institute for Health and Care Excellence recommended preventive CBT for people at high risk of psychosis.