Psychosis is a broad term that refers to a mental condition characterized by a disconnection from reality, which can manifest through various symptoms like hallucinations, delusions, and disorganized thinking.

Psychosis is not a disorder in itself but is usually a symptom or set of symptoms that can occur in various mental health conditions. It can also be triggered by traumatic experiences, substance abuse, or even certain medical conditions.

SIGNS AND SYMPTOMS OF PSYCHOSIS

Symptoms of psychosis are traditionally separated into positive symptoms and negative symptoms.

Positive Symptoms

Positive symptoms include hallucinations, delusions, and disorganized thinking (or behaviors).

Hallucinations: False perceptions, such as hearing voices, seeing things, or smelling things that are not present in the external environment.

Delusions: False beliefs strongly held despite evidence to the contrary, such as paranoid delusions or grandiose delusions. Common delusions include the following:

• Erotomanic type: Central theme of the delusion is that another person is in love with the patient

• Grandiose type: Central theme of the delusion is the conviction of having some great (but unrecognized) talent or insight or having made some important discovery.

• Jealous type: Central theme of the individual’s delusion is that his or her spouse or lover is unfaithful.

• Persecutory type: Central theme of the delusion involves the individual’s belief that he or she is being conspired against, cheated, spied on, followed, poisoned or drugged, maliciously maligned, harassed, or obstructed in the pursuit of long-term goals.

• Somatic type: Central theme of the delusion involves bodily functions or sensations.

• Mixed type: No one delusional theme predominates.

• Unspecified type: Dominant delusional belief cannot be clearly determined or is not described in the specific types

• With bizarre content: Delusions are deemed bizarre if they are clearly implausible, not understandable, and not derived from ordinary life experiences

Disorganized Thinking: This may manifest as incoherent speech, trouble concentrating, or difficulty with logical thought processes.

Negative Symptoms

Negative symptoms of psychosis include social withdrawal (i.e., isolating), apathy (i.e., indifference), alexithymia (i.e., difficulty articulating emotions), blunting of affect (i.e., minimal emotional expression), catatonic behaviors (i.e., unresponsiveness or lack of motor activity), avolition (i.e., no motivation or lack of goal-directed behavior), poverty of speech, anhedonia (i.e., lack of pleasure or joy), and cognitive symptoms (i.e. impaired memory, attention, executive functions, and/or insight).

In general, negative symptoms are associated with poorer outcomes in the long term. They are also more difficult to treat than positive symptoms.

CAUSES OF PSYCHOSIS

The exact cause of psychosis remains unclear. However, we know that psychosis, or psychotic episodes, are associated with the following:

• Mental Health Disorders: Conditions like schizophrenia, schizoaffective disorder, and bipolar disorder with psychotic features include psychosis as a symptom.

• Substance Abuse: Certain drugs can induce psychotic states.

• Trauma: Severe stress or traumatic experiences can trigger a psychotic episode.

• Medical Conditions: Neurological disorders, brain injuries, and some types of epilepsy can also cause psychosis.

• Medications: Steroids, opioids, anticholinergic toxicity, certain antibiotics.

• Other Factors: Lack of sleep, hormonal changes, and nutritional deficiencies can contribute to psychosis.

DIAGNOSIS

Diagnosis usually involves a comprehensive psychiatric evaluation and symptom assessment. Medical tests and imaging studies may be used to rule out other underlying causes.

TREATMENT

The treatments for acute (active) psychosis and prevention (maintenance) are outlined below.

Acute (active) Psychosis

• First line: Atypical Antipsychotics due to lower Extrapyramidal Side Effect, Tardive Dyskinesia, and neuroleptic malignant syndrome (also better tolerated)

• Second line: Typical Antipsychotics

• Treatment Resistant Psychosis (2 failed trials of antipsychotics): Clozapine (Clozaril)

• For Severe Cases (or for malignant catatonia): Electroconvulsive Therapy (ECT)

• Note: Benzodiazepines are used as augmentation agents (especially if mania or stimulant intoxication is present)

Prevention (Maintenance)

• First line: Atypical Antipsychotics due to lower Extrapyramidal Side Effect, Tardive Dyskinesia, and neuroleptic malignant syndrome (also better tolerated). Evidence supports the use of long acting injectables (Risperdal Consta, Invega sustenna, Invega Trinza, Abilify Maintenna, Aristada, Relprevv)

• Second line: Haldol Decanoate (Long acting injectable)

• Treatment Resistant Psychosis (2 failed trials of antipsychotics): Clozapine (Clozaril)

• For Severe Cases (or for malignant catatonia): Electroconvulsive Therapy (ECT)

• Note: Benzodiazepines are used as augmentation agents (especially if mania or stimulant intoxication is present)

• Psychotherapy: Cognitive behavioral therapy (CBT) is one form of psychotherapy often used to help manage symptoms and provide coping mechanisms.

• Hospitalization: In severe cases or when there is a risk of harm to oneself or others, inpatient care may be necessary.

• Supportive Treatments: Family support, community programs, and other supportive services can play a vital role in treatment and recovery.

Management of psychosis often requires a multi-faceted approach, including medication, psychotherapy, and support from family and community. Timely intervention is crucial for better outcomes, so if psychosis is suspected, immediate medical attention is recommended.

SCHIZOPHRENIA, SCHIZOAFFECTIVE DISORDER, AND BIPOLAR DISORDER WITH PSYCHOTIC FEATURES

SCHIZOPHRENIA

A chronic mental disorder primarily affecting thought processes, leading to diminished functionality and distorted perception of reality.

• Positive symptoms: Hallucinations, delusions, disorganized thinking.

• Negative symptoms: Affective flattening, anhedonia, poverty of speech.

• Cognitive symptoms: Impaired memory, attention, and executive functions.

Diagnosis: Diagnosis is based on clinical assessment, including a thorough psychiatric history and careful symptom evaluation. Neuroimaging may be used to rule out other conditions.

SCHIZOAFFECTIVE DISORDER

Schizoaffective disorder combines symptoms of schizophrenia, like hallucinations or delusions, with symptoms of a mood disorder like depression or bipolar disorder.

• Mood disorder symptoms: Either depressive or manic episodes, or sometimes both.

• Psychotic symptoms: Hallucinations, delusions, disorganized thinking.

Diagnosis: Schizoaffective disorder is challenging to diagnose because it features symptoms of both mood disorders and schizophrenia. Requires careful clinical evaluation to distinguish from other disorders.

BIPOLAR DISORDER WITH PSYCHOTIC FEATURES

Bipolar disorder is primarily characterized by extreme mood swings ranging from depressive episodes to manic episodes. In some cases, individuals may also experience psychotic symptoms like hallucinations or delusions during a manic or depressive episode. These are known as "psychotic features."

• Manic episodes: Elevated mood, hyperactivity, decreased need for sleep, grandiosity.

• Depressive episodes: Low mood, low energy, loss of interest in activities.

• Psychotic features: Hallucinations, delusions.

Diagnosis: Generally diagnosed through clinical evaluation, including a thorough psychiatric history and symptom assessment. May require ruling out other medical conditions and medication-induced effects.

KEY DIFFERENCES BETWEEN SCHIZOPHRENIA, SCHIZOAFFECTIVE DISORDER, AND BIPOLAR DISORDER WITH PSYCHOTIC FEATURES

Given the complexity and overlap in symptoms, it's often challenging to differentiate between these disorders. A comprehensive diagnostic assessment and careful follow-up are essential.

The Neurobiology of Psychosis

As with most psychiatric disorders, psychosis likely results from genetic vulnerability combined with environmental stressors during early development.

Two major theories have informed the pharmacological treatment of psychosis:

1. The dopamine hypothesis

2. The NMDA receptor hypothesis. 

The Dopamine Hypothesis

The Dopamine hypothesis suggests dopamine dysfunction within the major dopamine pathways in the brain (see below). Dopamine neurons represent a very small fraction of neurons in the brain and project to many areas of the brain within discrete pathways. About 80% of dopamine is found within and area of the brain called the basal ganglia. There are many dopamine projections in the brain but here we limit our discussion to the four dopamine pathways most relevant to psychosis. Dopamine is a neurotransmitter made from the amino acid L-Tyrosine and plays important roles in motivation, reward, movements, emotional expression, and cognitive functions.

There are four major dopamine pathways in the brain

Mesolimbic Tract: The mesolimbic dopamine tract begins with dopamine cell bodies located within an area of the brainstem known as the ventral tegmental area (VTA, see neuroanatomy in previous lessons). These dopamine neurons project to an area of the ventral striatum known as the nucleus accumbens. Dopamine released within the nucleus accumbens is partially responsible for the reinforcing aspects of many drugs of abuse. It turns out that too little dopamine in this area may lead to anhedonia, lack of interest, and low motivation. Too much dopamine in this area has been found to contribute to the positive symptoms of psychosis. Therefore, blocking the D2 dopamine receptors in the mesolimbic tract with antipsychotics decreases positive symptoms. For antipsychotics to be effective, approximately 80% of striatal D2 receptors must be blocked. 

Mesocortical Tract: The mesocortical dopamine tract begins with dopamine cell bodies located within the ventral tegmental area (same as mesolimbic) but these neurons project to areas of the prefrontal cortex where they play a role in cognitive (dorsolateral PFC) and emotional (ventromedial PFC) processing. Too little dopamine in the mesocortical tract contributes to the negative symptoms of psychosis: Decreased emotional expression, Decreased emotional responsiveness, Decreased interest, Decreased cognitive abilities, and Decreased socialization. Blocking dopamine D2 receptors in the mesocortical tract with antipsychotics worsens negative symptoms. This is why haloperidol and other high potency agents often cause blunting of affect and cognitive dysfunction.

Nigrostriatal Tract: The nigrostriatal dopamine tract begins with dopamine cell bodies located within the substantia nigra (in the midbrain). Dopamine cell bodies within the substantia nigra project to areas of the striatum (i.e., putamen and caudate nucleus). Dopamine in this tract is very much involved in the initiation and modulation of movement. Atrophy and destruction of dopamine neurons within the substantia nigra is seen in the hypokinetic movement disorder called Parkinson's Disease. Too little dopamine in the nigrostriatal tract leads to slowed movements (bradykinesia), pill rolling tremor, shuffling gait, and other symptoms we call "extrapyramidal symptoms (EPS)." We call them "extrapyramidal" because this system is outside of the primary motor pathways (i.e. corticospinal tract or pyramidal system). Blocking D2 receptors in the nigrostriatal tract with medications or poisons causes or exacerbates EPS. EPS includes dystonia, Parkinsonism, Tardive Dyskinesia, and Akathisia. 

Tuberoinfundibular Tract: The tuberoinfundibular tract begins with dopamine cell bodies located in the hypothalamus where they project and release dopamine into the pituitary circulation. Normally, Dopamine acts on lactotroph cells in the pituitary via D2 receptors and inhibits Prolactin Release. Blocking D2 receptors with antipsychotics increases Prolactin release from pituitary and may lead to side effects of hyperprolactinemia such as Galactorrhea, Menstrual irregularity, Sexual dysfunction, Vision changes, Infertility, and Headache.

Where did the dopamine theory of psychosis come from? 

The concept of dopamine hyperactivity emerged from a convergence of basic neuroscience findings, clinical observations, and advances in neuroimaging techniques. It was well known that dopaminergic drugs (L-Dopa, cocaine, amphetamines) induce psychosis in man that mimics the paranoia seen in patients with schizophrenia. In laboratory animals, administering high doses of amphetamines causes species-specific stereotyped, repetitive behaviors. In rodents, for example, high doses of amphetamine induce repetitive chewing, biting, grooming, and circular locomotion (i.e., running in circles in a cage). It was discovered that medications like chlorpromazine and haloperidol reduced these stereotyped behaviors in laboratory animals. In fact, chlorpromazine and haloperidol caused slowed movements and rigidity, called "neurolepsis," hence the term neuroleptic.

In 1952, Delay and Deniker published the first clinical trial demonstrating chlorpromazine's antipsychotic effects. These findings combined with chlorpromazine's ability to reduce stimulant-induced stereotyped behaviors in laboratory animals further supported dopamine's role in psychosis. It wasn't until later that chlorpromazine was found to be an antagonist at dopamine D2 receptors. In fact, early studies demonstrated that the higher a drug's potency of dopamine D2 receptor antagonism, the more it reduced the positive symptoms of psychosis in humans. The problem was, the more potent the drug at blocking D2 receptors, the more likely the emergence of side effects such as slowing of movement, rigidity, and catatonia similar to the neurolepsis seen in mice.

The NMDA Receptor Hypothesis

The NMDA Receptor hypothesis suggests hypofunctioning NMDA Receptors located on GABA interneurons within the cerebral cortex may contribute to psychosis. The NMDA Receptor hypothesis is supported by the observed clinical effects of NMDA receptor antagonists such as PCP and Ketamine, which mimic most of the symptom domains of schizophrenia (positive symptoms, Negative symptoms, cognitive symptoms, etc). It is important to know that GABA interneurons make up the majority of neurons within the cerebral cortex where they play a key role in modulating glutamatergic neurotransmission. GABA interneurons are also found within the Basal Ganglia where they also play an important role in modulating neurotransmission of glutamate and other neurotransmitters.  The dopamine hypothesis and the NMDA Receptor Hypothesis are not mutually exclusive, as downstream changes in glutamate neurotransmission due to hypofunctioning NMDA receptors may alter dopaminergic tone in key areas of the brain. However, here we discuss the dopamine theory of psychosis as it helps new learners understand the basics of antipsychotic mechanisms. 

Malfunctioning NMDA receptors located on GABA interneurons in the cerebral cortex lead to GABA interneurons being less active. This means Glutamate neurons become overactivated. Glutamate neurons that project to the Ventral Tegmental Area then overstimulate dopamine neurons that project to the nucleus accumbens via the mesolimbic dopamine tract.

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This post was reviewed by a licensed medical professional.