What is Psychosis?

Psychosis describes a detachment from reality. Symptoms of psychosis include disturbances in perceptions, thoughts, moods, and behaviors. It is important to note that symptoms of psychosis are traditionally separated into positive symptoms (hallucinations, delusions, and disorganized speech/behaviors) and negative symptoms (avolition, social withdrawal, depressed mood, apathy, blunting of affect, and catatonia).

What are Positive Symptoms?

Positive symptoms include hallucinations, delusions, and disorganized speech or behaviors. Hallucinations occur when a person perceives a stimulus when no stimulus is present. For example, one might hear voices when no one is there or see things that aren’t real. Sensory hallucinations may occur in any of the senses. Illusions, on the other hand, are not hallucinations and occur when a person misperceives a stimulus when there actually was one (e.g., misperceiving a piece of lint for a spider).

Delusions are strongly held beliefs that are false. They represent disturbances of thought that can occur during psychotic episodes.  Delusions are illogical and sometimes bizarre and persist despite refuting evidence. Common delusions include persecutory delusions (believing others are out to harm you), grandiose delusions (inflated sense of self-worth, invincibility, possessing special abilities), and referential delusions (believing ordinary events or normal human behaviors relate to you in some way). Sometimes, delusional systems or delusional themes can develop that are complex and elaborate. 

Disorganized behavior is self-contradictory or inconsistent. It may include childlike silliness, purposeless behavior, unpredictable agitation, or extreme emotional reaction (e.g., laughing after a catastrophe). A typical example is dressing in clothing inappropriate for the weather (e.g., wearing several layers on a hot day).

Disorganized speech is illogical, incoherent, and incomprehensible. Many times, a person with disorganized speech will answer questions inappropriately. 

What are Negative Symptoms?

Negative symptoms of psychosis include social withdrawal (isolating), apathy (i.e., indifference), alexithymia (i.e., inability to describe emotions), blunting of affect (i.e., minimal emotional expression), catatonic behaviors (e.g., standing in one position for long periods of time), avolition (i.e., no motivation or lack of goal-directed behavior), depression, anxiety, and sleep disturbances. In general, negative symptoms are associated with poorer outcomes in the long term. They are also more difficult to treat than positive symptoms.

What Causes Psychosis?

The exact cause of psychosis remains unclear. However, we know that psychosis, or psychotic episodes, are associated with illicit drug use, medical problems, medications, and primary psychiatric disorders. 

(1) Illicit drugs: Magic mushrooms/psilocybin, ecstasy/MDMA, methamphetamine, cannabis).

(2) Medical conditions: Thyroid disease, encephalitis, brain tumors, dementia/neurocognitive disorders, seizures/epilepsy)

(3) Medications: Steroids, opioids, anticholinergic toxicity, certain antibiotics.

(4) Primary psychiatric disorders: Schizophrenia, Bipolar disorder, or severe Depression. 

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 and 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.

Psychotic Disorders

Schizophrenia

Schizophrenia is a serious mental illness affecting a person’s thinking and behaviors. Individuals with schizophrenia often lose touch with reality, which makes it difficult for them to function at work, have healthy relationships, and be independent. Schizophrenia is diagnosed when symptoms such as delusions, hallucinations, disorganized speech, odd behaviors, and/or negative symptoms occur persistently for at least 6 months and are not attributable to any drug, medication, or medical condition. 

Schizoaffective Disorder

Schizoaffective disorder is similar to Schizophrenia but with the addition of mood episodes (manic and/or depressive) during the course of illness. 

Delusional Disorder

As stated above, delusions are strongly held beliefs that are false. They represent disturbances of thought that can occur during psychotic episodes.  Delusions are illogical and sometimes bizarre and persist despite refuting evidence. 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

Treatment of Psychotic Disorders

Treatment of psychosis depends upon the underlying cause. If medication-induced, then stopping the problematic medication is the treatment. If due to drug intoxication the treatment is supportive until the drug is out of the body–followed by interventions such as drug rehabilitation.

If the psychotic episode occurs as a result of a primary psychotic disorder such as schizophrenia or a mood disorder such as bipolar disorder with psychotic features, then a combination of medications and psychosocial interventions should be considered. 

Psychosocial interventions include group therapy, social skills training, recreational therapy, case management, and/or placement in a structured environment. Although the psychosocial treatment of psychosis is essential to recovery, it is not reviewed here in-depth. 

Below is a brief outline of the medical treatment of psychosis. 

Acute Psychosis (During the episode)

Antipsychotic Medications

• 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)
• Benzodiazepinesare used as augmentation agents (especially if mania or stimulant intoxication is present)

Electroconvulsive Therapy (ECT) in severe cases

Maintenance/Relapse Prevention

Antipsychotic Medications

• 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)

Electroconvulsive Therapy (ECT) in severe cases

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