Psychosis: Reducing Stigma Through Biology

Psychosis is often portrayed as an enigma, a condition shrouded in fear and misunderstanding. Until as recently as the mid-1900s, conditions like schizophrenia and bipolar disorder were thought to be caused by poor parenting or repressed emotions. Today, misconceptions persist, casting individuals with psychosis as unpredictable or morally flawed. Recent advancements in neuroscience and genetics teach us that psychosis is a brain-based condition arising from an interplay of multiple causes.

Reframing psychosis in biological terms can reduce stigma and foster compassion. It’s not about minimizing the impact of trauma or other life experiences, but about integrating all of the relevant factors: genetics, neurodevelopment, and environment. Understanding psychosis as a symptom, like a fever, highlights the underlying brain mechanisms at play.

The Brain in Psychosis: What’s Happening?

The first biological theories of psychosis centered on dopamine, a neurotransmitter involved in reward, motivation, and attention. In the mid-20^th century, antipsychotic medications like chlorpromazine and haloperidol were developed and found to reduce psychotic symptoms by blocking a specific dopamine receptor called the D2 receptor. This led to the dopamine hypothesis, suggesting that dysregulation in dopamine pathways, particularly in the mesolimbic system, contributed to positive symptoms like hallucinations and delusions.

However, the dopamine model was not able to explain everything. Ongoing research eventually identified other neurotransmitter systems, including glutamate, serotonin, and acetylcholine.

• Glutamate, particularly through NMDA receptors, appears crucial for cognitive functioning and attention. Dysfunction in these pathways can drive both positive and negative symptoms, such as apathy and cognitive impairment.
• Serotonin, known for its role in mood regulation, can also impact sensory processing, potentially contributing to perceptual disturbances. The 5HT3 receptor is both a target of psychedelics like LSD, which induce psychotic like symptoms by activating it, and is blocked by antipsychotics like olanzapine.
• Imbalances in Acetylcholine functioning, particularly Muscarinic receptors, can have an effect on sensory gating and cognitive functioning. A recently developed medication, under the brand name Cobenfy, targets these receptors and has been shown to improve both positive and negative symptoms of psychosis while improving cognition in individuals with dementia.

Neuroscience now emphasizes the concept of network dysconnectivity rather than isolated chemical imbalances. This refers to the science of multiple brain regions that work together in a structured way to create more complex systems, such as those around attention and motivation. Brain networks commonly implicated in psychosis include:

• Default Mode Network (DMN): Hyperactivity in this network may underlie self-referential delusions and hallucinations.
• Salience Network: Disrupted function here can lead to assigning undue importance to neutral stimuli, fueling paranoia.
• Central Executive Network: Impairment in this network may contribute to disorganization and cognitive deficits.

Chronicity and Brain Plasticity

Left untreated, psychosis can become more entrenched and difficult to treat. Chronic positive symptoms of psychosis are associated with excitotoxicity, a situation where overactivation of NMDA receptors leads to cell damage. This can exacerbate symptoms, reduce treatment responsiveness, and contribute to cognitive decline.

Genetic Vulnerability and Environmental Risks

Psychosis is polygenic, meaning risk arises from the cumulative effect of many small genetic variations. Genome-wide association studies (GWAS) have identified several risk-related single-nucleotide polymorphisms (SNPs); the catch is that specific SNPs don’t cause psychosis but statistical models show that an accumulation of certain commonly seen SNPs increases the likelihood of experiencing psychosis of any cause. Twin studies reveal that even in identical twins, who share all their DNA, one may develop schizophrenia while the other does not, suggesting a critical role for environmental factors.

Prenatal infections, birth complications like hypoxemia, childhood trauma, and environmental pollution all elevate risk. For instance, maternal influenza during pregnancy has been linked to increased psychosis risk, likely due to neuroinflammatory processes that alter fetal brain development.

Social context matters. Urban upbringing, discrimination, and social isolation have been linked to higher psychosis risk. Cannabis use, particularly during adolescence, is another potent factor, especially when combined with genetic vulnerability.

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A Psychoanalytic Perspective

From a psychoanalytic perspective, delusions and hallucinations may carry symbolic meaning. For instance, a paranoid delusion may reflect disowned aggression or a sense of vulnerability. Recognizing these underlying dynamics can provide therapeutic entry points, enriching biological and pharmacological interventions.

Psychosis is not a singular condition but a convergence of genetic, neurodevelopmental, and psychosocial factors. Understanding its biological foundations enables more targeted, compassionate care. By embracing complexity, we move away from stigmatizing narratives and toward a more nuanced, integrated approach to treatment and recovery.