- Selective dopamine D₂ receptor deletion from parvalbumin interneurons in mice causes a dysregulated dopaminergic system - including impaired inhibitory activity in the ventral hippocampus - since the D₂ receptor is necessary to modulate pyramidal neuron activity. The modulation of these interneurons may prevent overall dopaminergic dysregulation
- Disrupted parvalbumin interneuron (PVI) function is thought to be an integral part of the pathophysiology of schizophrenia. PVIs drive cortical gamma oscillations, which are important for working memory and why such impairments are common in schizophrenia patients. They are also critical for proper excitatory/inhibitory balance in the brain.
- Inhibitory activity starts to be promoted by DRD2 in the PVI around the time of adulthood, which could explain why schizophrenia manifests itself at this particular life stage


Connection Between DRD2, Parvalbumin Interneurons, and Schizophrenia

- DRD2 conditional mutant mice (where DRD2 is deleted) show a range of endophenotypes associated with schizophrenia and had a limited or blunted pharmacological response to aripiprazole 
- Adult conditional mutant mice showed an significant increase in overall locomotor activity, an increase in anxiety or risk-taking behaviors (evidenced by an increased proportion of time spent in the open arms of the test maze and a decrease in the amount of marbles they buried), showed working memory impairments by alternating significantly less times between the arms of the maze, and were shown to unravel significantly less cotton to buid their nests (suggesting decreased motivation)
- Conditional mice mutants spent an equal amount of time with new and familiar stimuli - which indicates they were treating all objects as if they were new, indicative of memory impairments.

The Effect of DRD2 Deletion from Parvalbumin Interneurons on Behavior

- Dopamine signaling through DRD2 regulates the spine morphology of pyrmidal neurons, so when DRD2 was deleted there was a marked decrease in dendritic spine density
- Reduced glycogen synthase kinase 3ꞵ (Gsk3ꞵ) seen in schizophrenia patients - including DRD2 conditional mutant mice
- Reduced mRNA expression of GAD67 and PV proteins reduced in the prefrontal cortex of conditional mutant mice without a significant change in parvalbumin interneuron (PVI) density
- NMDA receptor subunit NR2B was significantly reduced in conditional DRD2 mutant mice
- Alpha band (8-12 Hz) oscillations regulate the amplitude of the gamma band (30-70 Hz), and this was increased in the prefrontal cortex of conditional DRD2 mutant mice


Prefrontal Cortex Endophenotypes as a Result of DRD2 Deletion

There was a significant increase in dopamine metabolites in the striatum of DRD2 conditional mutant mice. Also there was a significant decrease in both dopamine and its metabolites in the prefrontal cortex of DRD2 conditional mutant mice


Cortico-striatal Imbalance in DRD2 Mice Mutants

DRD2 conditional mutant mice were shown to be hypersensitive to amphetamine in the open field locomotion test, the mice showing an increase in locomotion, and suggesting an endogenous mechanism for sensitization of the dopaminergic system.

Sensitivity to Amphetamine in DRD2 Mice Mutants

- DRD2 agonist quinpirole didn’t change the level of excitatory afferant stimulation, but it did significantly decrease inhibitory afferant activity in DRD2 mutant mice. This generated an excitatory/inhibitory imbalance in response to afferant activation - causing an increase in this ratio, which may lead to an increase in the response of pyramidal neurons when afferant activity arrives.
- Total locomotion was reduced down to basal levels in both controls and DRD2 mutants when risperidone was used in combination with amphetamine or NMDAR antagonist MK-801, which suggests that risperidone antagonism on DRD2 may have prevented the effect of massively released dopamine and that DRD2 expression in parvalbumin interneurons wasn’t required by risperidone to lower locomotor activity
- When treated with aripiprazole in combination with amphetamine, controls saw a significant decrease in total locomotion but only a partial decrease in DRD2 conditional mutants
- When treated with aripiprazole in combination with MK-801, control mice saw a significant decrease in locomotion but DRD2 mutants were resistant to aripiprazole treatment - which indicates that DRD2 expression on parvalbumin interneurons is required by this particular antipsychotic to recover from induced hyperlocomotion. 

Effect of Antipsychotics on Schizophrenic Behavioral Phenotypes in DRD2 Mouse Mutants

- Connection Between DRD2, Parvalbumin Interneurons, and Schizophrenia
- The Effect of DRD2 Deletion from Parvalbumin Interneurons on Behavior
- Prefrontal Cortex Endophenotypes as a Result of DRD2 Deletion
- Cortico-striatal Imbalance in DRD2 Mice Mutants
- Sensitivity to Amphetamine in DRD2 Mice Mutants
- Effect of Antipsychotics on Schizophrenic Behavioral Phenotypes in DRD2 Mouse Mutants


Macalester College

Schizophrenia is a severe psychological disorder that leads to a profound breakdown in an individual's ability to function, often necessitating hospitalization. It is characterized by significant disruptions in thought, perception, emotion, and behavior, including symptoms like hallucinations, delusions, incoherent thinking, bizarre actions, flat emotions, and a lack of motivation for basic activities. It is important to distinguish schizophrenia from dissociative identity disorder ('split personality'), as the term 'schizophrenia' refers to a 'splitting of psychic functions,' not a divided personality.

Schizophrenia

Tomasella, Eugenia, et al. “Deletion of Dopamine D₂ Receptors from Parvalbumin Interneurons in Mouse Causes Schizophrenia-like Phenotypes.” *Proceedings of the National Academy of Sciences*, vol. 115, no. 13, 12 Feb. 2018, pp. 3476–3481., https://doi.org/10.1073/pnas.1719897115. 


Deletion of dopamine D₂ receptors from parvalbumin interneurons in mouse causes schizophrenia-like phenotypes

Substantial evidence indicates a genetic foundation for schizophrenia. For instance, an individual's risk of developing the disorder is approximately six times higher if they have a parent with schizophrenia compared to someone who does not. Furthermore, the likelihood of developing schizophrenia is directly correlated with the degree of genetic similarity to family members who have been diagnosed with the condition.

Hereditary Component of Schizophrenia

Individuals with schizophrenia on average have lower overall physical health and are at increased risk of infection with COVID-19 due to decreased cognitive ability and decision making capacity. In addition, the psychotic symptoms associated with schizophrenia may be heightened due to social distancing and isolation practices. These practices can make basic services and support difficult to access for schizophrenic patients, making them more vulnerable to a negative impact on their mental health. 

Impact of COVID-19 on Individuals with Schizophrenia

Hypothesis: Schizophrenia results from an underactivation of glutamate receptors.

- Origin of Hypothesis

The Glutamate Hypothesis of Antipsychotics

Earlier, there were no treatments to help people who are suffering from schizophrenia. Add to this the neglected institutions where patients were not cared for, people were desperate for treatment and they resorted to a procedure called lobotomy.
Other treatments are: 
- Psychosurgery 
- Drug called Chlorpromazine

Currently, there are additional therapies used for treatment of schizophrenia.

In 2020, The American Psychiatric Association released a clinical practice guideline with pharmacotherapy and psychosocial intervention recommendations.

Pharmacotherapy recommendations:
- Antipsychotic medication (2nd generation agents)
- Clozapine for treatment-resistant patients OR patients with persistent suicidal thoughts/attempts OR consistent hostility and aggressive tendencies)

Psychosocial Intervention recommendations
- A specially coordinated care program created for patients who undergo their first episode of psychosis
- Cognitive-behavioral therapy

Treatment of Schizophrenia 

Studies have found that apart from the genetic factors that are responsible for schizophrenia, there is also a variety of stressful events that may increases the risk of developing schizophrenia. Some of them are: 

- Prenatal Stress

- Urban vs Rural Lifestyle

- Dependency on Anti psychotic Drugs 

- Parental Separation or Loss

Role of Environmental Factors in Schizophrenia 

There is evidence of increased neuroinflammation and inflammatory cytokines in the CSF of schizophrenia patients within 5 years of onset, as well as increased microglia density in the dorsolateral prefrontal cortex. Abnormal microglia density in the temporal lobe seems to be consistent across all schizophrenia patients, but there appears to be some nuanced differences among different subtypes and among the brains of patients who died by suicide versus not. Antipsychotic exposure seems to impact microglial density and inflammation, but this is not yet well understood.

Microglia in Schizophrenia

Though there is no cure for schizophrenia, many patients do well with minimal symptoms. A variety of antipsychotic medications are effective in reducing the psychotic symptoms present in the acute phase of the illness, and they also help reduce the potential for future acute episodes and their severity. Psychological treatments such as cognitive behavioral therapy or supportive psychotherapy may reduce symptoms and enhance function, and other treatments are aimed at reducing stress, supporting employment or improving social skills.

Schizophrenia Treatment 

- Every major review for the past half-century, including those authored by members 
of our group, has described schizophrenia as a disease of “unknown etiology,” one 
“suspected” of having developmental origins. While this is a valid characterization 
of an enigmatic disease, its consistent application belies the advances made in the 
field of schizophrenia research.
- For example, multiple risk factors for the disease have now been elucidated. 
Some meet the standard of reproducibility, and several findings have been replicated in population-based studies. Additionally, risk and vulnerability at key points 
throughout the lifespan have been investigated, and outcomes in this area have 
strengthened the plausibility and consistency of possible developmental origins. 


- Preconceptual
- Prenatal
- Perinatal

Environmental Risk Factors of Schizophrenia

An uninterrupted illness featuring at some time a major depressive episode, manic episode, or mixed episode concurrently with characteristic symptoms of schizophrenia (e.g., delusions, hallucinations, disorganized speech, catatonic behavior) and, in the same period, delusions or hallucinations for at least 2 weeks in the absence of prominent mood symptoms. DSM–5 identifies the mood episodes only as either major depressive or manic and emphasizes that mood disturbances must be present for a majority of the time.

Schizoaffective Disorder

- Abnormal prefrontal cortex circuitry and GABA neurotransmission in schizophrenia patients
- Expression of parvalbumin and calretinin mRNAs in area 9 of schizophrenic and control subjects
- Relationship to decreased GAD₆₇ mRNA expression in the prefrontal cortex of subjects with schizophrenia
- Parvalbumin mRNA expression in the prefrontal cortex of haloperidol-treated monkeys

Gene Expression Deficits in a Subclass of GABA Neurons in the Prefrontal Cortex of Subjects with Schizophrenia

Deletion of Dopamine D₂ Receptors from Parvalbumin Interneurons in Mouse Causes Schizophrenia-like Phenotypes

Schizophrenia References

Current studies show that there are cognitive similarities and differences in intellectual and executive functioning between those living with Schizophrenia and Asperger's syndrome. 

Similarities and differences between Schizophrenia and Asperger's Syndrome

Family caregivers take responsibility for providing emotional and economic support, supervising medication intake, maintaining treatment compliance, and promoting social interaction. However, family caregivers of patients with schizophrenia experienced poor quality of life (QOL) resulting from care giving. The difficulties that families and caregivers experience in having to care for chronically ill family members with schizophrenia which could lead to damage on their own mental health. 

Schizophrenia Patients' Family Members and Care Giver's Mental Health

A study found an association between the HLA-A*03 gene, delusional disorder, and paranoid schizophrenia. It is found that this gene alone, in combination with other HLA genes or other closely linked non-HLA genes, may lead to vulnerability to delusional disorder and paranoid schizophrenia.   

Genetic Association between Delusional Disorder and Paranoid Schizophrenia

A. Two or more of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated). At least one of these must be (1), (2), or (3): 

1. Delusions.

2. Hallucinations.

3. Disorganized speech.

4. Grossly disorganized or catatonic behavior.

5. Negative symptoms.

B. An episode of the disorder lasts at least 1 month but less than 6 months.

C. Schizoaffective disorder and depressive or bipolar disorder with psychotic features have been excluded because either 1) no major depressive or manic episodes have occurred or 2) mood episodes have been present for a small portion of the total duration of the active and residual periods of the illness during the active-phase symptoms.

D. The disturbance does not ascribe to physiological functions of drugs or another medical condition.


[DSM-5-TR] Diagnostic Criteria of Schizophreniform Disorder

Reference for Downward Drift

Downward drift is the term given to the deterioration of the lives of individuals suffering from schizophrenia in which the disorder leads them to poverty, which obstructs their capability to work.

Downward Drift 

Unlike what the name suggest, schizophrenia does not mean split personality. Rather it is encompass symptoms such as dissociative thinking, emotional disturbance, delusions and hallucinations. These symptoms can be broadly divided into three categories:

- Positive Symptoms: behaviors that are present or gained

- Negative Symptoms: behaviors that are absent or lost

- Cognitive Symptoms: difficulty in interpreting and acting on external information.

Symptoms of Schizophrenia

The primary symptoms of schizophrenia are categorized into five main types: hallucinations, delusions, disorganized thinking, disorganized or abnormal motor behavior, and negative symptoms. When the disorder is active, individuals may struggle to differentiate between real and unreal experiences. The severity, duration, and frequency of these symptoms can vary, and severe psychotic symptoms often decrease with age.

Schizophrenia Symptoms

Schizophrenia affects approximately 1% of the population over a lifetime. The disorder is typically first diagnosed in early adulthood, most commonly in the early to mid-20s.

Prevalence and Onset of Schizophrenia

Individuals with schizophrenia often face substantial challenges in daily functioning, including difficulties with employment, financial management, personal hygiene, and maintaining social relationships. The severity of the disorder frequently necessitates hospitalization. Even with treatment, many individuals continue to experience significant long-term social and occupational impairments.

Functional Impairment in Schizophrenia

The term 'schizophrenia' was coined in 1911 by the Swiss psychiatrist Eugen Bleuler. It is derived from the Greek words 'schizo' (splitting) and 'phrene' (psychic functions). This name was intended to describe a splitting of mental functions within a person, which is the origin of the widespread but incorrect association of the disorder with a 'split personality'.

Etymology of Schizophrenia

The dopamine hypothesis posits that schizophrenia is linked to irregularities in the dopamine system. The original theory suggested that the disorder was caused by a general excess of dopamine or an overabundance of dopamine receptors. However, this view has been refined. More recent research indicates that dopamine abnormalities are specific to different brain regions. An oversupply of dopamine in the limbic system is thought to be responsible for positive symptoms like hallucinations and delusions, while a deficit of dopamine in the prefrontal cortex is associated with negative symptoms such as avolition and alogia.

The Dopamine Hypothesis of Schizophrenia

While there is substantial evidence for a strong genetic basis for schizophrenia, environmental factors also play a crucial role in its development. The importance of this interplay is highlighted by findings from adoption studies, which help disentangle the respective contributions of genetics and upbringing.

Interaction of Genetic and Environmental Factors in Schizophrenia

A promising direction in schizophrenia research focuses on identifying individuals exhibiting prodromal symptoms—early signs of the disorder. By following these individuals over time, researchers aim to determine the key predictors of schizophrenia's development, which could enable the creation of early intervention strategies for those at highest risk.

Schizophrenia Research on Prodromal Symptoms and Early Intervention

Schizophrenia is associated with significant neurobiological factors, including abnormalities in brain structures and neurotransmitter systems. Research suggests these biological irregularities may be linked to environmental influences during development, such as obstetric complications or maternal exposure to viruses like influenza during pregnancy.

Neurobiological Factors in Schizophrenia

Based on the case study provided, analyze the individual's symptoms. Identify one symptom that represents an excess or distortion of normal functions and one symptom that represents a loss or deficit of normal functions. Explain your reasoning for categorizing each symptom.

Analyzing Symptoms of a Psychological Disorder

Certain symptoms of schizophrenia are linked to excessive dopamine activity. To treat these symptoms, antipsychotic medications function as dopamine antagonists. They bind to dopamine receptors without activating them, which blocks naturally occurring dopamine from attaching and prevents it from transmitting information to adjacent neurons.

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