Both typical and atypical antipsychotics appear to inhibit the release of pro-inflammatory cytokines and potentially promote regular neurogenesis in schizophrenia patients by decreasing oxidative stress. Studies of prenatal administration of some antipsychotics in mice models have demonstrated a decrease in psychosis-like behaviors in the offspring. Given that the microglial inflammatory mechanisms are particularly pronounced in schizophrenia, this is a particular area of interest for future pharmacological research.

Scripps College

Microglial dysfunction has been implicated in psychiatric conditions, such as depression, anxiety, bipolar disorder, and schizophrenia. 
Some proposed mechanisms include:
-overexpression of inflammatory cytokines as a response to psychological stressors (may be especially important in suicidality)
-abnormal phagocytosis and synaptic pruning (too much), as well as adult neurogenesis (not enough)
-decreasing development of oligodendrocyte progenitor cells, which results in decreased myelination/white matter function (especially associated with depression)

Microglia and Psychiatric Disorders

A class of drugs that typically alleviate symptoms of schizophrenia. (Also called neuroleptics)

- The Dopamine Hypothesis

- Typical Antipsychotics

- Long-Term Effects of Antipsychotic Drugs

- Atypical Antipsychotics

- The Glutamate Hypothesis

Antipsychotic Drugs

Rahimian, R., Wakid, M., O’Leary, L.A., Mechawar, N., 2021. The emerging tale of microglia in psychiatric disorders. Neuroscience & Biobehavioral Reviews 131, 1–29.. doi:10.1016/j.neubiorev.2021.09.023

"The emerging tale of microglia in psychiatric disorders"

Stressors can induce depression and depressive-like behaviors in mouse models, and this is associated with changes in microglia, particularly in the frontal cortex and the hippocampus. Furthermore, in post-mortem analysis of suicides, imaging reveals abnormal densities (both increased and decreased) of microglia in both MDD patients and in other psychiatric patients relative to healthy controls.

Microglia in Major Depressive Disorder

There is evidence that neuroinflammation plays a role in the pathology of bipolar disorder, but further investigation is necessary to determine whether or not microglia are involved in this. However, microglia do appear to be overactive in the context of BD during both the manic and depressive phases, and they under-produce BDNF, which is involved in synaptic plasticity. There is some gene expression that differentiates the microglial function in BD patients and those with schizophrenia, as well as differences in postmortem microglia expression in BD patients who died by suicide versus those who did not, with the non-suicide group expressing lower levels of microglia density. Typical mood stabilizer treatments (lithium and valproic acid) seem to act on microglia, but the mechanism is unknown.

Microglia in Bipolar Disorder

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

There is some evidence of substance-mediated responses in microglia. In particular, alcohol, cocaine, and methamphetamine show evidence (sometimes conflicting, however) of microglia-mediated neuroinflammation. Microglia may also have a modulatory effect on synaptic pruning in the dopaminergic circuit, which is implicated in addiction.

Microglia in Substance Use Disorders

SSRIs appear to regulate the activation state of microglia in addition to their effects on the serotonergic system when studied in vitro. Fluoxetine (Prozac) and its metabolite, norfluoxetine, have been shown to induce apoptosis in microglia, which limits the amounts of neuroinflammation they can cause. There appear to be both direct and indirect (modulating amount of serotonin available to microglia, or changing the extracellular environment) mechanisms by which this is done. 

Effects of SSRIs on Microglia

Effects of Antipsychotics on Microglia

Hypothesis: Schizophrenia results from an underactivation of glutamate receptors.

- Origin of Hypothesis

The Glutamate Hypothesis of Antipsychotics

While the discovery of antipsychotic drugs helped with the treatment of schizophrenia, there were quite significant side effects.

- Dyskinesia
- Tardive Dyskinesia
- Supersensitivity psychosis
- Involuntary movements of the arms, legs, tongue and facial muscles, resulting in Parkinson’s-like tremors

Long-Term Effects of Antipsychotic Drugs

These are a class of antipsychotic drugs that have a high affinity for other types of receptors and not dopamine receptors. They are also known as 2nd Generation Antipsychotics. They can be prescribed for Schizophrenia and other types of severe thought disorders. They can target dopamine and serotonin receptors to treat schizophrenia's negative symptoms, such as withdrawal and apathy; newer drugs may treat both positive and negative symptoms.

Atypical Antipsychotics include: 
- Aripiprazole (Abilify)

- Clozapine (Clozaril)

- Olanzapine (Zyprexa)

- Quetiapine (Seroquel)

- Risperidone (Risperdal)

- Ziprasidone (Geodon)

Atypical Antipsychotics

Typical Antipsychotic are separated into 1st Generation and 2nd Generation.

1st Generation Antipsychotics include:  
- Chlorpromazine

- Mesoridazine 

- Perphenazine 

- Thioridazine 

- Trifluoperazine 

- Butyrophenone 

- Haloperidol 

- Others:  Loxapine, Molindone, Thiothixene 


Typical Antipsychotics

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.

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