Question

Background: The biogenic amine neurotransmitter dopamine acts as an excitatory neurotransmitter when binding to excitatory receptors. Dopamine aids norepinephrine in the “feel good” effect in the brain. As the levels of dopamine are altered, different diseases/disorders can occur.

1. In patients with schizophrenia and psychosis, dopamine levels are often very high. This is known to contribute

to symptoms of hallucinations, delusions and unorganized speech and thoughts.

a. Knowing dopamine is an excitatory neurotransmitter, what is happening at the neuron level to cause

these symptoms?

b. What do you hypothesize could work best to treat these symptoms?

c. Research known pharmaceutical treatments for schizophrenia. Name two and how they work physiologically.

Answer 1

a)

"Our brain uses prior experiences to generate sensory expectations that help fill in the gaps when sounds or images are distorted or unclear," said Guillermo Horga, MD, PhD, assistant professor of clinical psychiatry at CUIMC and a research psychiatrist at NYSPI. "In individuals with schizophrenia, this process appears to be altered, leading to extreme perceptual distortions, such as hearing voices that are not there. Furthermore, while such hallucinations are often successfully treated by antipsychotic drugs that block the neurotransmitter dopamine in a brain structure known as the striatum, the reason for this has been a mystery since this neurotransmitter and brain region are not typically associated with sensory processing."

The researchers designed an experiment that induces an auditory illusion in both healthy participants and participants with schizophrenia. They examined how building up or breaking down sensory expectations can modify the strength of this illusion. They also measured dopamine release before and after administering a drug that stimulates the release of dopamine.

b) The first treatment option for hallucinations in schizophrenia is antipsychotic medication, which can induce a rapid decrease in severity. Only 8% of first-episode patients still experience mild to moderate hallucinations after continuing medication for 1 year. Olanzapine, amisulpride, ziprasidone, and quetiapine are equally effective against hallucinations, but haloperidol may be slightly inferior. If the drug of first choice provides inadequate improvement, it is probably best to switch medication after 2–4 weeks of treatment. Clozapine is the drug of choice for patients who are resistant to 2 antipsychotic agents. Blood levels should be above 350–450 μg/ml for maximal effect. For relapse prevention, medication should be continued in the same dose. Depot medication should be considered for all patients because nonadherence is high. Cognitive-behavioral therapy (CBT) can be applied as an augmentation to antipsychotic medication. The success of CBT depends on the reduction of catastrophic appraisals, thereby reducing the concurrent anxiety and distress. CBT aims at reducing the emotional distress associated with auditory hallucinations and develops new coping strategies. Transcranial magnetic stimulation (TMS) is capable of reducing the frequency and severity of auditory hallucinations. Several meta-analyses found significantly better symptom reduction for low-frequency repetitive TMS as compared with placebo. Consequently, TMS currently has the status of a potentially useful treatment method for auditory hallucinations, but only in combination with state of the art antipsychotic treatment. Electroconvulsive therapy (ECT) is considered a last resort for treatment-resistant psychosis. Although several studies showed clinical improvement, a specific reduction in hallucination severity has never been demonstrated.

c)    1.Glutathione precursor

Glutathione (GSH) is the primary endogenous antioxidant and it plays a critical role in protecting cells from damage by reactive oxygen and other radical species.GSH also potentiates the NMDA-R response to glutamate. In drug-naive patients with schizophrenia, a decrease of GSH levels was observed in cerebrospinal fluid and medial PFC.As such, GSH supplementation could be of clinical benefit in the treatment of schizophrenia by preventing oxidative stress and enhancing neurotransmission at NMDA-Rs. However, oral administration of GSH has been shown to have little effect on brain GSH levels.

N-acetylcysteine (NAC), a precursor of GSH, penetrates the blood–brain barrier and raises brain GSH levels in animal models .In a large-scale, double-blind, 6-month RCT of NAC as adjunctive therapy, NAC significantly improved psychopathological symptoms of schizophrenia, particularly negative symptoms in patients with chronic schizophrenia. Interestingly, NAC also improved akathisia, suggesting a beneficial effect of NAC for EPS. In an ancillary component of the primary study, NAC improved auditory cortical functioning as indexed by the mismatch negativity, a marker of glutamatergic function.Taken together, NAC supplementation appears to be a promising augmentation strategy in the treatment of schizophrenia that warrants further investigation.

  

2. Ampakines

Ampakines, a class of compounds that allosterically enhance AMPA (α-amino-3-hydroxy-5-methy-isoxazole-4-propionic acid) receptor function, represent another potential class of adjunctive treatments for schizophrenia . Ampakines enhance excitatory glutamatergic transmission and facilitate long-term potentiation, learning and memory in rodents. In a small double-blind RCT of schizophrenic patients who were partially refractory to treatment with FGAs, the ampakine CX-516 as a sole agent did not produce significant effects on positive symptoms or cognitive impairment. Moreover, in a placebo-controlled RCT of CX-516 added to clozapine, olanzapine or risperidone, no benefits were observed on cognition or symptoms of schizophrenia.Farampator (CX-691, ORG-24448), an AMPA potentiator, is currently in a phase II trial. In the case of AMPA ligands, it remains unclear whether agonists or partial agonists/modulators will have benefits in schizophrenia.