While the pathway by which excess dopamine (DA) in the limbic and striatal areas ultimately originates is not precisely known, it is well established that most antipsychotics occupy the D2 DA receptors. This blockade of the D2 receptors, in turn, decreases positive psychotic symptoms such as hallucinations and delusions.

"Imaging studies have repeatedly confirmed the existence of a striatal D2 receptor occupancy threshold (about 80 percent) above which extrapyramidal symptoms (EPS) are likely to occur (Farde et al., 1992). Together, these data suggest the existence of a therapeutic window between 50 and 80 percent striatal D2 receptor occupancy."

http://www.schizophreniaforum.org/for/curr/AbiDargham/.

There is also support for an alternative hypothesis for the generateion of positive psychotic symptoms that implicates the glutamate receptors.

"The NMDA receptor hypofunction hypothesis for schizophrenia receives support

from five separate types of investigation: NMDAR antagonist studies, brain

imaging studies, genetic studies, postmortem studies and pharmacologic interventions that enhance NMDAR function in subjects with schizophrenia. In fact, the results from the genetic studies over the last 5 years in the context of the four other types of evidence make a more compelling case for the role of glutamate/NMDAR in the endophenotype of schizophrenia than dopamine. And some evidence supports the notion that psychosis, which is not unique to schizophrenia, is secondary to NMDAR hypofunction."

Coyle, JT (2006). Glutamate and Schizophrenia: Beyond the Dopamine Hypothesis, Cellular and Molecular Neurobiology, 26 (4-6), 365-384.

Which of these mechanisms for the manifestation (and related treatment) of psychotic symptoms is most credible? Are there other hypotheses that have also been supported clinically and experimentally?

I have another reason to suspect that the condition that psychiatrists refer to as treatment refractive schizophrenia is connected to endocrine dysfunction. The drug Clozapine is the drug of choice in this condition, usually arrived at by a crude process of elimination after administering the range of drugs available for the treatment of psychoses.

Dopamine has been the main suspect in schizophrenia for years but to date this has not been categorically confirmed. Nevertheless the main treatment for schizophrenia has been the drugs in the dopamine receptor antagonist class, with some degree of success but with the distressing extrapyramidal side effects.

In treatment resistant forms of psychosis these drugs do not suppress the more florid symptoms, which indicate two possibilities. The first is that the patient cannot metabolize these drugs due to deficiencies in cytochrome P450’s, the principal enzyme responsible for metabolizing anti-psychotic medication. It is logical that a poor or non-metabolizer will not benefit from drugs requiring P4502D6, P450IA2, P4502C or P4503A. All the current drugs in the psycho-pharmacopeia require these cytochromes for metabolism and apart from the possibility that the patient may be deficient, many other drugs interfere with the metabolism and pharmacokinetic properties.

The drug Clozapine is unusual in that it is a weak antagonist at D2 receptors. This casts some doubt on the dopamine theory as a single cause of schizophrenia. Clozapine inhibits α-adrenoreceptors, muscarinic, 5-HT and histamine receptors. Risperidone is also a weak D2 antagonist and operates on 5-HT2 receptors.

The effect on 5-HT receptors is interesting in that elevation of cortisol after prolonged life stress may predispose a patient to psychosis by interfering with brain 5-HT function. This offers an alternative cause of psychotic episodes less reliant on dopamine levels. Endocrine disorders are associated with elevated cortisol. Plasma cortisol is increased in about half of patients with depression but this is not specific to any particular depressive disorder and occurs also in mania and schizophrenia.

Treatment refractive patients may not be suffering from classical dopamine related schizophrenia at all but their psychotic symptoms may be a result of an underlying endocrine dysfunction perhaps in the parathyroid or pituitary. It is hardly surprising that they would not respond to the classic psychiatric medications based on dopamine receptor antagonists.

Haulicinations and delusions are the positive symptoms of schizophrenia and seems to manifested by the imbalance of the the dopamine in cortical and subcortical regions of the brain. Most antipsychotics drugs (typical/atypical) were designed on the dopamine hypothesis of schizophrenia and works as blockade of D2 receptors in subcortical area or regulations of D1 receptor in cortical area of the brain. On the other hand PCP, a NDMA receptor antagonists known to induce these positive symptoms through glutamatergic neurotransmission. Clozapine know to be the most effective drug to help in reducing these symptoms but have several serious side effect like agranulocitosis etc. Due to the high affinity of the clozapine to several receptors which might be mediating these positive symptoms, the mechanism of action is still yet to reveled that how it affect the dopaminergic, serotonergic and glutamatergic neurotransmission specially in the event of sever side effects of this magic drug. In recent past it has been reveled that cholinergic neurotrnasmission mediated by different type of muscarinic receptors (mainly M1 and M4) regulate the Ach release also mediate the action of antipsychotics and its side effects related to these positive symptoms. hope this help

good luck

Psychosis is a phenotype that may be expressed by any human in response to life stressors. Some individual's are far more prone to psychosis, and there is substantial evidence that genetic factors heavily influence any individual's vulnerability.

We should not be seduced into believing that there is one single discreet cause for all cases where someone is diagnosed with a psychotic disorder. Our diagnostic criteria are based on groups of symptoms, and any or all of the above theoretical models may be acting in isolation or combination in greater or lesser degrees in different individuals to produce similar symptoms.

Paul.

Hi Neil,

There is a closely related discussion here;

https://www.researchgate.net/post/Are_there_alternatives_to_dopamine_hypothesis_in_order_to_explain_schizophrenia

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Paul.

New research on the relative efficacy of typical and atypical anti-psychotics;

Effectiveness of Paliperidone Palmitate vs Haloperidol Decanoate for Maintenance Treatment of SchizophreniaA Randomized Clinical Trial

McEvoy et al JAMA May 2014

doi:10.1001/jama.2014.4310.

http://jama.jamanetwork.com/article.aspx?articleid=1872816

.

>

Maintenance Treatment With Long-Acting Injectable AntipsychoticsComparing Old With New

Goff JAMA May 2014

doi:10.1001/jama.2014.4311

http://jama.jamanetwork.com/article.aspx?articleid=1872802

.

Discussion;

https://www.mja.com.au/insight/2014/18/antipsychotic-disappointment

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Paul.

My choice of antipsychotic is geodon:

http://www.rxlist.com/geodon-drug/clinical-pharmacology.htm:

Pharmacodynamics

Ziprasidone exhibited high in vitro binding affinity for the dopamine D2 and D3, the serotonin 5HT2A, 5HT2C, 5HT1A, 5HT1D, and α1-adrenergic receptors (Ki s of 4.8, 7.2, 0.4, 1.3, 3.4, 2, and 10 nM, respectively), and moderate affinity for the histamine H1 receptor (Ki=47 nM). Ziprasidone functioned as an antagonist at the D2, 5HT2A, and 5HT1D receptors, and as an agonist at the 5HT1A receptor. Ziprasidone inhibited synaptic reuptake of serotonin and norepinephrine. No appreciable affinity was exhibited for other receptor/binding sites tested, including the cholinergic muscarinic receptor (IC50 > 1 μM). Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of ziprasidone Geodon is an atypical antipsychotic.  Weight gain and dullness of mind do not seem to be a common problem.

http://www.ncbi.nlm.nih.gov/pubmed/14731061

Lamotragine:  The mechanism of action of the drug in patients with bipolar disorder may be related to the inhibition of sodium and calcium channels in presynaptic neurons and subsequent stabilisation of the neuronal membrane

Lamotrigine is a mood stabilizer (anticonvulsant) that needs no blood monitoring. 

Depakote is a mood stabilizer (anticonvulsant) that needs blood monitoring for the liver. function. Mechanism of action is unknown.

Lithium is a mood stabilizer.  Blood monitoring is necessary for renal function.  Mechanism of action is unknown.

The matter it ' s very complex and fascinating. The anti D 2 antagonism in mesolimbic and mesocortical tracts have always been regarded as a common mechanism of the antipsychotic action agents. As you remark, the mixed action of atypical antipsychotics have challenged this vision. In my view we can summarize that furter findings about atypical agents with these points 1) 5ht2 antagonism can imbalance some regulatory pathways and lead to a minor D 2 activity in the same D2 receptor that was blocked by traditional antipsychotics ( and maybe with minor extrapiramidal effects ) 2) D4 receptor antagonism can account for some alternative mechanism of some atypicals agents . it 's important to keep in mind that atypicals agents are a heterogeneous group of substances. For example the even superior action of clozapine that has an action over a broad range of cerebral receptor remains in my view partly unexplained, and there are other agents involved ( as @Krohn report here ).Generally speacking atypical can perform a therapeutic action that involve also the dopaminergic mesocortical and mesolimbic tracts without affecting mesostriatal dopaminergic tract.