I'm not sure if your question is a rhetorical one - you do seem to have answered it, in part at least. But the dopamine hypothesis really only provides an explanation for a partial mechanism of positive symptomatology and does not inform us about the neuronal pathology. You might like to look at the discussion from a while back:

https://www.researchgate.net/post/What_is_the_current_status_of_the_dopamine_hypothesis_in_the_etiology_of_schizophrenia?ev=tp_feed_post_xview

Thank you, Dr. Gavin Reynolds for your answer and the url. Yes, i find an interesting paper on glutamatergic model, but according to a psychiatrist whom i asked yesterday, there is no alternative to dopamine hypothesis. Therefore i ask this question looking for clues. Best wishes

In real world, in real patient we can not separate one monoamine. This is network of several neurotransmitters, (plastic) neuronal connection, influencing hormones etc. Dopamine hypothesis is the most simply hypothesis explaining effect of antipsychotics. This is easy to use as tool for educational activities. So, as simplification. Other simple hypothesis have less "applicability" But it is complex procedure and too find another simple hypothesis is not meaningful.

Dear Dr. Lubos Janu, thank you for your answer. Yes dopamine hypothesis is a simple model to comprehend, but in search of better drugs, perhaps we should look for better hypothesis. See for instance Joseph t. Coyle, Glutamate and schizophrenia, beyond the dopamine hypothesis, Cellular and molecular neurobiology, vol. 26, july august 2006. But i am not a psychiatrist or doctor, i am just curious on this question. Best wishes

Here (http://www.ncbi.nlm.nih.gov/pubmed/23699763) there is a different approach to treating schizophrenia that corroborates the Glu/NMDA/NO hypothesis, although further studies are necessary.

Dear Dr. Gavin Reynolds, i already read your posts in link that you give. Apparently you prefer to think that glutamatergic hypothesis can provide better answer. Can you please explain in simple words in which area glutamatergic hypothesis is better than dopamine hypothesis? I tried to read Javitt,s paper but cannot understand his arguments. See http://doctorsonly.co.il/wp-content/uploads/2011/12/2010_1_2.pdf. Thank you.

Ps: i am not a doctor or psychiatrist, i am a graduate student, working for a paper in counseling course.

Quite recently, also the GABAergic system has been associated with schizophrenia. For example:

http://www.ncbi.nlm.nih.gov/pubmed/14624191

http://link.springer.com/article/10.1007/s00213-005-2212-8

http://www.sciencedirect.com/science/article/pii/S0166223608000891

The last ten years there has been an increased interest in the anatomical and functional networks of the brain. Studies have shown that these networks are unbalanced in schizophrenia, with too high activity in some areas and too low in others. This actually matches the dopamine hypothesis, even though no studies can be found on the eventual correlation between these.

For example, see http://www.ncbi.nlm.nih.gov/pubmed/22981811

There is also the "inflammation hypothesis", suggesting systemic inflammatory conditions in individuals with schizophrenia and first episode psychosis. To my knowledge, studies have so far been inconclusive wheather this is of etiological relevance or if it reflects epiphenomena related to secondary complications (metabolic, stress, etc.).

For example: http://schizophreniabulletin.oxfordjournals.org/content/early/2013/09/25/schbul.sbt141.short

In response to your question, Victor, you might start by asking "hypothesis for what?" when you consider these various neurotransmitters implicated in schizophrenia. What the glutamate hypothesis does, and the closely related GABA hypothesis (my favourite for over 20 years!) does even better, is to provide an understanding of the real, if subtle, changes in the brain that occur in the disease, and link them to the symptoms - to positive symptoms via dopamine, more directly to negative and cognitive symptoms. Dopamine cannot really address much of that. It also provides a means of relating aetiology - genetic and environmental risk factors - to the neuronal and neurotransmitter pathology.

There is D-cell hypothesis.

D-neuron, i.e. trace amine neuron, induced from NSC, is a clue for pathogenesis of schizophrenia.

Article NSC-induced D-neurons are decreased in striatum of schizophr...

There are several articles of D-cell or D-neuron, as trace amine-producing cells, modulating monoamine functions.

Article “D-cell hypothesis” of schizophrenia: possible theory for me...

There is a recent line of evidence showing cholinergic muscarinic receptor inviolvement in schizophrenia. Brian dean And Elizabeth Scarr at University of Melbourne have published in this area

see recent PET studies by Rasmussen et al pointing to a role of serotonin 2A receptors: e.g.

Rasmussen H, Erritzoe D, Andersen R, Ebdrup BH, Aggernaes B, Oranje B, Kalbitzer J, Madsen J, Pinborg LH, Baare W, Svarer C, Lublin H, Knudsen GM, Glenthoj B (2010) Decreased frontal serotonin2A receptor binding in antipsychotic-naive patients with first-episode schizophrenia. Arch Gen Psychiatry 67:9-16

Rasmussen, H, Ebdrup B, Erritzoe D, Aggernaes B, Oranje B, Kalbitzer J, Pinborg LH, Baare W, Svarer C, Lublin H, Knudsen GM, Glenthoj B. Serotonin2A receptor blockade and clinical effect in first episode schizophrenia patients treated with quetiapine. Psychopharmacology, 2010

and numerous studies by H.Y Meltzer

There's a hypothesis for schizophrenia based on almost every single neurotransmitter and neurotrophin in the brain. Not to mention, the hypotheses that are being generated based on disrupted intracellular signaling processes. Pick, choose or even combine hypotheses depending on what you want to study.

Thank you very much to Ludmyla, Christoph, Ulla, Richard, Keiko, Susan, Susan, Hans, Anand, and Dr. Gavin Reynolds for all your answers. I am sorry i cannot address each of your answers, but i really appreciate your suggestions. Apparently there are various proposals related to schizophrenia, but so far i think dopamine and glutametergic hypothesis are the most promising. I would appreciate if there is an article reviewing the current status of various hypotheses. Does anybody know such an article? Best wishes.

Hi Victor,

This paper from 2008 discusses the "dual state" theory of dopamine dysregulation;

http://www.sciencedirect.com/science/article/pii/S000632230800646X

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There is a pretty sound review, written in Dec 2012, of the dopamine hypothesis here;

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

.

In regard to the many neurotransmitters and structures implicated in symptoms of schizophrenia, or the progression of the illness, this article (below) lists 20 potential targets for pharmacological treatment.;

>

http://www.tocris.com/researchArea.php?ItemId=128846#.UlYttxDqN4N

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Paul.

Thank you very much, Dr. Paul Dessauer, for the review article. I will read them. Best wishes

Hi Victor,

Avast- I'm not really a Doctor. You can call me Paul.

:-)

Paul.

I may be approaching this from a very differnet tangent -

But how can dopamine hypothesis 'explain' schizophrenia?

We may go further and ask what is schizophrenia? or perhaps the questions stated should be How does the dopamine hypothesis explain positive symptoms of psychosis rather than 'explaining' schizophrenia!

There have been many attempts to 'explain' schizophrenia and none of which have full backing and support from all the relevent grroups, agencies and fields of science. The heterogenous nature of the disorder has made diagnosis both difficult and inconsistent. Therefore only taking a biologically determined stand point may be misleading and uni-dimentional in allowing people to believe that as a 'disease' it can only be rectified by medication. This continues to only address one aspect of schizophrenia and fails to assist in the process of recovery for many people given this diagnosis as it serves to contain people in mental health services long-beyond the point of requiring this support.

Even if they are somewhat older (2008-2011), I like the "just the facts"-articles by Keshavan and kollegues; the article nearest to your question seem to be number two and number six:

http://www.ncbi.nlm.nih.gov/pubmed/18514488

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391657/

But I think all of these articles are very good to read; the authors have done an impressing work by collecting the "facts" about this group of diseases.

//M

Thank you, Paul, neither am I. Best wishes

Dear Keith and Michael, thank you very much for your points and urls. I will read them. Best wishes

Dear Keith, i see tha you have two publications related to schizophrenia. I have two additional questions:

A. One psychiatrist that i know says that schizophrenia needs life long medication. Is it possible to stop medicine if the condition is getting better, and when?

B. is it possible to use natural medicine as treatment for schizophrenia? Are there articles supporting this natural treatment?

If you can answer these questions, i will really appreciate. Thank you

Hi Victor,

There is a strong opinion that Schizophrenia should be treated with antipsyhcootic medication and that a person should be on this for life. There is also some evidence suggestive that relapse rates match non-compliance with medication too. But ... I have equally seen and heard from users of services with a diagnosis of schizophrenia that have recovered and no longer use medication. As with all aspects of schizophrenia there are individual factors so as far as an optimum time for reducing medication and stopping, for one person it may differ to another. I guess research has a tendency to value quantitative methodologies and pays less value to qualitative and narrative research which are more personal for individuals. It is this research approach that you would read more of recovery and managing medication free. I am not against medication, but I feel that other approaches can also be used such as talking therapies and empowering approaches. I have not heard of any effective herbal or natural treatments for schizophrenia but I am sure there will be some out there that people will advocate works for them.

Thank you, Keith, i see your points. Yes the problem with natural treatment is that often there is no quantitative record of positive results, only by stories of other persons, so it is less reliable as medicine. But of course i don,t mean that there is no effective natural treatment out there. Best wishes

Thank you, Emma. As far as i can understand your explanation, there similar anomalies for different symptoms, so another direction of research is to study these anomalies regardless of the disorder, am i right? Will this new direction of research lead eventually to a new type of treatment which could be valid for all disoreders? Could it be possible? Best wishes

Hi Victor,

I think schizophrenia is a disease that has a quite obscure etiology. Partly because individual candidate genes account for only a small fraction of SZ, leading to the suggestion that multigenetic pathways may be involved. Obviously, we cannot exclusively blame dopamnine for SZ. You may want to read our recent article, where we used an alternative hypothesis in order to understand the background of this complex neuropsychiatric disorder:

http://www.ncbi.nlm.nih.gov/pubmed/23554489

Dear Bence, thank you very much for the url of your paper. I can only read the abstract of your paper, which seems to suggest that cellular pathway may contribute to important psychiatric disorders such schizophrenia. Am i right? Do you mean that cellular pathway can be an alternative to dopamine hypothesis? Thank you and best wishes

Absolutely! :) The full version of the paper is accessible through RG, btw.

Dear Emma, thanks a lot for your explanations. If your approach is correct, then it would mean that we can understand a number of disorders from a new and different angle. But perhaps there are also different conditions, for example i once heard from a psychiatrist who was telling me that a borderline disorder is related to serotonin imbalance, not dopamine. Am i right? Then perhaps we should be more cautious to make generalizations of disorders. Anyway, hopefully you make success in your new approach. Best wishes

Dear Bence, thanks, i will try to read your paper. The problem is perhaps your paper is intended for researchers while i am not a psychiatrist nor a researcher in this field, so if there is an article more accessible for beginners or general readers, i will appreciate it. But it is okay if the is no such simple article. Best wishes

Dear Emma, thank you. I agree with you that what we mean with a disease or disorder is mostly related to a consensus, and there are a number of symptoms which are associated with schizophrenia. Does it mean that we can call a number of disorders as the same group of disorder (you wrote before that schizophrenia and bipolar may have similarities). best wishes

Thank you, Emma, for your answer. And best wishes to your research. Best wishes

Thanks Emma for your excellent points.

Victor's question is; "Are there alternatives to dopamine hypothesis in order to explain schizophrenia?"

Dysregulation of dopamine is quite clearly causally related to acute episodes of psychosis, but this is of an "explanation" for acute positive symptoms, not for schizophrenia itself.

Some studies suggest the chronic negative symptoms of schizophrenia are also related to dysregulation of dopamine- and it is probably significant that while toxic doses of dopaminergic drugs like methamphetamine can provoke a psychotic episode in otherwise "healthy" people, the symptoms of withdrawal from a serious methamphetamine dependence closely resemble the negative symptoms of schizophrenia- (lack of energy/enthusiasm, social withdrawal, dysthemia and anhedonia, problems with concentration and memory, problems with mood control).

However, once again, this does not explain WHY a person diagnosed with a psychotic disorder experiences high or low levels of dopamine at differing times or in different parts of the brain...

The distinction Emma has drawn between the way physical illnesses are diagnosed (typically by identifying the discreet disease causing agent) as opposed to how mental disorders are diagnosed (by clusters of symptoms) is an extremely important one.

I am increasingly of the opinion that there is no such thing as "true schizophrenia" at all (if by this we mean a discreet disease entity). All people have the potential to experience psychosis, (it is a phenotype, not a genotype), and also to experience the negative symptoms of schizophrenia, but vulnerability to experiencing these sorts of symptoms varies widely across the population.

Some people (due to a combination of co-occurring genetic risk factors, and/or infection, neurological insult, or injury in-utero or in early infancy, and/or certain types of life experiences- especially social dislocation and repeated social defeat) are far more prone to psychotic breaks, and some people are far more robust in this regard. Even the least vulnerable humans can experience psychotic states if you stress them enough, (prolonged sleep deprivation, malnutrition, dehydration, extreme fear or anxiety provoking environments, stimulant toxicity, etc).

25% of people who experience a “first episode psychosis” never experience a second episode. They don’t have a disorder. They have just had a bad experience that has triggered this sort of response.

Those people who are most vulnerable typically have a family history of psychotic disorders, and we know that a large part of your risk of being diagnosed is heavily influenced by heritable factors. There are many studies that clearly show an association between certain single nucleotide polymorphisms (SNiPs) and a diagnosis of psychotic disorders.

However studies in different populations identify completely different SNiPs as significant risk factors. There are dozens of them. And none is a sufficient or necessary causal factor in and of itself.

http://snpedia.com/index.php/Schizophrenia

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I am becoming more and more convinced that this means there is no real, single disease entity we can call Schizophrenia. Instead, I am tending towards the opinion that the cluster of acute symptoms that identify stress-related psychotic breaks, drug-induced psychosis, Schizophrenia, Schizophreniform disorders and Bi-Polar Affective Disorder are simply a phenotype that humans may express in response to stressors in their physical and social environment, but that the likelihood of any experience triggering this response in any individual is heavily modulated by genetics and experience in-utero, perinataly, in early childhood, and (perhaps to a less significant extent) by later life experience .

Those people with many co-occurring risk factors, who experience psychosis chronically, will typically get diagnosed with a form of Schizophrenia or a form of Bi-Polar Disorder.

Studies into the heritability of both disorders identify the same familial risk factors, and the same factors are also associated with Autism.

>

http://www.medscape.com/viewarticle/528669_3

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This is consistent with the idea that these diagnostic labels are not describing distinct disorders, but instead are describing different expressions of a wide spectrum of potential human behaviour.

http://archpsyc.jamanetwork.com/article.aspx?articleid=1206780

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http://www.medpagetoday.com/Pediatrics/Autism/33589

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http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=3405404

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http://journals.cambridge.org/production/action/cjoGetFulltext?fulltextid=1936780

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http://www.annualreviews.org/doi/abs/10.1146/annurev.clinpsy.032408.153506?journalCode=clinpsy

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http://schizophreniabulletin.oxfordjournals.org/content/38/3/475.short

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Paul.

Thank you Dr. Anthony Gordon, Paul, and Emma, for your answers. Best wishes

Dear all contributors, thank you very much for all your answers and discussion to the question posed about schizophrenia. If there is no objection, in two days i would like to summarize all your answers in a short article. Best wishes.

In schizophrenia currently glutamate hypothesis and gaba hypothesis are important.

In my opinion these theories are not rivals. Schizophrenia should be explain based on a multiple neurotransmitter hypotheses. For example, several evidence have indicate that an NMDA receptor dysfunction and an impairment of PV(+)-interneurons in schizophrenia could result in anomalies in dopaminergic neurotransmission.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3505861/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879641/

Thank you Shivraj, Dr. Anthony Gordon, Felipe and Emma, for your answers. Aside of dopamine and glutamate hypothesis, perhaps social isolation may also induce schizophrenia, at least according to a report in 2010. See http://www.sharecare.com/health/schizophrenia/social-isolation-increase-risk-schizophrenia

Dear Emma, thank you for your encouraging words. I will post the summary article here when it is ready. Best wishes to your research.

Dear Dr. Anthony Gordon, thank you for your comment. Yes it is possible that the increase of risk of schizophrenia in urban areas may be caused by other reasons. Best wishes

There is a nice review published in Nature about environmental factors and schizophrenia.

Thank you for Nature article, Felipe. best wishes

Dear all contributors, thank you so much for all your answers. Included here you can find a short article summarizing all answers up to now. Hopefully you will find it useful. All best wishes

Here is the article.

Dear all contributors, a few days ago I found an interesting article giving a list of references of possible alternative treatment of schizophrenia. In case you are interested, please find the article included here.

Have you looked at the Glutamate theory of schizophrenia

Imran, any references you can recommend? What are your thoughts on glutamate and GABA - particularly medications like gabapentin and pregabalin?

First and foremost, before we apply theories about the effect of one neurotransmitter over another we should perhaps define schizophrenia. Our normal method of defining 'disease' as a defect is not entirely effective here. Schizophrenia like other manifestations of psychosis are observed form the outside in patient behaviour. To date there has been no effective biological test or examination to diagnose it, in spite of dopamine theories etc.

We have no idea whether the 'dopamine disorders' are a cause or an effect of this condition or whether dopamine disorders require some trigger, either genetic or stress related to activate them. To cut to the chase dopamine may be implicated in the aetiology of schizophrenia, but a cause...we just don't know.

Thank you, Barry. Yes i agree with you that the true cause of schizophrenia remains a mystery. To find out that cause will need lots of study. Best wishes

Victor,

I have come to your discussion very late, but lots of great comments. I esp like Emma' and Paul's comments about the phenotypic nature of sz or psychosis in general. I don't think there is much controversy about the fact that sz is a multifactorial disorder and descriptive in nature, rather then etiological.

So my question to Emma, Paul and others is: "Is it reasonable to propose a multifactorial (multiple genes, epigenetic events) solution to explain the onset of sz (or perhaps a broad spectrum of psychotic disorders)? In other words, can we work toward a quasi-quantitative solution that essentially establishes a formula to show the threshold or statistical probability for sz or sz-like disorders to manifest? The formula might look something like this:

Gene A allele (all components weighted, perhaps a beta-weight in a regression equation) + Gene B + Gene C + Environmental factor (Env) A + Env B + Interaction of Env A & Gene A = numerical threshold or the statistical probability that a sz-like disorder will manifest.

Of course, this is a very simplistic version of what the data would show. But does the diversity of phenotypic manifestations of sz preclude such a model?

Dear Neil, thank you for your answers. Your idea seems interesting to ponder.

Another possible approach is perhaps we can explore connection between schizophrenia (also other neuro disorders) and self organized criticality. Although i am not a specialist in neuroscience, i read that there is recent trend in brain science to study self organized criticality. See for instance http://www.appliedneuroscience.com/PhaseresetDevelopment.pdf. best wishes

Dear Neil, thank you for your answers. Your idea seems interesting to ponder.

Another possible approach is perhaps we can explore connection between schizophrenia (also other neuro disorders) and self organized criticality. Although i am not a specialist in neuroscience, i read that there is recent trend in brain science to study self organized criticality. See for instance http://www.appliedneuroscience.com/PhaseresetDevelopment.pdf. best wishes

@Ali. Thanks for your links, i will try to read them soon. Best wishes