The Hypotheses of Schizophrenia

Little is known about the origins of schizophrenia. As a result, several hypotheses have surfaced concerning its causes.

Schizophrenia disrupts regular cognitive abilities and conduct. ¹ As such, there are two distinct sets of symptoms:

1. Positive Symptoms:
   • Delusions
   • Hallucinations
   • Unusual behavior
2. Negative Symptoms:
   • Lack of activity
   • Loss of interest
   • Unresponsive

The biggest issue surrounding schizophrenia is so little is known about it. As a result, several theories have arisen from a variety of sources – all with the same goal of trying to figure out what schizophrenia is. In this article, we review these hypotheses.

The Origin of These Hypotheses

When medical professionals first looked into schizophrenia, their main focus was on behavioral and stress-induced events. ² However, in more recent years, scientists have sought answers through research on biochemical complications. ³

The latter studies are more recognized due to the strong genetic factors associated with schizophrenia. ⁴ In fact, at least 50% of people with schizophrenia have a relative who likewise is struggling.

These biochemical hypotheses aim to discover the debilitation of the neurotransmitter system. Many focus on areas of a person’s brain where cognition and attention are faulty.

Since much of this information remains unknown, many theories have sprung about. Though nothing is conclusive, research has revealed there might be truth in each of the following hypotheses.

The Dopamine Hypothesis

Within the early days of schizophrenia research, it was discovered that drugs that blocked out dopamine had a therapeutic effect. In turn, this has led mental health professionals to believe people struggling with the condition have an overabundance of dopamine. ⁵

To further these beliefs, scientists have discovered much higher levels of D4 receptor bindings within post-autopsies in schizophrenic brains. ⁶ To top it off, too much dopamine triggered by drug use (particularly, amphetamines) has caused people to enter a schizophrenia-like psychosis. ⁷

The Membrane Hypothesis

The phospholipid metabolism plays a vital role in brain functioning. Each of our nerves is greatly composed of phospholipid membranes. In turn, this affects our brain’s neurotransmitter receptors, including dopamine and N-nitrosodimethylamine (NMDA) receptors. ⁸

Several studies link specific outside sources to disturbances within our neuron transmissions. The most notable being high levels of unsaturated fatty acids. ⁹ It’s suggested that due to this trigger, schizophrenia can develop.

The NMDA Receptor Hypothesis

NMDA receptors within our excitatory neurotransmitter glutamate are significant in the development of memory and cognition. From research on drugs such as ketamine and PCP, it’s understood that NMDA receptors are disturbed. In turn, causing these users to experience hallucinations similar to schizophrenia. ¹⁰

In effect, this theory critically points out issues that can further complicate the Membrane Hypothesis.

Under this theory, it’s believed that one of the chief causes of schizophrenia is abnormalities with NMDA receptors. Several studies are finding success in reversing this dysfunction and benefiting this area of the brain. ¹¹

The Single-Carbon Hypothesis

For some time now, it has been recognized that dysfunctions within the single-carbon folate pathway can lead to schizophrenia. ¹² One key area scientists continue to struggle with is attaching the response of the single-carbon folate pathway to neuronal transmissions such as those mentioned in the above theories.

What we do know is this:

• Metabolic pathways within the brain provide carbon groups for a versatile amount of biochemical reactions
• These reactions include synthesizing pruine and pyrimidine nucelotides as well as the methyl-donating amino acid methionine
• People with schizophrenia often have a disturbed methonine metabolism

The Future of Understanding Schizophrenia

Research continues to push for advancements in these theories. Though they may be merely educated predictions, the significance of the education backing them up is important to understanding how schizophrenia works.

As science and medicine continue to progress, so will our understanding.

References

¹ Schizophrenia. National Institute of Mental Health. Available at: https://www.nimh.nih.gov/health/topics/schizophrenia.

² Jablensky A. The diagnostic concept of schizophrenia: its history, evolution, and future prospects. Dialogues Clin Neurosci. 2010;12(3):271-87. doi: 10.31887/DCNS.2010.12.3/ajablensky. PMID: 20954425; PMCID: PMC3181977.

³ Berger PA. Biochemistry and the schizophrenia. Old concepts and new hypothesis. J Nerv Ment Dis. 1981 Feb;169(2):90-9. PMID: 7009786.

⁴ Gejman PV, Sanders AR, Duan J. The role of genetics in the etiology of schizophrenia. Psychiatr Clin North Am. 2010 Mar;33(1):35-66. doi: 10.1016/j.psc.2009.12.003. PMID: 20159339; PMCID: PMC2826121.

⁵ Brisch R, Saniotis A, Wolf R, Bielau H, Bernstein HG, Steiner J, Bogerts B, Braun K, Jankowski Z, Kumaratilake J, Henneberg M, Gos T. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Front Psychiatry. 2014 May 19;5:47. doi: 10.3389/fpsyt.2014.00047. Erratum in: Front Psychiatry. 2014;5:110. Braun, Anna Katharina [corrected to Braun, Katharina]; Kumaritlake, Jaliya [corrected to Kumaratilake, Jaliya]. PMID: 24904434; PMCID: PMC4032934.

⁶ Harrison PJ. Postmortem studies in schizophrenia. Dialogues Clin Neurosci. 2000 Dec;2(4):349-57. doi: 10.31887/DCNS.2000.2.4/pharrison. PMID: 22033474; PMCID: PMC3181616.

⁷ Bramness JG, Gundersen ØH, Guterstam J, Rognli EB, Konstenius M, Løberg EM, Medhus S, Tanum L, Franck J. Amphetamine-induced psychosis–a separate diagnostic entity or primary psychosis triggered in the vulnerable? BMC Psychiatry. 2012 Dec 5;12:221. doi: 10.1186/1471-244X-12-221. PMID: 23216941; PMCID: PMC3554477.

⁸ Cooper, G.M. (1970) Cell membranes, The Cell: A Molecular Approach. 2nd edition. Available at: https://www.ncbi.nlm.nih.gov/books/NBK9928/.

⁹ Chalon S, Vancassel S, Zimmer L, Guilloteau D, Durand G. Polyunsaturated fatty acids and cerebral function: focus on monoaminergic neurotransmission. Lipids. 2001 Sep;36(9):937-44. doi: 10.1007/s11745-001-0804-7. PMID: 11724466.

¹⁰ Powers AR 3rd, Gancsos MG, Finn ES, Morgan PT, Corlett PR. Ketamine-Induced Hallucinations. Psychopathology. 2015;48(6):376-85. doi: 10.1159/000438675. Epub 2015 Sep 12. PMID: 26361209; PMCID: PMC4684980.

¹¹ Newcomer JW, Farber NB, Olney JW. NMDA receptor function, memory, and brain aging. Dialogues Clin Neurosci. 2000 Sep;2(3):219-32. doi: 10.31887/DCNS.2000.2.3/jnewcomer. PMID: 22034391; PMCID: PMC3181613.

¹² Frankenburg FR. The role of one-carbon metabolism in schizophrenia and depression. Harv Rev Psychiatry. 2007 Jul-Aug;15(4):146-60. doi: 10.1080/10673220701551136. PMID: 17687709.