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Chemical imbalance is one hypothesis about the etiology of mental illness. Other causes that are debated include psychological factors and social causes.

The basic concept is that neurotransmitter imbalances within the brain are the main causes of psychiatric conditions and that these conditions can be improved with medication which corrects these imbalances. The phrase originated from the scientific study of brain chemistry. In the 1950s the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were accidentally discovered to be effective in the treatment of depression.[1]

These findings and other supporting evidence led scientist Joseph J. Schildkraut (1934–2006) to publish his paper called "The Catecholamine Hypothesis of Affective Disorders" in 1965.[2][3] Schildkraut associated low levels of neurotransmitters with depression.

Research into other mental illnesses such as schizophrenia also found that too much activity of certain neurotransmitters such as dopamine was correlated to these disorders. In the scientific community this hypothesis has been referred to as the "Monoamine hypothesis". This hypothesis has been a major focus of research in the fields pathophysiology and pharmacotherapy for over 25 years[4] and led to the development of new classes of drugs such as SSRIs (selective-serotonin reuptake inhibitors).[5]

This conceptual framework has been challenged within the scientific community, though no other demonstrably superior hypothesis has emerged. While the hypothesis has been shown to be simplistic and lacking, there is sufficient evidence to consider it as a useful heuristic in the aiding of our understanding of brain chemistry and explaining pharmacotherapy.[4][6]

Wayne Goodman, Chair of the US Food and Drug Administration Psychopharmacological Advisory Committee, has described the serotonergic theory of depression as a "useful metaphor" for understanding depression, though not one that he uses with his own psychiatric patients.[7] Recently, psychiatrist Peter Kramer stated that the serotonin theory of depression had been declared dead prematurely.[8] Kramer argues that recent scientific research actually shows a definitive role for serotonin deficiency in depression. An analysis of the studies Kramer cites argues that such statements are premature.[9]

Chemical imbalance theory was never a scientific theory. Current research in neuroscience does indicate roles for changes in the operation of neurotransmitters in the brain, and changes in neurons and neural structure in the pathophysiology of mental illness, but current models are more complex than simple chemical balances/imbalances. Causality (i.e. whether neurotransmitter changes cause mental illness or whether mental illness affects neurotransmitter levels) is uncertain.

Chemical imbalances[edit | edit source]

Changes in levels of neurotransmitters and other neural level phenomena are hypothesised to be the underlying psychopathology for certain mental illnesses, notably clinical depression and schizophrenia. In 1965, Joseph Schildkraut hypothesized that depression was associated with low levels of norepinephrine in the brain, and later researchers thought serotonin might be the culprit.[1]] Initially, relatively simple changes in the level of these neurotransmitters were thought to be found in individuals with depression. However, advanced findings began to fine tune the more simple explanations. For example, certain drugs used to treat depression were found to change the levels of neurotransmitters for several days, but then return to normal, well before any effect was observed on the depressive episode. Such findings implicate more complex mechanisms, such as changes in neurotransmitter production, transmission, re-uptake, and neural sensitivity.

In addition to depression, changes in levels of neurotransmitters have also been implicated in anxiety disorders, bipolar disorder (manic depressive disorder), schizophrenia, and Parkinson's disease. As well as changes in serotonin and norepinephrine, dopamine systems have also been considered.

So, while all biology is essentially chemical in nature, rather than being caused by simple chemical imbalances, mental illness is now widely recognized to be caused by complex and, in many cases, as-yet unknown factors. According to Jaelline Jaffe and Jeanne Segal:

"The misconception the [drug] commercials foster is that the brain somehow develops a chemical imbalance and the result is depression, occurring in a single directional process. In fact, the relationship between brain chemistry and experience is a two-directional phenomenon: Life experience affects brain chemistry at least as much as brain chemistry affects life experience. The 'chemical imbalance' hypothesis is not wrong. It's just not entirely correct."

Hypothesis relating to specific disorders[edit | edit source]

Monoamine hypothesis[edit | edit source]

Main article: Biology of depression#Monoamine hypothesis

The Monoamine hypothesis is a biological theory stating that depression is caused by the underactivity in the brain of monoamines, such as dopamine, serotonin, and norepinephrine.

In the 1950s the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were accidentally discovered to be effective in the treatment of depression. These findings and other supporting evidence led Joseph Schildkraut to publish his paper called "The Catecholamine Hypothesis of Affective Disorders" in 1965.[2] Schildkraut associated low levels of neurotransmitters with depression. Research into other mental impairments such as schizophrenia also found that too little activity of certain neurotransmitters were connected to these disorders.

The hypothesis has been a major focus of research in the fields pathophysiology and pharmacotherapy for over 25 years.[4] and led to the development of new classes of drugs such as SSRIs (selective serotonin reuptake inhibitors).[5]

==Dopamine hypothesis of schizophrenia==|

Main article: Dopamine hypothesis of schizophrenia

In studying the causes of schizophrenia, particular focus has been placed upon the function of dopamine in the mesolimbic pathway of the brain. This focus largely resulted from the accidental finding that a drug group which blocks dopamine function, known as the phenothiazines, could reduce psychotic symptoms. It is also supported by the fact that amphetamines, which trigger the release of dopamine may exacerbate the psychotic symptoms in schizophrenia.[10]

An influential theory, known as the Dopamine hypothesis of schizophrenia, proposed that a malfunction involving dopamine pathways was the cause of (the positive symptoms of) schizophrenia. This theory is now thought to be overly simplistic as a complete explanation, partly because newer antipsychotic medication (called atypical antipsychotic medication) can be equally effective as older medication (called typical antipsychotic medication), but also affects serotonin function and may have slightly less of a dopamine blocking effect.[11]

Limitations on the use of medications[edit | edit source]

Most disorders treated with medication have a hypothesised neural mechanism, but it is important to note that chemical imbalances are not believed to explain all psychiatric differences, nor are medications used to treat all neurological or psychiatric issues. Some mental illness, such as some patients with 'pure' Borderline Personality Disorder, may not have a significant biochemical basis underlying it; these patients will typically not find that their symptoms are usefully treated with drugs. Similarly, when significant neuroanatomical differences are involved, the effectiveness of drugs is limited. For example, autism researchers have found differences in gray and white matter volumes, neuron size, brain mass, and locus of brain function; differences which may be accounted by unknown factors, perhaps involving the interaction of 15 to 100 different genes. .

Controversy[edit | edit source]

According to critics, the chemical imbalance hypothesis has been overpromoted and continues to be advanced as factual by pharmaceutical companies. They believe the general population and many journalists have accepted this hypothesis into their understanding of mental illness uncritically.[12] They have pointed to the lack of an established chemical balance (without which, they claim, the notion of an "imbalance" is meaningless). Certain pharmaceutical companies such as Pfizer continue to promote drugs like Zoloft with advertisements asserting that mental illness may be due to chemical imbalances in the brain, and that their drugs work to "correct" this imbalance.[13] Most academics believe that the advertisements are oversimplified and don't fully explain what is happening.[14]

Chemical imbalance theories do not presume individual laboratory tests be obtained from a patient at the time of prescription, such as one would expect in the analogy to physical medicine. For example, someone suffering from schizophrenia is not given haloperidol on the basis of a laboratory test which shows that his or her dopamine level is too high.

Chemical imbalance theories distinguish between "side" and "main" drug effects in recording the response to the drug. "Side" effects are considered to be simple, direct, predictable, allowable effects which are merely "physical" but do include often flattened affect and memory, emotive and cognitive effects. These drug effects may then be cited capriciously as further evidence to confirm the diagnosis as correct, confusing cause and effect.[citation needed]

When "improvement" is measured in industry research studies, attention is given only to the "main" effect—typically a complex, indirect, interpersonal, perceptual, cultural change, thereby confusing cause with coincidence. In chemical imbalance theories, there are no effectiveness measures using standard social networks and associated tests before and after drug administration.[citation needed]

Chemical imbalance theories predominate in "streamline" public sector medicine for lower social class and homeless persons, where drugs constitute the only form of treatment. There is much wishful thinking in attribution of drug effect, particularly in cases like schizophrenia, where there no longer exists a patient [non-drug user] control group available.[citation needed]

One criticism while not outright rejecting the theory is that it has been scientifically proven[citation needed] that things other than drugs can influence brain chemistry. Exercise releases endorphins. Even our own thoughts change our brain chemistry. These natural methods of changing brain chemicals are claimed by critics to be preferable to drugs since drugs have side effects. Furthermore, some psychiatric drugs might[citation needed] alter the mind by disabling moods and emotions not just in circumstances where they're a problem but in circumstances where they're appropriate or even beneficial as well while natural ways to change brain chemistry can be used as needed.[citation needed]

There is also criticism that Chemical Imbalance theory does not take into account that there are feedback mechanisms in all neurotransmitter pathways.[citation needed] These feedback mechanisms are present in all mammals, and likely all forms of life utilizing neurons, and are absolutely required for information processing to function properly. Publications on chemical imbalance theory often do not properly follow the scientific method,[15][16] [citation needed] and often gather data on changes to neurotransmitter systems in patients who are taking, or have taken, psychotropic medication. This skews data by confusing the cause of the illness with feedback mechanisms potentiated by psychotropic drugs. Limited publications on changes detected in neurotransmitters pathways in psychotropic drug naive patients have not been reproducible. The primary neurotransmitter feedback mechanisms currently studied are:

  • Receptor deletion (uncoupling),
  • Receptor addition (supersensitivity),
  • increase or decrease of neurotransmitter metabolism (manufacture),
  • increase or decrease of neurotransmitter release,
  • increase or decrease of reuptake (removal process from the synaptic cleft),
  • increase or decrease of enzymatic breakdown of neurotransmitters (for monoamines like Dopamine, Serotonin, and Norepinephrine - this is done by the Monoamine Oxidase enzyme)

Receptor deletion and Receptor addition are implicated in causing psychiatric and physiological symptoms of dependence and withdrawal from psychotropic drugs. As feedback mechanisms also evolved to overcome the effect of molecules from eternal sources that interfere with receptors (and thereby interfere with information processing) through a variety of means, treatment with psychotropic drugs should produce 'withdrawal' like symptoms with long or even short term use of an unchanged dose (this is called dependence), thus the chemical imbalance theory is under attack due to published evidence on how feedback mechanisms respond to drugs - rather than a lack of evidence on changes in neurotransmitters in patients with mental illness. To date, all studied psychotropic drugs potentiate feedback mechanisms, some feedback mechanisms of which have been implicated in causing the same symptoms of the illness the drugs are approved to treat. It is currently understood that feedback mechanisms can lose their original reference point in some patients with some drugs (usually in long term treatment), meaning that a drug with the exact opposite effect is needed to repair the feedback mechanisms to end otherwise permanent drug withdrawal symptoms. The only class of drugs that had been studied in this manner are benzodiazepines, for treatment of 'protracted withdrawal syndrome' using a GABA agonist.

Critics also contend that psychiatric drugs, intended to alter neurochemical processes by manipulating neurotransmitter levels, are not always efficacious, not always safe, and not necessarily a scientifically sound method for improving mental health. The number of different chemicals in the brain and their unknown interactions limit understanding and increase the likelihood of unforeseen complications. Moreover, critics assert, the psychiatric establishment merely assumes patients who are diagnosed with a given mental illness always have a chemical imbalance in their brains, even though behavioral checklists, and not actual chemical measurements, are used to reach a diagnosis.

Psychiatric diagnostic practices in the United States have come under criticism for over-reliance upon these behavioral checklists rather than thorough, whole-body medical testing. For example, in a Florida psychiatric hospital study from the 1980s, one hundred patients diagnosed with a mental illness were subsequently given a complete medical exam, after which it was discovered nearly half of the patients’ psychiatric problems were secondary manifestations of an undiagnosed medical problem, such as hypothyroidism mimicking depression.[2] Most, if not all, hospitals in the United States currently require a medical exam be done on all patients admitted to an inpatient psychiatric unit. The author of the study, psychiatrist Mark Gold, remains a strong advocate that addiction and psychiatric disorders are rooted in complex chemical imbalances and that effective treatment is available for most correctly diagnosed psychiatric patients from various drug treatments -- an opinion that he shares with the majority of the medical community.

Even when neurological and neurochemical differences are associated with certain behaviors, the practice of pathologizing these behaviours has been questioned by some activists and people who have been diagnosed with mental illnesses. Because neural mechanisms imply a physiological difference underlying mental illnesses, they appear to justify the use of medication in treatment. Critics argue that the legitimacy given to medication by neural mechanisms can lead to an over-reliance on medication. Similarly, the perceived efficacy of medication as a treatment implies an underlying neural mechanism.

In 2003, members of the nonprofit organization MindFreedom International held a hunger strike called the "Fast for Freedom in Mental Health" to demand that the American Psychiatric Association produce evidence of a biological basis, such as a chemical imbalance, for any major psychiatric disorder.[3] In an exchange between the American Psychiatric Association and the Scientific Advisory Board for MindFreedom International, no evidence was offered for a biological basis.[4]

Critics also allege that pharmaceutical companies have a conflict of interest when they fund research into biochemical mechanisms behind mental illness and the efficacy of medication at reducing behavior differences.

Further controversy is engendered by the links between certain critics of psychiatry and the Church of Scientology. While Anti-psychiatry is not equivalent to Scientology, Scientology maintains several organizations like the Citizens Commission on Human Rights which have been outspoken critics of the biological basis of mental illness, sponsoring websites critical of "chemical imbalance" [5][6]. Here also, there may exist a substantial conflict of interest as Scientology advocates and sells an alternative and expensive non-pharmacological treatment known as Dianetics.

Popular culture and advertising[edit | edit source]

The chemical imbalance theory, according to critics, is routinely presented as ‘fact’ so often it has become widely accepted as fact, despite having been challenged repeatedly. For example, Pfizer has heavily promoted its antidepressant drug, Zoloft, with ads asserting that mental illness may be due to a chemical imbalance in the brain, and that "Zoloft works to correct this imbalance."

Without mentioning its own name, Eli Lilly urges viewers to seek treatment for depression, and to visit their website,, because "Many researchers believe depression is caused by an imbalance of naturally occurring chemicals, serotonin and norepinephrine, in the brain and the body."

Diagnostic utility[edit | edit source]

There are advanced imaging techniques such as Positron Emission Tomography (PET Scans) that can test for chemical imbalances. Changes in levels of neurotransmitter metabolites are detectable in urine and cerebrospinal fluid and have been associated with certain mental illnesses, but are not sufficiently predictive for successful diagnosis.

Thus, Psychiatric diagnoses are usually made based on algorithmic (DSM-IV) criteria outlined in diagnostic manuals, primarily through reference to the Diagnostic and Statistical Manual of Mental Disorders (DSM). In practice, psychiatric diagnoses rely upon a physician's judgments about a patient's medical history, clinical evaluation of symptoms, and from patient response to psychiatric drugs.

Pharmaceutical company literature continues to explain the operation of psychoactive drugs in terms of chemical imbalances, and restoring a chemical balance closer to 'normal'. The research underlying the mechanism by which the drugs are thought to work is typically justified by clinical trials demonstrating their efficacy.

Cautionary measures[edit | edit source]

An important consideration with regard to chemical intervention is the potential for relapsing into depression or other psychiatric conditions when medication is discontinued abruptly or without medical supervision. Aside from malnutrition, the only certain means of creating chemical imbalances in the brain is the use of psychotropic chemicals, a category which includes both legal prescription drugs and illegal drugs like LSD or cocaine. Side effects from psychotropic drugs can be significant. Great care must be taken to prevent severe withdrawal symptoms after using psychotropic drugs. Neuroleptic drugs (typically used in the treatment of schizophrenia) are particularly dangerous to withdraw from quickly. Rebound psychosis is common and can leave a patient more unstable than they were prior to taking the neuroleptic in the first place.

See also[edit | edit source]

Current neuroscience perspectives[edit | edit source]

Critical perspectives[edit | edit source]

References[edit | edit source]

  1. Drugs and the Brain: Antidepressants
  2. 2.0 2.1 The catecholamine hypothesis of affective disorders: a review of supporting evidence. 1965 [classical article] - Schildkraut 7 (4): 524 - J Neuropsychiatry Clin Neurosci
  3. Joseph J. Schildkraut obituary, New York Times (July 8, 2006)
  4. 4.0 4.1 4.2 Looking Beyond the Monoamine Hypothesis
  5. 5.0 5.1 Mental Illness - GSU Biology 4102 / 6102
  6. The Catecholamine Hypothesis of Affective Disorders: A review of Supporting Evidence - Schildkraut 122 (5): 509 - Am J Psychiatry
  7. Television adverts for antidepressants cause anxiety, from New Scientist. Published November 12, 2005; accessed November 17, 2007.
  8. The "Chemical Imbalance" Theory: Dead or Alive?
  9. Is Clinical Depression Caused by a Serotonin Imbalance? A Response to Peter Kramer.
  10. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB (1996). Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proceedings of the National Academy of Sciences of the USA 93 (17): 9235–40.
  11. Jones HM, Pilowsky LS (2002). Dopamine and antipsychotic drug action revisited. British Journal of Psychiatry 181 (4): 271–275.
  12. (2007). The Media and the Chemical Imbalance Theory of Depression. Society 45 (1): 35.
  13. Lacasse JR, Leo J (2005 Dec). Serotonin and depression: a disconnect between the advertisements and the scientific literature. PLoS Medicine 2 (12): e392.
  14. Advertisements for SSRIs may be misleading.
  15. Roggenbach, J, Müller-Oerlinghausen, B; Franke, L (2002-12-15). Suicidality, impulsivity and aggression--is there a link to 5HIAA concentration in the cerebrospinal fluid?. Psychiatry research 113 (1-2): 193–206.
  16. L, McHenry (2006). Ethical issues in psychopharmacology. J Med Ethics..

External links[edit | edit source]

Current neuroscience theories[edit | edit source]

Critical views[edit | edit source]

  • CCHR - Scientology-affiliated Psychiatric Watchdog Speaks Out About Tom Cruise Speaking Out on Antidepressants
  • - 'Ritalin: Role Models in a Bottle, Social Discipline in a Capsule'
  • - 'There are no "Chemical Imbalances"', Eaton T. Fores Research Center Against Psychiatry
  • - Online discussion of ETFRC's 'There are no "Chemical Imbalances"'

Proponent views[edit | edit source]

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