The first of these drugs was called chlorpromazine. It was initially developed as an anti-histamine with the aim of using it to control people's allergies. Unfortunately its side-effects were too strong for it to be useful as an anti-allergenic. It had, however, been suggested that strong anti-histamines could be used to reduce dangerous drops in blood-pressure which can occur under general anaesthesia. A number of different anti-histamines were tested for their pre-operative effects on patients. Again unfortunately the predicted effects on blood-pressure were never found, it was, however, noticed that many of these drugs seemed to have a marked calming influence on patients without actually making them lose consciousness. At the start of the 1950's these drugs were in common use as pre-operative tranquillisers. In 1952 trials were begun on the effects of chlorpromazine, which had been recognised as having the strongest tranquillising effect of all the anti-histamines tested up to that time, on psychiatric patients, including a number of schizophrenics. It was observed that, in addition to its sedative and tranquillising properties, chlorpromazine also reduced the severity or occurrence of hallucinations and delusions in these schizophrenics. Within two years chlorpromazine had been licensed for use in treating schizophrenia in the USA. It soon became the dominant form of treatment for schizophrenia and was followed by many other similar compounds.
Coincidentally a drug called reserpine which was derived from the roots of rawolfia plants which had been used in Asia for centuries in the treatment of insanity and high blood-pressure was also investigated as an anti-psychotic at the start of the 1950's in the west. It too appeared to control some schizophrenic symptoms but had even more severe side-effects than chlorpromazine and so did not gain such widespread use.
At the time it was not clear what the precise action of these drugs was not known, however, some of their side effects began to provide clues which were later tested directly as new analytic techniques were developed. One of the most important of the side-effects of chlorpromazine is the development of tremors and jerkiness in patients movements. Usually this motor-effects do not persist when then dose of the drug is reduced, in some patients, however, the damage is permanent. Even when they stop taking chlorpromazine altogether they are still left with pronounced tremors and movement difficulties. These symptoms are essentially indistinguishable from Parkinson's disease. It had been discovered that Parkinson's disease could be treated using L-dopa, a precursor of the neurotransmitter dopamine. As L-dopa reduces Parkinsonism and chlorpromazine induces it is likely that they have opposite effects in the brain. L-dopa increased the amount of dopamine available in the brain, so it seemed likely that chlorpromazine must be diminishing the effectiveness of dopamine.
As it became possible to radioactively label chemicals and measure the extent to which they are taken up in different parts of the brain it was found that chlorpromazine and dopamine bound to the same neurons. When dopamine bound to a receptor on a neuron it opened ion channels in the membrane of the neuron which increased the likelihood that it would produce an action-potential which would in turn produce signal in other neurons. Chlorpromazine would bind to the same receptor but would not have any effect on ion-channels in the neural membrane. Chlorpromazine and dopamine compete to occupy these receptors - if a receptor has a chlorpromazine molecule bound to it then naturally released dopamine cannot bind to the site. Chlorpromazine therefore has the effect of blocking the action of dopamine in the brain. These discoveries lead to the proposal of the dopamine hypothesis of schizophrenia in the early 1970's (notice the 20 year gap between the large-scale introduction of chlorpromazine and the proposal of a theory of its action). The dopamine hypothesis suggests that an overabundance of dopamine, or alternatively an excess of dopamine receptors, causes schizophrenia. In addition to evidence from the psychological and neurochemical action of neuroleptics a number of other lines of supporting evidence were cited implicating dopamine overactivity in schizophrenia. Reserpine, although not a dopamine-blocker also acted to reduce the effectiveness of dopamine by depleting the amount of dopamine stored inside neurons so that when an action potential triggered release of dopamine less than the usual amount was available. It was also known that the consumption of large amounts of amphetamines could produce a psychotic state similar to schizophrenia and that one of the actions of amphetamines was to increase the amount of dopamine that would be released with each action-potential. Taken together these facts provide a strong link between dopamine and schizophrenia.
The most straightforward problem for the dopamine hypothesis is that not all symptoms and not all schizophrenics are susceptible to dopamine treatment. In general, neuroleptics effect positive (type 1 e.g. delusions, hallucinations, thought disorder) but not negative (type 2 e.g. flattened affect, lack of motivation) schizophrenic symptoms. Traditional neuroleptics also act primarily on one particular type of dopamine receptor - the D2 receptor. It has, however, been found more recently that clozapine, an atypical anti-psychotic drug, often helps patients who are unresponsive to traditional neuroleptics. It has been shown that clozapine acts on another type of dopamine receptor - the D1 receptor and that it also blocks the transmitter 5-HT (serotonin). These findings at least complicate the dopamine overactivity hypothesis even if they do not discredit it.
Measuring these metabolites is far from easy - they can only be accurately measured in cerebrospinal fluid and can be strongly effected by a patients diet - so in order to study the difference between schizophrenics and normal patients it is necessary to give all of your subjects lumbar-punctures (not a pleasant procedure) and to control their food intake for a day or so before the puncture is made. If you wish to study differential effects of drugs on metabolite levels in normals and schizophrenics you must give all of your subjects a number of lumbar punctures! Even in the face of these problems and number of studies have been undertaken. Drug treatment will, of course, effect metabolite levels directly, so in order to discover whether changes in dopamine levels are associated with schizophrenia independently of treatment patients should be tested when drug-free (ideally they should never have taken anti-psychotic drugs).
The results of metabolite studies are hard to interpret and often inconclusive. Measurements of HVA levels vary markedly between subjects - it appears that some symptoms produce stronger effects than others. Particularly interesting work has measured HVA and 5-HIAA levels in normals and schizophrenics with and without drug-treatment. In addition the strength of schizophrenics' symptoms were measured after each lumbar puncture. The results showed that the neuroleptic used - haloperidol - increased the amount of HVA found (as the dopamine naturally released fails to bind to postsynaptic receptors not as much of it can be reabsorbed by the presynaptic neuron so more HVA is found after dopamine blockade). When changes in HVA and 5-HVIAA levels were correlated with changes in symptoms it was found that symptoms only reduced if both HVA and 5-HVIAA levels were elevated, implying that both types of receptors must be blocked, and only if the proportionate effect on HVA was greater than that on 5- HVIAA, implying the necessity of a stronger effect on dopamine than on 5-HT.
Dopamine has also been implicated in signalling reward. In recent years it has become apparent that dopaminergic neurons are not so much signalling reward by directly transiting hedonic signals during the consumption of a reward but rather are involved in signalling the anticipation of those qualities. A function which is closely related, but not identical, with is action gating function in the nigro-striatal system. This reward-related function is though to be mediated through neurons in the meso-limbic and meso-cortical dopamine systems.
Finally, dopamine may have a role in the control of appetite (that is, specifically in the control of response to food rewards). Dopaminergic neurons in the hypothalamus were thought to be involved, perhaps indirectly, with signalling hunger. Much work has been directed at finding out exactly which neurons are involved, the current state of research implicates peptides in the hypothalamus more than dopamine, however, dopamine may still have a specific role in the control of appetite.
All of this suggests that if schizophrenia was simply due to a general overabundance of, or over-reactivity to (too many receptors, for example) dopamine then schizophrenia should be a quite different condition to that which we observe - as one paper discussing dopamine's involvement in reward put it - why aren't all schizophrenics fat and happy?
This leads us into the question of whether any structural abnormalities can be found in schizophrenic brains. Again there is a problem that prolonged drug-treatment could lead to structural changes - making attribution of any differences between schizophrenic and normal brain to schizophrenia rather than its treatment impossible. For this reason much research relies upon analysis of the brains of schizophrenic who dies before the 1954 introduction of widespread chlorpromazine therapy. One major and reliable finding, discovered as early as 1927, is that the ventricles of the schizophrenic brains (in particular the lateral ventricles) are abnormally enlarged - this may imply some abnormality in the tissue surrounding these ventricles. This ventricular enlargement is not, however, seen in all schizophrenics. Measurement of brain activity in schizophrenics has also shown reduced cerebral blood flow in the dorso-lateral prefrontal cortex. In addition to these cortical effects research on post-mortem brains has revealed abnormal asymmetries in schizophrenic brains - notably in the amygdala. Interestingly both the amygdala and the frontal cortex receive dopaminergic projections.
We have reviewed some of the evidence for a biological basis for schizophrenia. It must be stressed that this evidence is correlational - we cannot tell if the abnormalities described cause schizophrenia or if schizophrenia, caused by some external factor, leads to particular patterns of brain activity which result in long-term changes to the chemistry and structure of the brain.
Attempts to uncover a genetic basis for schizophrenia use a number of methods. Twin studies compare the probability that identical and non-identical twins will both develop schizophrenia. If one of a pair of identical twins develops schizophrenia there is a 50% chance that his or her sibling will do so also. This can be compared with the 10% (figures range from 3 to nearly 20%) probability that the non-identical twin of a schizophrenic will develop schizophrenia. The problem with these studies is that they fail to account for the effects of upbringing. One of the most powerful determining factor for schizophrenia is having schizophrenic parents. It is unclear whether this fact can be attributed to genetic factors of upbringing and the home environment. It is also unclear whether high concordance rates for schizophrenia in identical twins can be attributed to differences in the ways they are treated compared to dizygotic twins or whether their genetic similarity is the crucial factor. One method of addressing this problem is to study the development of schizophrenia in adopted and non-adopted children. Ideally we would like to combine twin and adoption studies but not many families can be found in which only one of a pair of identical twins, one of whom later develops schizophrenia, can be found! Real adoption studies compare the probability that adopted children will develop schizophrenia. These comparisons can be made between children whose biological mother did or did not have schizophrenia or between adopted children who developed schizophrenia and their biological relatives. In both cases there appears to be a higher than average risk of developing schizophrenia if you are related to schizophrenics whether or not you were raised in a schizophrenic household.
These results have encouraged researchers to search for a 'schizophrenia gene', perhaps associated with coding the development of dopamine related structures in the brain. As yet, however, this search appears unsuccessful. This may be because schizophrenia is not linked to a single gene, but rather to interactions between many genes. This hypothesis is consistent with the partial inheritance of schizophrenia and the variations in the types and severities of the illness.
Finally, we can look at two hypotheses concerning environmental causes - both involving viri. One intriguing hypothesis, which may never be testable, holds that studies of literature fails to mention classical schizophrenic symptoms before about 1750, although other mental illnesses are clearly described. It is suggested that an virus then swept through the population which is now endemic. There are a lot of problems with this theory. There is, however, some more convincing evidence for viral involvement in schizophrenia.
Exposure of a foetus to the flu virus during the second trimester of pregnancy has been found to be a predictor of the development of schizophrenia. Interestingly, other factors associated with second trimester abnormalities can be compared in grown twins as a way of linking epigenetic (developmental) problems with schizophrenia. In the case of both identical and non-identical twins these markers of abnormal development (such as abnormal fingerprint ridge counts - fingertip skin cells develop during the second trimester) tend to be found only in the schizophrenic twin.
In conclusion, there is considerable evidence for some genetic basis for schizophrenia although individual studies tend to be hard to interpret on their own and some co-factor such as viral infection or social conditions may also be necessary for schizophrenia to develop. Similarly, evidence for neurochemical abnormalities is hard to interpret, but overall there is considerable evidence that dopamine abnormalities, along with other less well identified cofactors may mediate the disease. It is still not clear to what extent drug therapy can specifically target these abnormalities and, even if it can, to what extent it is treating the causes rather than just the symptoms of the disease.