Critique of the Dopamine Hypothesis of Schizophrenia

Schizophrenia is a serious and chronic mental disorder that affects 1% of the world’s population. It is characterized by a range of striking disturbances in mental functioning that can be grouped into both positive and negative symptoms, and also cognitive and psychosocial dysfunctions (Hales, Yudofsky, & Gabbard, 2008) (Abi-Dargham, 2004) (DeLeon, Patel, & Crismon, 2004). The aetiology of schizophrenia is yet to be concluded and while there are several hypotheses that are generally accepted such as genetics and environmental factors, it is the classical dopamine hypothesis that is discussed in this paper.

The classical dopamine hypothesis postulates that the mental disorder is a manifestation of a hyperdopaminergic state (Davis, Kahn, Ko, & Davidson, 1991). It had emerged in the 1960s through the observation of the effects of antipsychotic drugs and stimulants that increase dopaminergic activity (Birtwistle & Baldwin, 1998) (van Rossum, 1966). It will be argued in this paper that while the dopamine hypothesis is compelling there are limitations to be considered.

Using the study of first generation antipsychotics such as chlorpromazine and sympathomimetic drug amphetamine it will be asserted that the classical theory does not account for the negative symptoms of schizophrenia. Further, using the study of a second generation antipsychotic or atypical antipsychotic, aripiprazole, it would elucidate that other neurotransmitter systems may be involved in the pathophysiology of schizophrenia. The early dopamine hypothesis had focused on excessive dopamine neurotransmission as the main aetiology of schizophrenia.

This was supported when positive symptoms of the illness and other psychotic behaviors in patients were alleviated after the administration of antipsychotic drugs chlorpromazine (Carlsson & Lindqvist, 1963) (van Rossum, 1966). According to Creese, Burt, & Snyder (1976) the reason behind its effectiveness was directly due to its ability to block dopamine D2 receptors hence suggesting the role of neurotransmitter dopamine in the aetiology of schizophrenia.

In addition, sympathomimetic drug amphetamine was found to produce a psychotic reaction which could be reversed by dopamine receptor blocking antipsychotics thus further supporting the theory of dopamine as the leading neurotransmitter in the pathophysiology of schizophrenia (Feldman, Meyer, & Quenzer, 1997). However, what the early hypothesis failed to factor was the negative symptoms, which are acknowledged as essential components of the mental disorder.

Dopamine-blocking agents have been found to be effective in reducing or moderating the positive symptoms of schizophrenia however it has not been shown to be effective in treating negative symptoms. Patients who were administered first generation antipsychotic, chlorpromazine, reported to have reduced impact of abnormal mental phenomena such as hallucinations and delusions (positive symptoms), however it was reported it had none to very little effect in alleviating the negative or deficit symptoms such as avolition and blunted affect (Andreasen & Olsen, 1982).

These finding would suggest a contradiction of the dopamine hypothesis where it theorizes over activity of dopamine as the aetiology of schizophrenia. While, the hypothesis may be supported with evidence of alleviation of positive symptoms, it lacks validation when studies do not account for the negative symptoms and so implying that hyperdopaminergia is not a sufficient theory as aetiology of schizophrenia. Moreover, dopaminergic agents have also not been shown to induce negative symptoms.

When patients were induced with sympathomimetic drug amphetamine positive symptoms generally worsen (Angrist, Peselow, Rubinstein, Wolking & Rotrosen, 1985) and when in those without the illness, psychotic like symptoms occur (Moncrieff, 2009) (Feldman et al. , 1997) (Howes & Kapur, 2009). From the dopamine hypothesis it would imply that excessive dopamine neurotransmission to account for schizophrenic symptoms. However, from these studies whereby only part of the symptoms was recreated it would suggests that while the theory may be persuasive it is only so up to where it could be accountable for.

In addition, second generation or atypical antipsychotics such as aripiprazole have been thought to act through multiple neurotransmitter systems on top of dopamine thus indicating that dopamine is not the only neurotransmitter to be involved in the pathophysiology of schizophrenia. Second generation antipsychotics differ from the first in the way that they produce 5-HT2A receptor antagonism while maintaining blockade of D2 receptors and thus acts only as a partial agonist at dopaminergic receptors.

Aripiprazole has been found to display high affinity for diverse monoaminergic receptors, including serotonergic, histaminergic, muscarinic, and adrenergic receptors, in addition to the D2 receptor, and have therefore led to the hypothesis that other neurotransmitter systems may be involved in the pathophysiology of schizophrenia. This is a direct dispute to the dopamine hypothesis as it implies that not only is it more likely that schizophrenia is caused by subcortical hyperdopaminergia and hypodopaminergia in the cortex but also that dopamine is not the only neurotransmitter involved in the pathophysiology of schizophrenia (DeLeon et al., 2004) (Abi-Dargham, 2004).

As compelling as the dopamine hypothesis has been to schizophrenia research, there are limitations to this theory which are to be acknowledged. While it is quite undeniable that the neurotransmitter dopamine has an involvement with the pathophysiology of schizophrenia, as according to studies of antipsychotics, both first and second generation, and also sympathomimetic drug amphetamine, it fails to factor other parts of the symptoms and the involvement of other neurotransmitter systems.

It does not account for negative symptoms, which are essential components of the illness, dopamine-blocking agents have not been shown to be effective in treating negative symptoms, nor have dopaminergic agents been shown to induce negative symptoms and finally atypical antipsychotics are thought to have high affinity for diverse monoaminergic receptors in addition to dopamine. Further, though it can account for a part of the aetiology of schizophrenia it is by no means able to explain every aspect and thus is not a sufficient theory.

References Abi-Dargham, A. (2004). Do we still believe in the dopamine hypothesis? New data bringnew evidence. The International Journal of Neuropsychopharmacology. 7(Supplement 1), S1-5. Andreasen, N. C. , & Olsen, S. A. (1982). Negative vs. positive schizophrenia: Definition andvalidation. Archives of General Psychiatry, 39, 789-794. Angrist, B. , Peselow, E. , Rubinstein, M. , Wolking, A. , & Rotrosen, J. (1985). Amphetamineresponse and relapse risk after depot neuroleptic discontinuation. Psychopharmacology(Berlin), 85, 277-283.

Birtwistle, J. , & Baldwin, D. (1998). Role of dopamine in schizophrenia and parkinson’sdisease. British Journal of Nursing, 7 (14), 832-4. Carlsson, A. , & Lindqvist, M. (1963). Effect of chlorpromazine or haloperidol on formationof 3 methoxytyramine and normetanephrine in mouse brain. Acta PharmacologyToxicology 20,140-144. Creese, I. , Burt, D. R. , & Snyder, S. H. (1976) Dopamine receptor binding predicts clinicaland pharmacological potencies of antischizophrenic drugs. Science 19, 481-483.

Davis, K. L. , Kahn, R. S. , Ko, G., & Davidson, M. (1991). Dopamine in schizophrenia: Areviewand reconceptualization. American Journal of Psychiatry, 148 (11), 14741486. DeLeon, A. , Patel, N. C. , & Crismon, M. L. (2004). Aripiprazole: A comprehensive reviewof its pharmacology, clinical efficacy, and tolerability. Clinical Therapeutics, 26 (5),649-666. Feldman, R. S. , Meyer, J. F. , & Quenzer, L. T. (1997). Principles ofneuropsychopharmacology. Sunderland, MA: Sinauer Associates Incorporated. (pp. 783-818). Hales, R. E. , Yudofsky, S. C. , & Gabbard, G. O. (Eds. ). (2008).

The american publishingtextbook of psychiatry, 5th edition. Washington, DC: American PsychiatricPublishing, Inc. Howes, O. D. , & Kapur, S. (2009). The dopamine hypothesis of schizophrenia: Versioniii—the final common pathway. Schizophrenia Bulletin, 35(3), 549-562. Moncrieff, J. (2009). A critique of the dopamine hypothesis of schizophrenia and psychosis. Harvard Review of Psychiatry, 17(3), 214-225. Van Rossum, J. M. (1966). The significance of dopamine-receptor blockade for themechanism of action of neuroleptic drugs. Arch Int Pharmacodyn Ther, 160:492–4.

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