Schizophrenia and Antipsychotics: Part 2

In our second installment from Adrian Dutkiewicz, he discusses the next wave of treatment and an updated view of schizophrenia.  Adrian writes:

The Second Generation

In 1971 the Swiss chemical research company Wander and a group led by Hans Hippius developed the new drug clozapine (Clozaril™), which had been invented as an anti-depressant (antidepressant pharmacology was booming at the time). Clozapine was found to have the most powerful antipsychotic properties of any known drug, but follow-up research studies over several years found that clozapine had a poor affinity for D2 receptors. Although clozapine is considered a dopamine-acting drug because it antagonizes (blocks) dopamine signaling, the efficacy of clozapine in treating patients showed that D2 was not the “schizophrenia receptor” because it could treat the symptoms of schizophrenia better than first-generation drugs, even though it had poor affinity for D2. In addition to binding dopamine receptors, clozapine also binds to cholinergic and serotonergic receptors and thus complicating their simple explanation.5,14-17 Furthermore clozapine had reduced rates of extrapyramidal dysfunction – motor tics and related motor side-effects that develop from prolonged use of antipsychotics. Such an observation contradicted Jean Delay’s belief that these motor tics were signs of improvement and inseparable from a potential cure.5 Unfortunately clozapine is associated with agranulocytosis, a potentially deadly side-effect that reduces white blood cell count. This feature severely limits its use, but the drug sparked a new wave of antipsychotic drug research. However little was known at the time about a potential mechanism that linked dopamine to manifestations of schizophrenia despite these new drugs.

Second generation neuroleptics are numerous and sundry. Ziprasidone (Geodon™), for example, was introduced in 2001 as a mixed antagonist of dopamine, serotonin, adrenergic, and histamine receptor. However its affinity for serotonin receptors is much higher than its affinity for the traditional D2 receptors.18,19 Risperidone (Risperdal™), which was introduced in 1993 has a roughly similar binding profile. Interestingly the second-generation antipsychotics such as risperidone and ziprasidone, with their unique binding profiles, do a much better job of treating the negative symptoms of schizophrenia as well as cognitive deficits associated with the disease.20,21 Their unique binding profiles separate them from the first-generation (“typical”) antipsychotics, and thus the newer ones are called “atypical” antipsychotics. Many of the second-generation drugs are simply small variations of one another. They expanded the clinical treatment options available to doctors, as they had slightly different binding profiles and side-effects, but they were being designed somewhat randomly and people had little clue as to why the drugs were working now that the D2 receptor was effectively debunked as the schizophrenia receptor. However with radioligand binding assays becoming easier to use, we began to understand how the atypical neuroleptics interact with the brain.

Evidence from binding assays

By the early 1980s scientists were finally able to put the pieces in place and find out why first-generation antipsychotics frequently caused motor tics, and failed to treat the negative and cognitive symptoms of schizophrenia. Radioligand binding data revealed that very few D2 receptors reside in the PFC, which seemed to be the site of dysfunction for negative and cognitive symptoms. Thus the first-generation drugs were having little effect on the PFC. The same studies also revealed that D2 receptors are abundant throughout the nigrostriatal pathway – a pathway that mediates movement. Apparently by blocking the dopamine signaling in the nigrostriatal pathway, the drugs were inadvertently causing Parkinsonian-like movement disorders in schizophrenic patients.22-24 These movement disorders include tardive dyskinesia. This is a permanent and disabling facial tic that resembles gum-chewing and it is commonly confused for a symptom of psychosis rather than treatment. Atypical antipsychotics had a reduced tendency to cause these side-effects because they had relatively poor affinity for D2 – though all of them interfere with dopamine signaling to some extent. Meanwhile they discovered that treating the positive symptoms of schizophrenia was directly related to D2 binding in the striatum, suggesting that this was the true origin of psychotic hallucinations.3 We still need more context to understand how the atypical drugs alleviate psychosis without acting strongly on D2.

A better hypothesis of schizophrenia

By 1991, as mentioned in a review by Kenneth L. Davis, the balance of research had failed to find definitive proof of brain-wide hyperactivity in the dopamine signaling of schizophrenics.25 For instance, dopamine metabolites were not elevated in people with schizophrenia (showing that dopamine levels were normal, taken on the brain’s total average) and many patients with schizophrenia were still resistant to the full range of antipsychotics.26 Davis consolidated his research on schizophrenia to predict that underactive dopamine signaling in people with schizophrenia had been causing negative symptoms of schizophrenia through dopamine receptors in the pre-frontal cortex, and that hyperactive dopamine signaling in striatal areas was causing positive symptoms. Anti-psychotics are unlikely to worsen negative symptoms (despite blocking dopamine signaling) because there are not enough D2 receptors in the PFC to cause an effect. The researchers Howes and Kapur describe this new iteration of the dopamine hypothesis as “version II” to illustrate this amendment to the original dopamine hypothesis.26

Causal origins of various diseases benefited immensely from the findings of the Human Genome Project (HGP), which was launched in 1990 and concluded in 2003. This project compiled and sequenced all human genes which now made possible endeavors to locate specific genes and discover how they influence development of human diseases. The HGP made it feasible to build correlations between diseases, genes, and environmental factors that interact with genes. Voluminous statistical studies conducted over decades have compiled lists of environmental factors that contribute to dopamine dysfunction found in schizophrenia, such as social isolation, exposure to toxins and pre or post-natal stress.27,28 Further characterizations of schizophrenia’s dimensions made it possible to break down the disease into components that are easier to quantify and correlate with specific brain structures. For instance, the eminent neuroscientist Dr. Patricia Goldman–Rakic posited that deficient dopamine signaling mediated by dopamine receptor 1 (D1) in the PFC is responsible for the cognitive deficits of schizophrenia.29

References:

14.  Glatt, C. E., Snowman, A. M., Sibley, D. R. & Snyder, S. H. Clozapine: selective labeling of sites resembling 5HT6 serotonin receptors may reflect psychoactive profile. Molecular Medicine 1, 398-406 (1995).

15.  Harris, T. W., Smith, H. E., Mobley, P. L., Manier, D. H. & Sulser, F. Affinity of 10-(4-methylpiperazino)dibenz[b,f]oxepins for clozapine and spiroperidol binding sites in rat brain. Journal of Medicinal Chemistry 25, 855-858, doi:10.1021/jm00349a018 (1982).

16.  Hauser, D. & Closse, A. 3H-clozapine binding to rat brain membranes. Life Sciences 23, 569-573, doi:http://dx.doi.org/10.1016/0024-3205(78)90034-6 (1978).

17.  Grunder, G. et al. The Striatal and Extrastriatal D2//D3 Receptor-Binding Profile of Clozapine in Patients with Schizophrenia. Neuropsychopharmacology 31, 1027-1035 (2005).

18.  Seeger, T. F. et al. Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. Journal of Pharmacology and Experimental Therapeutics 275, 101-113 (1995).

19.  Ichikawa, J. et al. 5‐HT2A and D2 receptor blockade increases cortical DA release via 5‐HT1A receptor activation: a possible mechanism of atypical antipsychotic‐induced cortical dopamine release. Journal of neurochemistry 76, 1521-1531 (2001).

20.  Olié, J.-P., Spina, E., Murray, S. & Yang, R. Ziprasidone and amisulpride effectively treat negative symptoms of schizophrenia: results of a 12-week, double-blind study. International Clinical Psychopharmacology 21, 143-151, doi:10.1097/01.yic.0000182121.59296.70 (2006).

21.  Rossi, A. et al. Risperidone, negative symptoms and cognitive deficit in schizophrenia: an open study. Acta Psychiatrica Scandinavica 95, 40-43, doi:10.1111/j.1600-0447.1997.tb00371.x (1997).

22.  Hall, H., Farde, L. & Sedvall, G. Human dopamine receptor subtypes—in vitro binding analysis using3H-SCH 23390 and3H-raclopride. J. Neural Transmission 73, 7-21, doi:10.1007/BF01244618 (1988).

23.  Dawson, T. M., Gehlert, D. R., Yamamura, H. I., Barnett, A. & Wamsley, J. K. D-1 dopamine receptors in the rat brain: Autoradiographic localization using [3H]SCH 23390. European Journal of Pharmacology 108, 323-325, doi:http://dx.doi.org/10.1016/0014-2999(85)90458-3 (1985).

24.  Dawson, T., Gehlert, D., McCabe, R., Barnett, A. & Wamsley, J. D-1 dopamine receptors in the rat brain: a quantitative autoradiographic analysis. The Journal of neuroscience 6, 2352-2365 (1986).

25.  Davis, K. L., Kahn, R. S., Ko, G. & Davidson, M. DOPAMINE IN SCHIZOPHRENIA – A REVIEW AND RECONCEPTUALIZATION. American Journal of Psychiatry 148, 1474-1486 (1991).

26.  Howes, O. D. & Kapur, S. The Dopamine Hypothesis of Schizophrenia: Version III—The Final Common Pathway. Schizophrenia Bulletin 35, 549-562, doi:10.1093/schbul/sbp006 (2009).

27.  Watanabe, M., Nonaka, R.-i., Hagino, Y. & Kodama, Y. Effects of prenatal methylazoxymethanol treatment on striatal dopaminergic systems in rat brain. Neuroscience Research 30, 135-144, doi:http://dx.doi.org/10.1016/S0168-0102(97)00123-5 (1998).

28.  Henry, C. et al. Prenatal stress in rats facilitates amphetamine-induced sensitization and induces long-lasting changes in dopamine receptors in the nucleus accumbens. Brain Research 685, 179-186, doi:http://dx.doi.org/10.1016/0006-8993(95)00430-X (1995).

29.  Goldman-Rakic, P., Castner, S., Svensson, T., Siever, L. & Williams, G. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology 174, 3-16, doi:10.1007/s00213-004-1793-y (2004).

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