In our final installment, Adrian Dutkiewicz discusses the current understanding of schizophrenia as well as the way drug development and pharmacology are less straight forward than one might think. Adrian writes:
Notes on the second generation drugs
So how do second-generation antipsychotic medications work if they interact with D2 receptors less than first-generation neuroleptics? Research demonstrates that agonizing (activating a receptor instead of blocking it) certain serotonin receptors actually increases dopamine release in the PFC to correct for deficient dopamine signaling there. Interestingly, activation of the 5-HT2A serotonin receptor (seen with some psychedelics like LSD) can cause hallucinations and illustrating a connection between serotonin and psychosis.30 Recall that the deficient dopamine stimulation of the PFC may be responsible for the negative symptoms of schizophrenia, and that the atypical drugs bind to serotonin receptors efficiently – only they activate another type of serotonin receptor, specifically the 5-HT1A receptor; activation of 5-HT1A serotonin receptors then stimulates dopamine release in the PFC. Such an explanation wouldn’t have been possible without thorough knowledge of the PFC’s circuitry.19,30 While not all antipsychotics activate 5HT1A (risperidone does not), some act to block 5HT2A which causes the same antipsychotic effect. However atypical antipsychotics do elicit their effect through interfering with dopamine signaling too. For instance second-generation drugs like clozapine and remoxipride (Roxiam™) tend to prefer variants of dopamine receptors that, fortuitously, do not mediate movement – hence they have little tendency to induce the movement disorders that typical antipsychotics cause.31
Aripiprazole (Abilify™) is an exception to the rule that all antipsychotics interfere with dopamine signaling. This drug started development by Otsuka Pharmaceuticals in the late 1970s as more came to be understood about dopamine signaling and its receptors. Otsuka was inspired by Arvid Carlsson’s 1972 research that demonstrated the existence of autoreceptors (receptors that prevent synapses from overfilling with neurotransmitters like dopamine) though it wasn’t approved by the FDA for schizophrenia until 2002.32,33 Activating dopamine autoreceptors could, hypothetically and paradoxically, reduce dopamine signaling; cells would shut off their dopamine signaling because they are being “informed” that the synapse is overflowing with dopamine. Furthermore aripiprazole activates dopamine receptors less than dopamine itself can, thus it blocks dopamine from binding while activating the receptor only slightly.34 The end result is hypoactive dopaminergic signaling in the PFC becomes more active by aripiprazole’s stimulation, meanwhile hypoactive dopamine signaling in the striatum is inhibited by aripiprazole’s occupancy of the receptors. There was quite a bit of “top-down” planning that went into this drug because it arose from 2 decades of research and a better understanding of schizophrenia that evolved from the development of antipsychotics. Clinically, however, the drug causes roughly the same side-effects as dopamine-blocking drugs but with less frequency.35
This table summarizes some of the second-generation medications I have discussed:
|Clozapine||Dopamine antagonist with weak affinity to D2||Activates M4: Increases salivation||Activates 5-HT1A: Stimulates PFC dopamine release19||Orthostatic hypotension (dizziness after standing up)*||Drowsiness and weight gain36*||Causes agranulocytosis|
|Risperidone||Dopamine antagonist||(None)||Blocks 5HT-2A:
Stimulates PFC dopamine release19
|Drowsiness, sedation*||Treats negative symptoms effectitively (likely due to PFC dopamine release)|
|Ziprasidone||Dopamine antagonist||(None)||Activates 5HT-1A: Stimulates dopamine release in the PFC37
May increase signaling by inhibiting reuptake38
May enhance some adrenergic signaling by inhibiting reuptake38
|Less drowsiness than risperidone (less affinity for H1)*|
|Aripiprazole||Weak dopamine agonist||(None)||Activates 5-HT1A and blocks 5-HT2A: Increases PFC dopamine release||Some blocking of adrengeric receptors, but less than others listed here*||Comparable to risperidone||“Normalizes” dopamine signaling in schizophrenia people|
|Quetiapine||Dopamine antagonist, but much weaker than other drugs here||(None)||Activates 5-HT1A and blocks 5-HT2A: Increases PFC dopamine release||Orthostatic hypotension||Very high relative affinity for H1: profound drowsiness||May be more effective for negative symptoms: Note weak affinity for D2, but its strong effects on serotonergic system|
*Much of the information on binding affinities is from Wikipedia
The most current understanding of schizophrenia integrates data accumulated over the decades. The researchers Howes and Kapur believe that dopamine release onto receptors is overactive in people with schizophrenia – hence blocking the receptors is an indirect, but somewhat effective, means of treating the underlying issue.26 This hypothesis is compiled, in part, based on pharmacological data described in the preceding pages of this post, and it will be put to the test in the future by even more pharmacological data and unanticipated innovations. Future therapies of schizophrenia may evolve from expanding on drugs that regulate dopamine release – or even drugs that treat various components of schizophrenia, depending on the symptoms that the individual schizophrenic patient is experiencing. Modulators of dopamine release – other neurotransmitters or numerous regulators of activity within the cell – may be the treatments of the future. This is unlikely to be the last word on the matter and we may find our understanding evolve as potential treatments are put to the test.
Although this story emphasizes the role of pharmacology and how it has guided our understanding of schizophrenia, this is far from a romantic tale about serendipity and fate; mountains of data are now identifying not only neurotransmitters like dopamine, but also causal genes, environmental exposures and neurodevelopment malformations that contribute to the disease. Furthermore the discovery of the original antipsychotic, chlorpromazine was driven largely by Henri Laborit’s quest for a better surgical sedative and his fascination with chlorpromazine. He was able to enlist the help of other doctors to conduct large-scale studies to investigate his speculations.5
Schizophrenia is no longer believed to be a disease of only the dopaminergic system. Other neurotransmitter systems are believed to be involved, such as the glutamatergic systems. Evidence for involvement of these systems comes from other pharmacological studies that show that drugs that block glutamate NMDA receptors can induce schizophrenic psychosis, as well as negative and cognitive symptoms of schizophrenia.39,40 This has spawned the “glutamate hypothesis” which is sometimes presented to complement the dopamine hypothesis, but also sometimes as a rival hypothesis.30 As you can see, this is a hypothesis that is also driven by pharmacological studies. Given the broad range of affected neural systems, schizophrenia is likely to be a disease of neurodevelopment and the neurotransmitter abnormalities are downstream effects of the main dysfunction. These additional hypotheses may become better integrated into a comprehensive explanation in the future, as we learn more about development of the nervous system.
Pharmacology of antipsychotics provides an interesting example of how bottom-up pharmacology leads scientists, rather than the other way around. In many ways pharmacological studies have propelled our understanding of schizophrenia (as well as other complex diseases), but it has also constrained investigations of those diseases. Dopamine blocking drugs oversimplified the issue; their efficacy was attributed to a bad explanation for the disease – that schizophrenia was a disease of too much dopamine. Paradoxically, other pharmacological data from the discovery of clozapine dislodged this belief from common acceptance. A big fear among researchers has been that by fixating on the role of dopamine, we may be ignoring the contributions of other neurotransmitters like serotonin, glutamate, and GABA. Thus antipsychotics may be occluding our view about the whole picture of schizophrenia. Even with modern scientific tools we must be able to recognize when we are being led by our instruments and find ways to explore beyond their circumscribed boundaries.
30. Rolland, B. et al. Pharmacology of Hallucinations: Several Mechanisms for One Single Symptom? BioMed Research International 2014, 9, doi:10.1155/2014/307106 (2014).
31. Malmberg, A., Jackson, D., Eriksson, A. & Mohell, N. Unique binding characteristics of antipsychotic agents interacting with human dopamine D2A, D2B, and D3 receptors. Molecular pharmacology 43, 749-754 (1993).
32. Pharmaceutical, O. A. <http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021436s038,021713s030,021729s022,021866s023lbl.pdf> (2014).
33. Yasuo Oshiro, T. K., Takash, i Hiyama, N. M., Seiji Sato & (Otsuka Pharmaceutical Co., L. Research and Development of the
Novel Antipsychotic Aripiprazole, <http://www.pharm.or.jp/eng/127th/data/AL2.pdf> (
34. Potkin, S. G., Saha, A. R., Kujawa, M. J. & et al. ARipiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Archives of General Psychiatry 60, 681-690, doi:10.1001/archpsyc.60.7.681 (2003).
35. Swainston Harrison, T. & Perry, C. M. Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder. Drugs 64, 1715-1736 (2004).
36. Humbert-Claude, M., Davenas, E., Gbahou, F., Vincent, L. & Arrang, J. M. Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo. Psychopharmacology (Berl) 220, 225-241, doi:10.1007/s00213-011-2471-5 (2012).
37. Sprouse, J. S., Reynolds, L. S., Braselton, J. P., Rollema, H. & Zorn, S. H. Comparison of the Novel Antipsychotic Ziprasidone with Clozapine and Olanzapine: Inhibition of Dorsal Raphe Cell Firing and the Role of 5-HT1A Receptor Activation. Neuropsychopharmacology 21, 622-631 (1999).
38. Tatsumi, M., Jansen, K., Blakely, R. D. & Richelson, E. Pharmacological profile of neuroleptics at human monoamine transporters. European Journal of Pharmacology 368, 277-283, doi:http://dx.doi.org/10.1016/S0014-2999(99)00005-9 (1999).
39. Luby, E. D., Gottlieb, J. S., Cohen, B. D., Rosenbaum, G. & Domino, E. F. MODEL PSYCHOSES AND SCHIZOPHRENIA. American Journal of Psychiatry 119, 61-67, doi:10.1176/ajp.119.1.61 (1962).
40. Coyle, J. T. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cellular and molecular neurobiology 26, 363-382 (2006).