Serotonin_2A Receptors and Schizophrenia: The Controversies Continue
A new study reporting decreased serotonin_2A receptor (HTR2A) density in drug naïve first-episode schizophrenia (Rasmussen et al., 2010) has again raised the issue of the role of that receptor in the pathophysiology of the disorder.

The notion that the HTR2A is involved in pathophysiology and treatment of schizophrenia remains an open issue. The observation that a number of the atypical antipsychotic drugs are high-affinity antagonists at the receptor would suggest that blocking stimulation of the receptor can have some therapeutic benefit (Meltzer, 1995). It is also significant that, overall, available data from postmortem studies would suggest that the HTR2A is decreased in density in the cortex of subjects with schizophrenia (Dean, 2003). This could either be due to altered gene expression per se or an appropriate agonist induced...  Read more

Serotonin_2A Receptors and Schizophrenia: The Controversies Continue
A new study reporting decreased serotonin_2A receptor (HTR2A) density in drug naïve first-episode schizophrenia (Rasmussen et al., 2010) has again raised the issue of the role of that receptor in the pathophysiology of the disorder.

The notion that the HTR2A is involved in pathophysiology and treatment of schizophrenia remains an open issue. The observation that a number of the atypical antipsychotic drugs are high-affinity antagonists at the receptor would suggest that blocking stimulation of the receptor can have some therapeutic benefit (Meltzer, 1995). It is also significant that, overall, available data from postmortem studies would suggest that the HTR2A is decreased in density in the cortex of subjects with schizophrenia (Dean, 2003). This could either be due to altered gene expression per se or an appropriate agonist induced downregulation of the receptor due to chronic overactivation (Rahimian et al., 1995). Recently, it has been suggested that different outcomes from the postmortem studies are due to differing methodologies (Dean et al., 2008); the differences being due to studies using particulate membrane separating a component in the cytosol which regulates receptor binding from the receptor protein. It is becoming clear that the HTR2A is part of protein complexes in the membrane (Gonzalez-Maeso et al., 2008), and, therefore, it could well be that further exploration of the interactions between the HTR2A and its membrane complexes as well as the cytosol are required to make postmortem data on the HTR2A more interpretable.

As with postmortem studies, positron emission tomography studies appear to be giving disparate outcomes regarding the levels of HTR2A in schizophrenia (Table 1). Clearly, in these studies different results cannot be accounted for by separating the receptor from intracellular regulatory proteins or membrane complexes. Moreover, whilst there are differences in the number of subjects in each study, an analysis of cohort sizes (Fisher exact test) shows this measure does not differ significantly across studies (p = 0.09). Finally, the radioligand used would not appear to be influencing outcomes, as studies using [¹⁸F]setoperone and [¹⁸F]altanserin have both given different outcomes in different studies of levels of HTR2A in subjects with schizophrenia.

One intriguing observation is that, if current studies are ranked by the mean age of the total cohort of subjects studied, then the two studies reporting decreases in the HTR2A in schizophrenia were completed on the youngest of the seven cohorts (Table 1). This raises the possibility that decreases in the HTR2A may be detectable by neuroimaging early in the disease process. If that is the case, could a decrease in cortical HTR2A be a potential prodromal marker to predict the transition from high risk to frank schizophrenia?

References:

Rasmussen, H, et al., (2010) Decreased frontal serotonin_2A receptor binding in antipsychotic-naive patients with first-episode schizophrenia, Arch. Gen. Psychiatry 67, 9-16. Abstract

Meltzer, HY, (1995) The role of serotonin in schizophrenia and the place of serotonin-dopamine antagonist antipsychotics, J. Clin. Psychopharmacol. 15, 2S-3S. Abstract

Dean, B, (2003) The cortical serotonin_2A receptor and the pathology of schizophrenia: a likely accomplice, J. Neurochem. 85, 1-13. Abstract

Rahimian, R, et al., (1995) Possible role of protein kinase C in regulation of 5-hydroxytryptamine 2A receptors in rat brain, Can. J. Physiol Pharmacol. 73, 1686-1691. Abstract

Dean, B, et al., (2008) Evidence for altered post-receptor modulation of the serotonin 2a receptor in schizophrenia, Schizophr. Res. 104, 185-197. Abstract

Gonzalez-Maeso, J, et al., (2008) Identification of a serotonin/glutamate receptor complex implicated in psychosis, Nature 452, 93-97. Abstract

Ngan, ET, et al., (2000) Decreased serotonin 2A receptor densities in neuroleptic-naive patients with schizophrenia: A PET study using [(18)F]setoperone, Am. J. Psychiatry 157, 1016-1018. Abstract

Okubo, Y, et al., (2000) Serotonin 5-HT2 receptors in schizophrenic patients studied by positron emission tomography, Life Sci. 66, 2455-2464. Abstract

Trichard, C, et al., (1998) No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET, Schizophr. Res. 31, 13-17. Abstract

Erritzoe, D, et al., (2008) Cortical and subcortical 5-HT2A receptor binding in neuroleptic-naive first-episode schizophrenic patients, Neuropsychopharmacology 33, 2435-2441. Abstract

Lewis, R, et al., (1999) Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects, Am. J. Psychiatry 156, 72-78. Abstract

Verhoeff, NP, et al., (2000) A voxel-by-voxel analysis of [18F]setoperone PET data shows no substantial serotonin 5-HT(2A) receptor changes in schizophrenia, Psychiatry Res. 99, 123-135. Abstract

The search for biomarkers in complex psychiatric disorders such as schizophrenia has been a crucial goal in clinical research, but remains to be fully accomplished. Serotonin 5-HT_2A receptors have been associated with the pathophysiology and pharmacotherapy of schizophrenia for two main reasons: 5-HT_2A receptor agonists such as LSD elicit hallucinogenic states in humans and second-generation, atypical antipsychotics are effective 5-HT_2A receptor antagonists. However, 5-HT_2A receptor agonists usually evoke visual hallucinations, whereas those associated with schizophrenia are commonly auditory (Hollister, 1962). Contradictory changes in 5-HT_2A receptor density in cortical areas of the brain have been detected in several postmortem studies. The case-control study of Rasmussen and coworkers (Rasmussen et al., 2010) shows decreased 5-HT_2A binding in the frontal cortex of antipsychotic-free, first-episode schizophrenics. Although similar findings were previously observed...  Read more

The search for biomarkers in complex psychiatric disorders such as schizophrenia has been a crucial goal in clinical research, but remains to be fully accomplished. Serotonin 5-HT_2A receptors have been associated with the pathophysiology and pharmacotherapy of schizophrenia for two main reasons: 5-HT_2A receptor agonists such as LSD elicit hallucinogenic states in humans and second-generation, atypical antipsychotics are effective 5-HT_2A receptor antagonists. However, 5-HT_2A receptor agonists usually evoke visual hallucinations, whereas those associated with schizophrenia are commonly auditory (Hollister, 1962). Contradictory changes in 5-HT_2A receptor density in cortical areas of the brain have been detected in several postmortem studies. The case-control study of Rasmussen and coworkers (Rasmussen et al., 2010) shows decreased 5-HT_2A binding in the frontal cortex of antipsychotic-free, first-episode schizophrenics. Although similar findings were previously observed (Ngan et al., 2000; Erritzoe et al., 2008), the present study used the largest sample of patients to date, which gives further strength and validity to the results.

A question that remains to be answered is, What causes this reduced 5-HT_2A binding? Although a hyperactive serotonergic transmission in the prefrontal cortex has been implicated in schizophrenia (Meltzer, 1989), the precise role of cortical serotonin on this effect is not fully understood. It has been shown in an animal model of the illness that antagonists of the NMDA glutamate receptor increased serotonin release in prefrontal cortex (Adams and Moghaddam, 2001; Amargós-Bosch et al., 2006; López-Gil et al., 2007), an effect prevented by atypical but not typical antipsychotic drugs (López-Gil et al., 2007; 2010). If these changes also occur in schizophrenia, the decreased 5-HT_2A binding might be a compensatory effect resulting from increased cortical serotonergic transmission. Interestingly, although negative symptoms are usually thought to be associated with impaired serotonergic transmission in schizophrenia (Reynolds, 2004), the present study found a significant negative correlation between 5-HT_2A binding in the frontal cortex and positive symptoms in the group of male patients. A study with a larger population is likely needed to draw unequivocal conclusions on that matter. Also, an important point not to be missed is that PET measures were performed, for obvious reasons, in a resting state. Differences in serotonergic changes may thus exist, depending on the pathological phase of the illness.

From a pharmacological point of view, it is worth noting that blockade of 5-HT_2A receptors alone does not confer antipsychotic activity. Thus, clinical evaluation of the selective 5-HT_2A antagonist, M100907, failed to demonstrate therapeutic efficacy (de Paulis, 2001), despite the high level of 5-HT_2A receptor occupancy achieved in frontal cortex (Offord et al., 1999). With the exception of dopamine D2 receptor antagonists (Seeman et al., 1976), no other monoamine receptor antagonist has been shown to possess antipsychotic activity per se. Therefore, there is a clear need for targeting different transmitter receptors in order to achieve better treatment (as well as a lower side effect profile) of schizophrenia. What the study by Rasmussen and coworkers clearly points out is that 5-HT_2A receptors in the frontal cortex are involved in the pathophysiology of schizophrenia, and this region plays a role in the pharmacological effects of antipsychotic drugs.

References:

Adams BW, Moghaddam B. Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex. Biol Psychiatry. 2001;50:750–757. Abstract

Amargós-Bosch M, López-Gil X, Artigas F, Adell A. Clozapine and olanzapine, but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine. Int J Neuropsychopharmacol. 2006;9:565–573. Abstract

De Paulis T. M-100907 (Aventis). Curr Opin Investig Drugs. 2001;2:123-132. Abstract

Erritzoe D, Rasmussen H, Kristiansen KT, Frokjaer VG, Haugbol S, Pinborg L, Baaré W, Svarer C, Madsen J, Lublin H, Knudsen GM, Glenthoj BY. Cortical and subcortical 5-HT2A receptor binding in neuroleptic-naïve first-episode schizophrenic patients. Neuropsychopharmacology. 2008;33:2435-2441. Abstract

López-Gil X, Babot Z, Amargós-Bosch M, Suñol C, Artigas F, Adell A. Clozapine and haloperidol differently suppress the MK-801-increased glutamatergic and serotonergic transmission in the medial prefrontal cortex of the rat. Neuropsychopharmacology. 2007;32:2087-97. Abstract

López-Gil X, Artigas F, Adell A. Unraveling monoamine receptors involved in the action of typical and atypical antipsychotics on glutamatergic and serotonergic transmission in prefrontal cortex. Curr Pharm Des. 2010. Abstract

Meltzer HY. Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology. 1989;99. S18–S27. Abstract

Ngan ET, Yatham LN, Ruth TJ, Liddle PF. Decreased serotonin 2A receptor densities in neuroleptic-naïve patients with schizophrenia: a PET study using [18F]setoperone. Am J Psychiatry. 2000;157:1016-1018. Abstract

Offord SJ, Wong DF, Nyberg S. The role of positron emission tomography in the drug development of M100907, a putative antipsychotic with a novel mechanism of action. J Clin Pharmacol. 1999;39:17S-24S. Abstract

Rasmussen H, Erritzoe D, Andersen R, Ebdrup BH, Aggernaes B, Oranje B, Kalbitzer J, Madsen J. Decreased frontal serotonin2A receptor binding in antipsychotic-naïve patients with first-episode schizophrenia. Arch Gen Psychiatry. 2010;67:9-16. Abstract

Reynolds GP. Receptor mechanisms in the treatment of schizophrenia. J Psychopharmacol. 2004;18:340-345. Abstract

Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature. 1976;261:717-719. Abstract

Implicit in the findings of Schmid et al. is the idea that the relationship among ligand, receptor signaling, and cellular context is an extremely complex one that will take a great deal more work to tease out. Thus, Dr. Bryan Roth has proposed on a number of occasions (see, for example, Gray and Roth, 2007; Abbas and Roth, 2005) that novel approaches for drug discovery may prove more effective in producing schizophrenia drugs that have greater therapeutic efficacy with lower side effect liability. Since it will likely be many years before the field has a detailed understanding of the "nitty-gritty" of the receptor signaling and trafficking relevant to schizophrenia and its treatment, we have suggested a number of approaches that are less reliant on such information.

For example, approaches based on screening for drugs that either mimic the gene expression profiles of gold standard drugs such as clozapine or normalize schizophrenia-associated changes in gene expression are being...  Read more

Implicit in the findings of Schmid et al. is the idea that the relationship among ligand, receptor signaling, and cellular context is an extremely complex one that will take a great deal more work to tease out. Thus, Dr. Bryan Roth has proposed on a number of occasions (see, for example, Gray and Roth, 2007; Abbas and Roth, 2005) that novel approaches for drug discovery may prove more effective in producing schizophrenia drugs that have greater therapeutic efficacy with lower side effect liability. Since it will likely be many years before the field has a detailed understanding of the "nitty-gritty" of the receptor signaling and trafficking relevant to schizophrenia and its treatment, we have suggested a number of approaches that are less reliant on such information.

For example, approaches based on screening for drugs that either mimic the gene expression profiles of gold standard drugs such as clozapine or normalize schizophrenia-associated changes in gene expression are being explored. Another approach is behavior-based screening, in which targeted screens are performed with drugs to find those that have efficacy in animal disease models. A further related approach, exemplified by Psychogenics' Smartcube(TM) (the associated database is called Smartbase[TM]) involves injecting drugs and monitoring the resulting behavior using computer-based machine learning to generate a multidimensional behavioral signature for gold standard drugs. Drugs can then be screened to look for those that mimic gold standard drugs in terms of their signatures. Though Psychogenics does not appear to have done much (at least publicly) with this approach, it represents the sort of innovative thinking that may prove fruitful in future behavior-based drug discovery efforts since it is not dependent on knowing anything about the mechanism. In the end, at least in the near future, we believe such approaches may prove extremely useful in drug discovery efforts since they do not rely on extensive mechanistic knowledge of the processes underlying schizophrenia.

References:

Gray JA, Roth BL. The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct ;12(10):904-22. Abstract

Abbas A, Roth B. Progress towards better understanding and treatment of major psychiatric illnesses. Drug Discov Today. 2005 Jul 15;10(14):960-2. Abstract

The results of this study are surprising. In those with schizophrenia, those on clozapine had by far the lowest relative risk of death (compared to patients on other antipsychotics). Compared to older medications, atypical antipsychotics, to date, do not seem to be impacting on the relative risk of death.

I congratulate the authors on this impressive study. The study is another reminder of the utility of population-based record linkage studies. Thank heavens for the Nordic countries' health registers.

A few years ago we wondered if the differential mortality rate for schizophrenia was worsening over time (Saha et al., 2007). In addition to differential access to health care, we worried that the adverse effects of atypical antipsychotics might be a “ticking time bomb” for worsening mortality in the decades to come. The new Finnish study shows a more nuanced picture emerging.

While the results are thought provoking, let’s not forget about the main game. We all agree that there is still much more work to be done in...  Read more

The results of this study are surprising. In those with schizophrenia, those on clozapine had by far the lowest relative risk of death (compared to patients on other antipsychotics). Compared to older medications, atypical antipsychotics, to date, do not seem to be impacting on the relative risk of death.

I congratulate the authors on this impressive study. The study is another reminder of the utility of population-based record linkage studies. Thank heavens for the Nordic countries' health registers.

A few years ago we wondered if the differential mortality rate for schizophrenia was worsening over time (Saha et al., 2007). In addition to differential access to health care, we worried that the adverse effects of atypical antipsychotics might be a “ticking time bomb” for worsening mortality in the decades to come. The new Finnish study shows a more nuanced picture emerging.

While the results are thought provoking, let’s not forget about the main game. We all agree that there is still much more work to be done in optimizing the general physical health of people with schizophrenia.

References:

Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry . 2007 Oct 1 ; 64(10):1123-31. Abstract

Clozapine: A First-Line Antipsychotic?
Tiihonen et al., of the University of Kuopio in Finland, compared mortality rates in over 66,000 patients with schizophrenia with the entire population of Finland and concluded that clozapine should be used as a first-line drug in the treatment of this disorder. Clozapine is a very effective antipsychotic, and for patients who have received it for several years, the improvement in clinical status can be quite remarkable (Lindstrom, 1988; Agid et al., 2008). Additionally, the improved mortality rate of patients on clozapine may be attributable, at least in part, to the close monitoring of their white blood cell count (WBC).

The stipulation that weekly or biweekly blood samples must be drawn is not an issue that can be viewed lightly, because approximately 1-2 percent of patients on clozapine may show significant decreases in their WBC. This may be a harbinger of agranulocytosis, a potentially lethal form of morbidity in which the...  Read more

Clozapine: A First-Line Antipsychotic?
Tiihonen et al., of the University of Kuopio in Finland, compared mortality rates in over 66,000 patients with schizophrenia with the entire population of Finland and concluded that clozapine should be used as a first-line drug in the treatment of this disorder. Clozapine is a very effective antipsychotic, and for patients who have received it for several years, the improvement in clinical status can be quite remarkable (Lindstrom, 1988; Agid et al., 2008). Additionally, the improved mortality rate of patients on clozapine may be attributable, at least in part, to the close monitoring of their white blood cell count (WBC).

The stipulation that weekly or biweekly blood samples must be drawn is not an issue that can be viewed lightly, because approximately 1-2 percent of patients on clozapine may show significant decreases in their WBC. This may be a harbinger of agranulocytosis, a potentially lethal form of morbidity in which the bone marrow loses its ability to generate leukocytes; death remains a significant risk for patients taking this drug (Taylor et al., 2009). To some, this may seem like a small price to pay for an improved quality of life. For others, however, it represents an unacceptable degree of risk. Additionally, many patients consider the requirement for frequent blood drawing as intrusive and/or painful and refuse to have it done (personal observation).

Perhaps the greatest source of resistance to using clozapine as a “first-line” drug is the psychiatrist who is faced with this decision. In general, most believe that they would be exposing their patient to unnecessary risk and prefer to look toward other, more “benign” antipsychotic drugs (APDs) for treatment options. In practice, however, the second-generation atypical APDs are not necessarily better candidates for “first-line” use, because they may be even more likely to cause excessive weight gain, diabetes mellitus, and cardiovascular disease (Wehring et al., 2003; Henderson et al., 2005) and result in increased mortality (Meatherall and Younes, 2002). In addition to the risk of agranulocytosis, clozapine may also cause unacceptable amounts of sedation, drooling, and weight gain. Typical APDs, on the other hand, are associated with other side effects that can be quite debilitating. These include extrapyramidal movement disorders, such as 1) akathisia, a condition that may cause a worsening of symptoms as a result of agitation; 2) drug-induced Parkinsonism, in which hypokinesia usually complicates the negative symptoms of schizophrenia; and 3) tardive dyskinesia, a syndrome in which there are involuntary movements of the tongue and lips that can result in significant disability and even disfigurement (Peacock et al., 1996).

In considering the choice of an APD for a “first-episode” patient with schizophrenia, all of these factors must be considered. It is impossible to know how a particular patient with no prior history of having taken an APD will respond to any given drug. What may be an excellent “first-line” drug for one patient may not be so for another. So, the choice of a “first-line” drug requires that the doctor and patient work together to identify the APD that is most appropriate at a particular time in the course of the illness, particularly if the patient has a treatment-sensitive or treatment-resistant form of schizophrenia (Wang et al., 2004).

References:

Agid O, Kapur S, Remington G. Emerging drugs for schizophrenia. Expert Opin Emerg Drugs. 2008;13:479-95. Abstract

Henderson DC, Nguyen DD, Copeland PM, Hayden DL, Borba CP, Louie PM, Freudenreich O, Evins AE, Cather C, Goff DC. Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study. J Clin Psychiatry. 2005;66:1116-21. Abstract

Lindstrom LH. The effect of long-term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand. 1988;77:524-9. Abstract

Meatherall R, Younes J. Fatality from olanzapine induced hyperglycemia. J Forensic Sci. 2002;47:893-6. Abstract

Peacock L, Solgaard T, Lublin H, Gerlach J . Clozapine versus typical antipsychotics. A retro- and prospective study of extrapyramidal side effects. Psychopharmacology (Berl). 1996; 124:188-96. Abstract

Taylor DM, Douglas-Hall P, Olofinjana B, Whiskey E, Thomas A. Reasons for discontinuing clozapine: matched, case-control comparison with risperidone long-acting injection. Br J Psychiatry. 2009;194:165-7. Abstract

Wang PS, Ganz DA, Benner JS, Glynn RJ, Avorn J. Should clozapine continue to be restricted to third-line status for schizophrenia?: a decision-analytic model. J Ment Health Policy Econ. 2004;7:77-85. Abstract

Wehring HJ, Kelly DL, Love RC, Conley RR. Deaths from diabetic ketoacidosis after long-term clozapine treatment. Am J Psychiatry. 2003;160:2241-2. Abstract

Dr. Benes notes that clozapine is "...a very effective antipsychotic, and...improvement in clinical status can be quite remarkable." The mortality figures reported by Tihonen et al. have proved quite striking to schizophrenia researchers. The perception within the psychiatry community that clozapine is too risky for first-line therapy needs further assessment and discussion. Only about 5 percent of schizophrenics in the U.S. receive clozapine (Lieberman, 2009), leaving the vast majority of patients undermedicated because of this perception. The major issue with starting a patient on clozapine is WBC monitoring. I would like to call upon the NIMH to establish a major study in which schizophrenics are introduced to clozapine on an inpatient basis for 30-60 days to establish safety. It is well known that most WBC events associated with clozapine occur in the first few weeks of treatment. Also, I note that current prescribing practice with clozapine actually allows for monthly blood monitoring after 12 months of continuous clozapine use. Thus, the burden of monitoring diminishes...  Read more

Dr. Benes notes that clozapine is "...a very effective antipsychotic, and...improvement in clinical status can be quite remarkable." The mortality figures reported by Tihonen et al. have proved quite striking to schizophrenia researchers. The perception within the psychiatry community that clozapine is too risky for first-line therapy needs further assessment and discussion. Only about 5 percent of schizophrenics in the U.S. receive clozapine (Lieberman, 2009), leaving the vast majority of patients undermedicated because of this perception. The major issue with starting a patient on clozapine is WBC monitoring. I would like to call upon the NIMH to establish a major study in which schizophrenics are introduced to clozapine on an inpatient basis for 30-60 days to establish safety. It is well known that most WBC events associated with clozapine occur in the first few weeks of treatment. Also, I note that current prescribing practice with clozapine actually allows for monthly blood monitoring after 12 months of continuous clozapine use. Thus, the burden of monitoring diminishes sharply after one year.

References:

Lieberman J. A Beacon of Hope: Prospects for Preventing and Recovering from Mental Illness. NARSAD Research Quarterly 2 (1), Winter 2009.