bipolar disorder & serotonin 5-HT2C receptors
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(Updated 8/25/04)

Lerer B, Macciardi F, Segman RH, Adolfsson R, Blackwood D, Blairy S, Del Favero J, Dikeos DG, Kaneva R, Lilli R, Massat I, Milanova V, Muir W, Noethen M, Oruc L, Petrova T, Papadimitriou GN, Rietschel M, Serretti A, Souery D, Van Gestel S, Van Broeckhoven C, Mendlewicz J.
Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder.
Mol Psychiatry 2001 Sep;6(5):579-85
"We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser),5 in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, 2 = 20.9, df 9, P = 0.01). Logistic regression analysis demonstrated that over and above this inter-population variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD (2 = 7.34, df 1, P = 0.006) and BP (2 = 5.45, df 1, P = 0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder." [Full Text]

Gutierrez B, Fananas L, Arranz MJ, Valles V, Guillamat R, van Os J, Collier D.
Allelic association analysis of the 5-HT2C receptor gene in bipolar affective disorder.
Neurosci Lett 1996 Jul 5;212(1):65- 7
"These results suggest that the ser23 allele may increase susceptibility to bipolar affective disorder in women." [Abstract]

Gutierrez B, Arias B, Papiol S, Rosa A, Fananas L.
Association study between novel promoter variants at the 5-HT2C receptor gene and human patients with bipolar affective disorder.
Neurosci Lett. 2001 Aug 24;309(2):135-7.
Two recently described adjacent DNA polymorphisms [(GT)12-18 and (CT)4-5] in the 5'-regulatory region of 5-HT2C receptor gene were analysed in a sample of 88 bipolar patients and 162 controls, all of Spanish origin. Statistical analyses revealed no overall allele or genotype associations with the disease. A haplotype analyses between the (GT)12-18/(CT)4-5 motif and a Cys23Ser variant of the 5-HT2C gene (which had previously been genotyped in the same sample) showed similar distributions between cases and controls. Only a slight increase of s-Ser23 haplotype was found in the subgroup of bipolar women with family history of psychiatric illness (OR=1.24 [95%CI: 1.12-1.38]). [Abstract]

Meyer J, Saam W, Mossner R, Cangir O, Ortega GR, Tatschner T, Riederer P, Wienker TF, Lesch KP.
Evolutionary conserved microsatellites in the promoter region of the 5-hydroxytryptamine receptor 2C gene (HTR2C) are not associated with bipolar disorder in females.
J Neural Transm. 2002 May;109(5-6):939-46.
Two polymorphic dinucleotide repeats separated by a short spacer are localized in the promoter region of the serotonin receptor 2C gene ( HTR2C). One of the repeats was found to be evolutionary conserved between humans and rhesus monkeys. Although promoter-associated microsatellites have previously been shown to regulate expression of different genes, we did not find any significant influence of distinct HTR2C promoter microsatellite alleles on transcriptional efficiency as measured by luciferase activity and receptor availability as assayed by [(3)H]-mesulergine binding. Furthermore, no association of specific alleles with bipolar disorder was found. These results indicate that the HTR2C promoter polymorphism does not contribute significantly to the etiopathogenesis of bipolar disorder in females. [Abstract]

Iwamoto K, Kato T.
RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders.
Neurosci Lett. 2003 Aug 7;346(3):169-72.
"The importance of serotonin 2C receptor (HTR2C) in mental disorders has been implicated by studies of HTR2C-deficient mice and linkage and association studies. Recent studies have revealed that RNA editing of HTR2C is involved in mental disorders. Here we examined RNA editing efficiencies of site A and D of HTR2C in the prefrontal cortex samples of patients with bipolar disorder, schizophrenia, and major depression as well as control subjects by using primer extension combined with denaturing high performance liquid chromatography. Postmortem samples were donated by the Stanley Foundation Brain Collection. We could not find significant alterations of RNA editing efficiencies of these sites in patients. However, we found trends for increased RNA editing efficiencies of site D in depressive patients (P=0.08) and site A in suicide victims (P=0.07). These findings are in accordance with the previous findings, and suggest that altered RNA editing of HTR2C may have some significance in major depression and suicide." [Abstract]

Niswender CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, Stockmeier CA, Emeson RB, Sanders-Bush E.
RNA editing of the human serotonin 5-HT2C receptor. alterations in suicide and implications for serotonergic pharmacotherapy
Neuropsychopharmacology 2001 May;24(5):478-91 .
"An examination of the efficiencies of RNA editing of the 5-HT(2C)R in prefrontal cortex of control individuals vs. subjects diagnosed with schizophrenia or major depressive disorder revealed no significant differences in RNA editing among the three populations. However, subjects who had committed suicide (regardless of diagnosis) exhibited a statistically significant elevation of editing at the A-site, which is predicted to change the amino acid sequence in the second intracellular loop of the 5-HT(2C)R. These findings suggest that alterations in RNA editing may contribute to or complicate therapy in certain psychiatric disorders." [Abstract]

Gurevich I, Tamir H, Arango V, Dwork AJ, Mann JJ, Schmauss C.
Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims.
Neuron. 2002 Apr 25;34(3):327-8.
"Five adenosines within the coding sequence of the serotonin 2C receptor (5-HT2C) pre-mRNA are converted to inosines by RNA editing (named A, B, C' (E), C, and D sites). In human prefrontal cortex (PFC), the most abundant 5-HT2C mRNA sequences result from editing at the A site, or from the editing combinations AC'C, ABCD, and ABD. In suicide victims with a history of major depression, C' site editing is significantly increased, D site editing is significantly decreased, and the C site shows a trend toward increased editing. Treatment of mice with the antidepressant drug fluoxetine (Prozac) causes changes in C', C, and D site editing that are exactly opposite to those seen in suicide victims. Thus, one outcome of fluoxetine treatment may be to reverse the abnormalities in 5-HT2C pre-mRNA editing seen in depressed suicide victims." [Abstract] [PDF]

Gurevich I, Englander MT, Adlersberg M, Siegal NB, Schmauss C.
Modulation of serotonin 2C receptor editing by sustained changes in serotonergic neurotransmission.
J Neurosci 2002 Dec 15;22(24):10529-32
"Serotonin 2C (5-HT2C) receptor pre-mRNA is a substrate for RNA editing enzymes that convert five adenosines (named A, B, C', C, and D editing sites) to inosines. Editing of two of these sites (C' and C) is crucial for decreasing the efficiency of the receptor to activate G-protein. Nucleotide sequence analysis of mouse forebrain neocortical 5-HT2C mRNA isoforms revealed that editing at these two sites is regulated in a serotonin-dependent manner. In serotonin-depleted mice, C'- and C-site editing is significantly decreased. This results in an increased expression of 5-HT2C mRNA isoforms encoding receptors with higher sensitivity to serotonin. In contrast, a 4 d treatment with the 5-HT2A/2C agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane significantly increases the editing frequency at the C' site and leads to increased expression of 5-HT2C mRNA isoforms encoding receptors that activate G-protein least efficiently. None of the drug treatments led to alterations in cytoplasmic 5-HT2C mRNA levels. These data indicate that editing of 5-HT2C pre-mRNA is a mechanism that retains basic response properties of 5-HT2C receptors in the face of changing synaptic input to keep receptor activation within an optimal range for information processing." [Abstract] [PDF]

Stout, Brian D., Clarke, William P., Berg, Kelly A.
Rapid Desensitization of the Serotonin2C Receptor System: Effector Pathway and Agonist Dependence
J Pharmacol Exp Ther 2002 302: 957-962
"The serotonin2C (5-HT2C) receptor couples to multiple effector mechanisms, including phospholipase A2-mediated arachidonic acid (AA) release and phospholipase C-mediated production of inositol phosphates (IP). Agonist relative efficacy differs depending upon which response (AA release or IP accumulation) is measured. In this study, we investigated the characteristics and agonist dependence of rapid desensitization of 5-HT2C receptor-mediated AA release and IP accumulation measured simultaneously from the same cell population. Pretreatment with 5-HT reduced the ability of a maximal concentration of 5-HT to elicit AA release and IP accumulation by about 60%; however, the AA response desensitized more rapidly (t1/2 = 1.3 min) than the IP response (t1/2 = 6.9 min). In addition, desensitization of the IP response was more sensitive (occurred at lower receptor occupancy levels) than the AA response. Moreover, in response to submaximal 5-HT concentrations, after an initial transient desensitization, the AA response was enhanced by up to ~250%. After maximal desensitization, both responses recovered, but recovery of the AA response was complete and faster than that for IP. Desensitization of both responses was also agonist-dependent, and the capacity of agonists to elicit desensitization was not related to their efficacy to activate signaling. These data suggest that desensitization of the 5-HT2C receptor system is both agonist- and effector pathway-dependent and underscore the need to study multiple cellular responses to multiple agonists to understand receptor-mediated signaling systems." [Abstract]

On site link: 5-HT2C Receptor Research

On site link: Bipolar Disorder Genetic Research

Oruc L, Verheyen GR, Furac I, Jakovljevic M, Ivezic S, Raeymaekers P, Van Broeckhoven C.
Association analysis of the 5-HT2C receptor and 5-HT transporter genes in bipolar disorder.
Am J Med Genet 1997 Sep 19;74(5):504-6
"We selected 42 patients with bipolar disorder type I (BPI) and 40 healthy controls for genetic analysis of DNA polymorphisms in the serotonin receptor 2c (5-HTR2c) and serotonin transporter (5-HTT) genes. No significant associations were found in the total patient sample. However, when the individuals were divided according to gender, trends for association with both polymorphisms (P = 0.051 for 5-HTR2c and P = 0.049 for 5-HTT) in female patients were observed. These results suggest that variations in these genes may be responsible for a minor increase in susceptibility for bipolar disorder in women." [Abstract]

Lindberg N, Virkkunen M, Tani P, Appelberg B, Virkkala J, Rimon R, Porkka-Heiskanen T.
Effect of a single-dose of olanzapine on sleep in healthy females and males.
Int Clin Psychopharmacol 2002 Jul;17(4):177-84
"The difference between the sexes could not be explained by differences in body mass index. Olanzapine affects sleep probably through 5-HT2C receptors. The receptor gene is located on the X-chromosome, inducing an allelic difference between the females and males. This difference may contribute to the different effects of olanzapine on sleep." [Abstract]

Berg, KA, Maayani, S, Clarke, WP
5-hydroxytryptamine2C receptor activation inhibits 5- hydroxytryptamine1B-like receptor function via arachidonic acid metabolism
Mol Pharmacol 1996 50: 1017-1023
"Consistent with our previous report and in contrast to activation of 5-HT2C or purinergic receptors, activation of 5-HT2A receptors had no effect on CHO/5-HT1B receptor function, although 5-HT2A receptor-mediated activation of PLA2 was measured. Interestingly, purinergic receptor-mediated inhibition of CHO/5-HT1B receptor function was blocked when 5-HT2A receptors were activated simultaneously. These data suggest that the lack of 5-HT2A mediated regulation of CHO/5-HT1B receptors may be due to activation of a third pathway (in addition to PLC and PLA2 pathways), which results in the inhibition of the production or the actions of a cyclooxygenase- dependent arachidonic acid metabolite." [Abstract]

Heisler LK, Tecott LH.
A paradoxical locomotor response in serotonin 5-HT(2C) receptor mutant mice.
J Neurosci 2000 Apr 15;20(8):RC71
"We report that a single receptor gene mutation produces a paradoxical response to the nonspecific serotonin receptor agonist m-chlorophenylpiperazine (mCPP). Although this compound normally suppresses locomotion, it produces hyperactivity in mice bearing a targeted mutation of the 5-HT(2C) receptor gene. This effect was blocked by pretreatment with a 5-HT(1B) receptor antagonist, indicating that the behavioral consequences of mCPP-induced 5-HT(1B) receptor stimulation are unmasked in animals devoid of 5-HT(2C) receptor function." [Abstract]

Evans J, Reeves B, Platt H, Leibenau A, Goldman D, Jefferson K, Nutt D.
Impulsiveness, serotonin genes and repetition of deliberate self-harm (DSH).
Psychol Med 2000 Nov;30(6):1327-34
"Males with the 5-HT2c serine variant were more impulsive than those with the cysteine variant (039 standardized units, P = 0.041, 95% CI 0.017 to 0.076)." [Abstract]

 

 

 

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Recent 5-HT2C and Bipolar Disorder Research

1) Ciszowski K, Sein Anand J, Wilimowska J, Jawień W
[The clinical picture of acute olanzapine poisonings].
Przegl Lek. 2011;68(8):426-33.
[PubMed Citation] [Order full text from Infotrieve]

2) Prieto E, Micó JA, Meana JJ, Majadas S
Neurobiological bases of quetiapine antidepresant effect in the bipolar disorder.
Actas Esp Psiquiatr. 2010 Jan-Feb;38(1):22-32.
Bipolar disorder is considered an important public health problem in the world. The depressive phase is the most important in terms of frequency, duration, and impairment of the quality of life. Common treatment of bipolar depression usually includes antidepressants, mood stabilizers and antipsychotics in different combinations, despite not having a specific indication for that. Quetiapine is the first drug in Europe that has obtained a specific indication for the treatment of bipolar depression, due to a pharmacologic profile that makes it to act on the three neurotransmitter systems involved in bipolar depression neurobiology. Regarding the dopaminergic pathway, quetiapine leads to an increasing of prefrontal dopamine release by antagonism of5-HT2A receptors, partial agonist of 5-HT1A and antagonism of a2 adrenoceptors. Quetiapine also enhances the serotoninergic transmission by increasing the density of receptors5-HT1A in the prefrontal cortex and by antagonism of 5-HT2A receptors and a2 adrenoceptors. On the other hand, norquetiapine, the main active metabolite of quetiapine, actsas a 5-HT2C antagonist and is a potent inhibitor of norepinephrine transporter (NET). NET inhibition leads to an increase of noerpinephrine in the synapse, and together with the increase of prefrontal dopamine and serotonin, could explain the antidepressive effect demonstrated by quetiapine in several clinical trials. Quetiapine?s action on glutamatergicand GABAergic receptors represents an interesting object of research, together with a potential neuroprotective effect that have already been observed in animal models. [PubMed Citation] [Order full text from Infotrieve]

3) Mazza M, Mandelli L, Martinotti G, Di Nicola M, Tavian D, Negri G, Colombo E, Missaglia S, De Ronchi D, Colombo R, Janiri L, Serretti A
Further evidence supporting the association between 5HTR2C gene and bipolar disorder.
Psychiatry Res. 2010 Dec 30;180(2-3):151-2.
Three 5HTR2C polymorphisms were investigated in bipolar (BD) spectrum disorders. The functional rs6318 G (Cys) allele was more frequent in BD patients than in controls (P=0.0036). Thus, 5HTR2C may have a role in BD. Further investigation is required to understand its involvement in co-morbidity for substance use disorders (SUDs). [PubMed Citation] [Order full text from Infotrieve]

4) Manchia M, Zai CC, Squassina A, Vincent JB, De Luca V, Kennedy JL
Mixture regression analysis on age at onset in bipolar disorder patients: investigation of the role of serotonergic genes.
Eur Neuropsychopharmacol. 2010 Sep;20(9):663-70.
Bipolar Disorder (BPD) is a complex psychiatric disease with a relevant underlying genetic basis. HTR2A T102C, HTR2C Cys23Ser, SLC6A4 5-HTTLPR and rs25531 polymorphisms were genotyped in 230 BPD patients and inserted as covariates in a mixture regression model of age at onset (AAO). 5-HTTLPR polymorphism associated with early onset component under recessive and additive model. HTR2A T102C, HTR2C Cys23Ser and 5-HTTLPR interaction terms associated with early onset component under dominant, recessive and additive model. These findings suggest a role of genes codifying for elements of the serotonergic system in influencing the AAO in BPD. [PubMed Citation] [Order full text from Infotrieve]

5) Bundo M, Iwamoto K, Yamada K, Yoshikawa T, Kato T
Mutation screening and assessment of the effect of genetic variations on expression and RNA editing of serotonin receptor 2C in the human brain.
Psychiatry Clin Neurosci. 2010 Feb;64(1):57-61.
[PubMed Citation] [Order full text from Infotrieve]

6) Iwamoto K, Bundo M, Kato T
Serotonin receptor 2C and mental disorders: genetic, expression and RNA editing studies.
RNA Biol. 2009 Jul-Aug;6(3):248-53.
Serotonin receptor 2C (HTR2C) is one of the attractive candidate genes for studying pathophysiology of mental disorders. Here we overviewed the genetic, expression and RNA editing studies suggesting the close relationship between HTR2C and major mental disorders including schizophrenia, bipolar disorder and major depression. We especially focused on the human studies as well as with reference to relevant cellular and animal models. Possible significance of genetic variations affecting expression and RNA editing and appropriate animal models that mimic human mental disorders were discussed. [PubMed Citation] [Order full text from Infotrieve]

7) De Luca V, Tharmaligam S, Strauss J, Kennedy JL
5-HT2C receptor and MAO-A interaction analysis: no association with suicidal behaviour in bipolar patients.
Eur Arch Psychiatry Clin Neurosci. 2008 Oct;258(7):428-33.
The serotonin 2C (HTR2C) receptor has been implicated in suicide-related behaviours, however there are not many studies to date about HTR2C and suicidality. We studied HTR2C haplotypes in suicide attempters, where our sample composed of 306 families with at least one member affected by bipolar disorder. HTR2C (Cys23Ser and a common STR in the promoter) variants were analyzed with respect to attempter status and the severity of suicidal behaviour. The X-linked haplotype analysis in relation to suicide attempt did not reveal any significant association. Furthermore, we performed a particular gene-gene interaction for the X-linked serotonergic genes (HTR2C and MAOA), and found no association among this intergenic haplotype combination and suicidal behaviour in bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

8) Pae CU, Serretti A, Patkar AA, Masand PS
Aripiprazole in the treatment of depressive and anxiety disorders: a review of current evidence.
CNS Drugs. 2008;22(5):367-88.
Despite the availability of different classes of drugs for the treatment of depressive and anxiety disorders, there are a number of clinically significant unmet needs, such as a high prevalence of treatment resistance, partial response, subsyndromal symptomatology, recurrence and relapse. With the approval of atypical antipsychotics, which are associated with a lower adverse effect burden than typical antipsychotics, consideration of their off-label use for the treatment of affective disorders and various other psychiatric disorders has become a viable option. However, consideration should be given to the US FDA black box warning indicating that atypical antipsychotics may increase mortality risk, particularly in the elderly population with dementia-related psychosis. There has been much conjecture about the utility of these atypical drugs to facilitate traditional antidepressant therapy, either in combination (from the initiation of therapy) or as adjunctive therapy (in the case of partial/incomplete response). Nevertheless, at present, available evidence from randomized, placebo-controlled trials is sparse, and a formal risk/benefit assessment of the use of these agents in a nonpsychotic patient population is not yet possible. As a representative agent from the atypical antipsychotic class with a novel mechanism of action and a relatively low adverse effect burden, aripiprazole represents an interesting potential treatment for depressive and anxiety disorders. In this review, we focus on the rationale for the use of aripiprazole in these disorders. Preclinical data suggests that aripiprazole has a number of possible mechanisms of action that may be important in the treatment of depressive and anxiety disorders. Such mechanisms include aripiprazole action at serotonin (5-HT) receptors as a 5-HT1A partial receptor agonist, a 5-HT2C partial receptor agonist and a 5-HT2A receptor antagonist. Aripiprazole also acts as a dopamine D2 partial receptor agonist, and has a possible action at adrenergic receptors. Furthermore, aripiprazole may have possible neuroprotective effects. Clinical studies demonstrate that aripiprazole may be useful in the treatment of bipolar depression, major depressive disorder, treatment-resistant depression and possibly anxiety disorders. Clinical data also suggest that aripiprazole may have a lower adverse effect burden than the other atypical drugs. Future research may confirm the potential utility of aripiprazole in the treatment of depressive and anxiety disorders. [PubMed Citation] [Order full text from Infotrieve]

9) Iwamoto K, Kato T
[RNA editing of serotonin 2C receptor and major mental disorders].
Yakugaku Zasshi. 2008 Apr;128(4):521-5.
A-to-I RNA editing has mainly been found in various receptors and ion channels in the central nervous system, including the serotonin 2C receptor, glutamate receptor, GABA receptor, and potassium channel. Interestingly, most of them are suggested to be involved in the pathophysiology of major mental disorders such as schizophrenia, bipolar disorder, and major depression. Here we review studies examining the relationship between the serotonin 2C receptor and major mental disorders. [PubMed Citation] [Order full text from Infotrieve]

10) Shahid M, Walker GB, Zorn SH, Wong EH
Asenapine: a novel psychopharmacologic agent with a unique human receptor signature.
J Psychopharmacol. 2009 Jan;23(1):65-73.
Asenapine is a novel psychopharmacologic agent under development for the treatment of schizophrenia and bipolar disorder. We determined and compared the human receptor binding affinities and functional characteristics of asenapine and several antipsychotic drugs. Compounds were tested under comparable assay conditions using cloned human receptors. In comparison with the antipsychotics, asenapine showed high affinity and a different rank order of binding affinities (pKi) for serotonin receptors (5-HT1A [8.6], 5-HT1B [8.4], 5-HT2A [10.2], 5-HT2B [9.8], 5-HT2C [10.5], 5-HT5 [8.8], 5-HT6 [9.6] and 5-HT7 [9.9]), adrenoceptors (alpha1 [8.9], alpha2A [8.9], alpha2B [9.5] and alpha2C [8.9]), dopamine receptors (D1 [8.9], D2 [8.9], D3 [9.4] and D4 [9.0]) and histamine receptors (H1 [9.0] and H2 [8.2]). It had much lower affinity (pKi[PubMed Citation] [Order full text from Infotrieve]

11) Westrin A, Lam RW
Seasonal affective disorder: a clinical update.
Ann Clin Psychiatry. 2007 Oct-Dec;19(4):239-46.
[PubMed Citation] [Order full text from Infotrieve]

12) Dracheva S, Patel N, Woo DA, Marcus SM, Siever LJ, Haroutunian V
Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide.
Mol Psychiatry. 2008 Nov;13(11):1001-10.
Suicide is a major public health problem with approximately 1 million victims each year worldwide. Up to 90% of adults who commit suicide have at least one psychiatric diagnosis such as major depression, bipolar disorder (BPD), schizophrenia (SZ), substance abuse or dependence. A question that has remained unanswered is whether the biological substrates of suicide are distinct from those of the psychiatric disorders in which it occurs. The serotonin 2C receptor (5-HT 2C R) has been implicated in depression and suicide. We, therefore, compared the frequencies of its mRNA editing variants in postmortem prefrontal cortical specimens from subjects who committed suicide or who died from other causes. All suicides occurred in the context of either SZ or BPD. The non-suicide cases included subjects with either SZ or BPD as well as subjects with no psychiatric diagnosis. We identified 5-HT 2CR mRNA editing variations that were associated with suicide but not with the comorbid psychiatric diagnoses, and were not influenced by demographic characteristics (age and sex) and alcohol or drug use. These variations consisted of a significant increase in the pool of mRNA variants (ACD and ABCD) that encode one of the most prevalent and highly edited isoforms of 5-HT 2C R, that is, VSV (Val156-Ser158-Val160). Because the VSV isoform of 5-HT 2C R exhibits low functional activity, an increase in its expression frequency may significantly influence the serotonergic regulation of the brain. Thus, at least in patients with SZ or BPD, overexpression of the VSV isoform in the prefrontal cortex may represent an additional risk factor for suicidal behavior. [PubMed Citation] [Order full text from Infotrieve]

13) Massat I, Lerer B, Souery D, Blackwood D, Muir W, Kaneva R, Nöthen MM, Oruc L, Papadimitriou GN, Dikeos D, Serretti A, Bellivier F, Golmard JL, Milanova V, Del-Favero J, Van Broeckhoven C, Mendlewicz J
HTR2C (cys23ser) polymorphism influences early onset in bipolar patients in a large European multicenter association study.
Mol Psychiatry. 2007 Sep;12(9):797-8.
[PubMed Citation] [Order full text from Infotrieve]

14) Kumar HB, Purushottam M, Kubendran S, Gayathri P, Mukherjee O, Murthy AR, Ghosh S, Chandra P, Reddy YC, Benegal V, Brahmachari SK, Jain S
Serotonergic candidate genes and puerperal psychosis: an association study.
Psychiatr Genet. 2007 Oct;17(5):253-60.
[PubMed Citation] [Order full text from Infotrieve]

15) Serretti A, Mandelli L, Giegling I, Schneider B, Hartmann AM, Schnabel A, Maurer K, Möller HJ, Rujescu D
HTR2C and HTR1A gene variants in German and Italian suicide attempters and completers.
Am J Med Genet B Neuropsychiatr Genet. 2007 Apr 5;144B(3):291-9.
The serotonin 2C (HTR2C) and 1A (HTR1A) receptors have been involved in suicide-related behaviors. We studied gene variants of both receptors in suicide attempters and completers. The sample was composed of 167 German suicide attempters (affective spectrum n = 107, schizophrenia spectrum n = 35, borderline personality disorder n = 25), 92 Caucasian individuals who committed suicide, 312 German healthy subjects, 152 Italian suicide attempters (major depression n = 68 and bipolar disorder n = 84), and 131 Italian healthy volunteers. HTR2C (SNP: rs547536, rs2192372, rs6318, rs2428707, rs4272555, rs1801412) and HTR1A (SNP: rs1423691, rs878567, and rs6295) variants were analyzed in the German sample. HTR2C rs6318 and HTR1A rs6295 were analyzed in the Italian sample. Haplotype analysis in relation to suicidal behaviors did not reveal any significant association. Single markers and haplotypes were not or only marginally associated with other related features, such as violence of suicide attempt, family history for suicide attempt or State-Trait Anger Expression Inventory (STAXI) and Questionnaire for Measuring Factors of Aggression (FAF) scores. In conclusion, our study does not support the notion that HTR2C and HTR1A gene variants are major contributors to suicide-, anger-, or aggression-related behaviors in our sample. [PubMed Citation] [Order full text from Infotrieve]

16) Uzun S, Kozumplik O, Mimica N, Folnegović-Smalc V
Aripiprazole: an overview of a novel antipsychotic.
Psychiatr Danub. 2005 Jun;17(1-2):67-75.
Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors, moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors. The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydroaripiprazole, respectively. Steady-state concentrations are attained within 14 days of dosing for both active moieties. At least 1 to 2 weeks, and sometimes up to 4 weeks, may pass before aripiprazole reaches its full effect. The efficacy of aripiprazole was investigated in the treatment of schizophrenia, in the treatment of acute manic episode associated with Bipolar I Disorder, and in the treatment of psychosis associated with Alzheimer's dementia. Aripiprazole has demonstrated superiority to placebo in clinical studies of the treatment of both schizophrenia and acute bipolar mania. Aripiprazole has been evaluated for safety in 5592 patients who participated in multiple dose, premarketing trials in schizophrenia, bipolar mania, and dementia of the Alzheimer's type. The recommended starting and target dose for aripiprazole is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. Aripiprazole has been systematically evaluated and shown to be effective in a dose range of 10 to 30 mg/day. Dosage increases should not be made before 2 weeks of continuous therapy, the time needed to achieve steady state. At least 1 to 2 weeks, and sometimes up to 4 weeks, may pass before aripiprazole reaches its full effect. In this presentation was given an overview of novel antipsychotic aripiprazole. [PubMed Citation] [Order full text from Infotrieve]

17) Dmitrzak-Weglarz M, Rybakowski JK, Suwalska A, Słopień A, Czerski PM, Leszczyńska-Rodziewicz A, Hauser J
Association studies of 5-HT2A and 5-HT2C serotonin receptor gene polymorphisms with prophylactic lithium response in bipolar patients.
Pharmacol Rep. 2005 Nov-Dec;57(6):761-5.
Lithium is one of the most commonly used drugs in the prophylaxis and treatment of bipolar disorder. The mechanisms of mood stabilization by lithium incorporate its effect on serotonergic neurotransmission. This paper investigates a relationship between response to lithium prophylaxis and polymorphisms in two genes: T102C of 5-HT2A receptor and G68C (Cys23Ser) of 5-HT2C serotonin receptor gene. Genotypes were estimated in 92 bipolar patients (39 males and 53 females) who have been taking lithium for at least 5 years. The patients were classified as excellent responders, partial responders and non-responders to lithium. The obtained results suggest that these polymorphisms may not be related to the degree of prophylactic lithium response. [PubMed Citation] [Order full text from Infotrieve]

18) Gao K, Calabrese JR
Newer treatment studies for bipolar depression.
Bipolar Disord. 2005;7 Suppl 5:13-23.
[PubMed Citation] [Order full text from Infotrieve]

19) Rasmussen K, Benvenga MJ, Bymaster FP, Calligaro DO, Cohen IR, Falcone JF, Hemrick-Luecke SK, Martin FM, Moore NA, Nisenbaum LK, Schaus JM, Sundquist SJ, Tupper DE, Wiernicki TR, Nelson DL
Preclinical pharmacology of FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: a potential novel antipsychotic with lower histamine H1 receptor affinity than olanzapine.
J Pharmacol Exp Ther. 2005 Dec;315(3):1265-77.
FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene] is a potential novel antipsychotic with high affinity for dopamine D2 (Ki= 6.3 nM), 5-HT(2A) (Ki= 7.3 nM), and 5-HT6 (Ki= 8.0 nM) human recombinant receptors and lower affinity for histamine H1 (Ki= 30 nM) and 5-HT2C (Ki= 102 nM) human recombinant receptors than olanzapine. Oral administration of FMPD increased rat nucleus accumbens 3,4-dihyroxyphenylacetic acid concentrations (ED200 = 6 mg/kg), blocked 5-HT2A agonist-induced increases in rat serum corticosterone levels (ED50= 1.8 mg/kg), and inhibited the ex vivo binding of [125I]SB-258585 [4-iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide] to striatal 5-HT6 receptors (ED50= 10 mg/kg) but failed to inhibit ex vivo binding of [3H]pyrilamine to hypothalamic histamine H1 receptors at doses of up to 30 mg/kg. In electrophysiology studies, acute administration of FMPD selectively elevated the number of spontaneously active A10 (versus A9) dopamine neurons and chronic administration selectively decreased the number of spontaneously active A10 (versus A9) dopamine neurons. FMPD did not produce catalepsy at doses lower than 25 mg/kg p.o. In Fos-induction studies, FMPD had an atypical antipsychotic profile in the striatum and nucleus accumbens and increased Fos expression in orexin-containing neurons of the hypothalamus. FMPD produced only a transient elevation of prolactin levels. These data indicate that FMPD is an orally available potent antagonist of dopamine D2, 5-HT2A, and 5-HT6 receptors and a weak antagonist of H1 and 5-HT2C receptors. FMPD has the potential to have efficacy in treating schizophrenia and bipolar mania with a low risk of treatment-emergent extrapyramidal symptoms, prolactin elevation, and weight gain. Clinical trials are needed to test these hypotheses. [PubMed Citation] [Order full text from Infotrieve]

20) Quintin P, Thomas P
[Efficacy of atypical antipsychotics in depressive syndromes].
Encephale. 2004 Nov-Dec;30(6):583-9.
Depression is a frequent symptom in psychiatry, either isolated (major depression) or entangled with other psychiatric symptoms (psychotic depression, depression of bipolar disorders). Many antidepressant drugs are available with different pharmacological profiles from different classes: tricyclic antidepressants, monoamine oxydase inhibitors, selective serotonin reuptake inhibitors (SSRI). However, there are some limitations with these drugs because there is a long delay before relief for symptoms, some patients with major depression are resistant to treatment, there is a risk to induce manic symptoms in patients with bipolar disorders and these drugs have no effect on the psychotic symptoms frequently associated to major depression. The leading hypothesis for the search of more efficient new antidepressants has been the amine deficit hypothesis: noradrenaline and/or serotonin deficit and more recently dopamine deficit. Moreover, a dopamine deficit has been also hypothesized as the central mechanism explaining the negative symptoms of schizophrenia. These symptoms are the consequence of a deficit of normal behaviours and include affective flattening, alogia, apathy, avolition and social withdrawal. There is thus a great overlap between symptoms of depression and negative symptoms of schizophrenia. Atypical antipsychotics, in contrast with conventional neuroleptics, have been shown to decrease negative symptoms, most probably through the release of dopamine in prefrontal cortex, thus improving psychomotor activity, motivation, pleasure, appetite, etc. The dopamine deficit in cortical prefrontal areas was thus an unifying hypothesis to explain both some symptoms of depression and negative symptoms of schizophrenia. Studies in animal confirm this view and show that the association of an atypical antipsychotic drug and an SSRI (olanzapine plus fluoxetine) increases synergistically the release of dopamine in prefrontal areas. Moreover, most of the atypical antipsychotics have a large action spectrum, beyond the only dopamine receptors: their effects on the serotonin receptors--particularly the 5-HT2A and 5-HT2C receptors--suggest that their association to SSRI could be a promising treatment for depression. Indeed, SSRI act mainly by increasing the serotonin level in the synapse, thus leading to a non specific activation of all pre- and post-synaptic serotonin receptors. Among them, 5-HT2A/2C receptors have been involved in some of the unwanted effects of SSRI: agitation, anxiety, insomnia, sexual disorders, etc. The inhibition of these receptors could be thus beneficial for patients treated with SSRI. Amisulpride is an unique atypical antipsychotic that selectively blocks dopamine receptors presynaptically in the frontal cortex, possibly enhancing dopaminergic transmission. The antidepressant effect of amisulpride was shown in dysthymia in many clinical studies versus placebo, tricyclic antidepressants, SSRI or others. However, a shorter delay for symptom relief was not demonstrated for amisulpride as compared to comparative antidepressants. Other atypical antipsychotics (clozapine, olanzapine), which act on a large variety of receptors, have shown antidepressant effects--mainly in association with SSRI--in different psychiatric diseases: treatment-resistant major depression, major depression with psychotic symptoms and depression of bipolar disorders, with no increase of manic symptoms in this latter case. Moreover, the delay for symptom relief was greatly shortened. More comparative double-blind studies are required to confirm and to precise the antidepressant effects of atypical antipsychotics. Nevertheless, these studies suggest that atypical anti-psychotics could be of great value in depressive conditions reputed for their resistance to treatment with usual antidepressants. Particularly, new strategies emerge that combine atypical antipsychotics and antidepressants for greater efficacy and more rapid relief of depression symptoms. [PubMed Citation] [Order full text from Infotrieve]