Going back to basics prior to mentioning the use of antipsychotics in patients with pain, the International Association for the Study of Pain (IASP) definition of pain can be summarized as an unpleasant experience, composed of sensory experience caused by actual tissue damage and/or emotional experience caused by potential tissue damage. Less used than antidepressants, antipsychotics have also been used for treating this unpleasant experience as adjuvant analgesics without sufficient evidence from research. Because recently developed atypical antipsychotics reduce the adverse reactions of extrapyramidal symptoms, such as acute dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia caused by typical antipsychotics, they are expected to be used more frequently in various painful conditions, while increasing the risk of metabolic syndromes (weight gain, diabetes, and dyslipidemia). Various antipsychotics have different neurotransmitter receptor affinities for dopamine (D), 5-hydroxytryptamine (5-HT), adrenergic (α), histamine (H), and muscarinic (M) receptors. Atypical antipsychotics antagonize transient, weak D₂ receptor bindings with strong binding to the 5-HT(2A) receptor, while typical antipsychotics block long-lasting, tight D₂ receptor binding. On the contrary, antidepressants in the field of pain management also block the reuptake of similar receptors, mainly on the 5-HT and, next, on the norepinephrine, but rarely on the D receptors. Antipsychotics have been used for treating positive symptoms, such as delusion, hallucination, disorganized thought and behavior, perception disturbance, and inappropriate emotion, rather than the negative, cognitive, and affective symptoms of psychosis. Therefore, an antipsychotic may be prescribed in pain patients with positive symptoms of psychosis during or after controlling all sensory components.
Affective Symptoms ; Analgesics ; Antidepressive Agents ; Antipsychotic Agents ; Delusions ; Dopamine ; Drug-Related Side Effects and Adverse Reactions ; Dystonia ; Hallucinations ; Histamine ; Humans ; Movement Disorders ; Norepinephrine ; Pain Management ; Prolactin ; Psychomotor Agitation ; Psychotic Disorders ; Receptor, Serotonin, 5-HT2A ; Receptors, Neurotransmitter ; Serotonin ; Weight Gain

Genes related to serotonin are associated with responses to treatment for depression. We examined associations between the serotonin transporter (5-HTT) and serotonin 2a receptor (5-HTR2a) genes and responses to treatment for depressive disorders in acute coronary syndrome (ACS). A total of 255 patients who met the DSM-IV major or minor depressive disorder and recently developed ACS were randomly assigned to the escitalopram (n=127) or placebo (n=128) group in this 24-week double-blind trial (ClinicalTrial.gov identifier: NCT00419471). Remission was defined as a Hamilton Rating Scale for Depression (HAMD) score < or =7. Assays were performed for the 5-HTTLPR, STin2 VNTR, 5-HTR2a 102T/C, and 5-HTR2a 1438A/G genotypes. Escitalopram was superior to placebo for treating depressive disorder with ACS but there were no significant associations between serotonergic genes and treatment responses even when considering ACS severity. The effect of escitalopram was independent of 5-HTT and 5-HTR2a polymorphisms.
Acute Coronary Syndrome* ; Citalopram* ; Depression ; Depressive Disorder* ; Diagnostic and Statistical Manual of Mental Disorders ; Genotype ; Humans ; Receptor, Serotonin, 5-HT2A ; Serotonin ; Serotonin Plasma Membrane Transport Proteins

Ketamine is an anesthetic with hypertensive effects, which make it useful for patients at risk of shock. However, previous ex vivo studies reported vasodilatory actions of ketamine in isolated arteries. In this study, we reexamined the effects of ketamine on arterial tones in the presence and absence of physiological concentrations of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) by measuring the isometric tension of endothelium-denuded rat mesenteric arterial rings. Ketamine little affected the resting tone of control mesenteric arterial rings, but, in the presence of 5-HT (100~200 nM), ketamine (10~100 µM) markedly contracted the arterial rings. Ketamine did not contract arterial rings in the presence of NE (10 nM), indicating that the vasoconstrictive action of ketamine is 5-HT-dependent. The concentration-response curves (CRCs) of 5-HT were clearly shifted to the left in the presence of ketamine (30 µM), whereas the CRCs of NE were little affected by ketamine. The left shift of the 5-HT CRCs caused by ketamine was reversed with ketanserin, a competitive 5-HT(2A) receptor inhibitor, indicating that ketamine facilitated the activation of 5-HT(2A) receptors. Anpirtoline and BW723C86, selective agonists of 5-HT(1B) and 5-HT(2B) receptors, respectively, did not contract arterial rings in the absence or presence of ketamine. These results indicate that ketamine specifically enhances 5-HT(2A) receptor-mediated vasoconstriction and that it is vasoconstrictive in a clinical setting. The facilitative action of ketamine on 5-HT(2A) receptors should be considered in ketamine-induced hypertension as well as in the pathogenesis of diseases such as schizophrenia, wherein experimental animal models are frequently generated using ketamine.
Animals ; Arteries ; Blood Pressure ; Humans ; Hypertension ; Ketamine* ; Ketanserin ; Mesenteric Arteries* ; Models, Animal ; Norepinephrine ; Rats* ; Receptor, Serotonin, 5-HT2A ; Schizophrenia ; Serotonin ; Shock ; Vasoconstriction

5-hydroxytryptamine (5-HT) released in inflammatory tissues plays a pivotal role in pain hypersensitivity. However, it is not clear whether 5-HT2A receptors in the inflamed tissues mediate this effect. The present study investigated the contribution of 5-HT2A receptors in the periphery to chronic inflammatory pain. Complete Freund's adjuvant (CFA) was injected subcutaneously in the hindpaw of rats. The selective 5-HT2A receptor antagonist ketanserin was given in the inflamed site. Paw withdrawal latency responding to heat or mechanical stimuli was measured. Expression of neuropeptide Y (NPY) in the spinal dorsal horn and dorsal root ganglia (DRG) was assayed using immunohistochemistry technique. The results showed that ketanserin administered in the inflamed site inhibited thermal hyperalgesia in a dose-dependent manner (20, 40 and 80 µg) induced by the intraplantar injection of CFA. Ketanserin given once per day at a dose of 80 µg abolished heat hyperalgesia and also attenuated mechanical allodynia on the third day. CFA injection increased the expression of NPY in superficial laminae of the spinal cord, but not in the DRG. The local treatment of ketanserin completely inhibited CFA-induced increase in NPY expression in superficial laminae of the spinal cord. These results indicated that activation of 5-HT2A receptors in the inflamed tissues was involved in the pathogenesis of inflammatory pain and the blockade of 5-HT2A receptors in the periphery could relieve pain hypersensitivity and normalize the cellular disorder in the spinal dorsal horn associated with pathological pain. The present study suggests that the peripheral 5-HT2A receptors can be a promising target for pharmaceutical therapy to treat chronic inflammatory pain without central nervous system side effects.
Animals ; Freund's Adjuvant ; adverse effects ; Ganglia, Spinal ; metabolism ; Hot Temperature ; Hyperalgesia ; chemically induced ; drug therapy ; Inflammation ; drug therapy ; Ketanserin ; pharmacology ; Neuropeptide Y ; metabolism ; Pain ; drug therapy ; Pain Measurement ; Rats ; Receptor, Serotonin, 5-HT2A ; metabolism ; Serotonin ; Serotonin 5-HT2 Receptor Antagonists ; pharmacology ; Spinal Cord Dorsal Horn ; metabolism

BACKGROUNDTo evaluate whether serotonin (5-HT), 5-HT2A receptor (5-HT2AR), and 5-HT transporter (serotonin transporter [SERT]) are associated with different disease states of depression, myocardial infarction (MI) and MI co-exist with depression in Sprague-Dawley rats.

METHODSAfter established the animal model of four groups include control, depression, MI and MI with depression, we measured 5-HT, 5-HT2AR and SERT from serum and platelet lysate.

RESULTSThe serum concentration of 5-HT in depression rats decreased significantly compared with the control group (303.25 ± 9.99 vs. 352.98 ± 13.73; P = 0.000), while that in MI group increased (381.78 ± 14.17 vs. 352.98 ± 13.73; P = 0.000). However, the depression + MI group had no change compared with control group (360.62 ± 11.40 vs. 352.98 ± 13.73; P = 0.036). The changes of the platelet concentration of 5-HT in the depression, MI, and depression + MI group were different from that of serum. The levels of 5-HT in above three groups were lower than that in the control group (380.40 ± 17.90, 387.75 ± 22.28, 246.40 ± 18.99 vs. 500.29 ± 20.91; P = 0.000). The platelet lysate concentration of 5-HT2AR increased in depression group, MI group, and depression + MI group compared with the control group (370.75 ± 14.75, 393.47 ± 15.73, 446.66 ± 18.86 vs. 273.66 ± 16.90; P = 0.000). The serum and platelet concentration of SERT in the depression group, MI group and depression + MI group were all increased compared with the control group (527.51 ± 28.32, 602.02 ± 23.32, 734.76 ± 29.59 vs. 490.56 ± 16.90; P = 0.047, P = 0.000, P = 0.000 in each and 906.38 ± 51.84, 897.33 ± 60.34, 1030.17 ± 58.73 vs. 708.62 ± 51.15; P = 0.000 in each).

CONCLUSIONSThe concentration of 5-HT2AR in platelet lysate and SERT in serum and platelet may be involved in the pathway of MI with depression. Further studies should examine whether elevated 5-HT2AR and SERT may contribute to the biomarker in MI patients with depression.

Animals ; Depression ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Male ; Myocardial Infarction ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Serotonin, 5-HT2A ; metabolism ; Serotonin ; metabolism ; Serotonin Plasma Membrane Transport Proteins ; metabolism

Serotonin (5-hydroxytryptamine (5-HT)) is a neurotransmitter that regulates a variety of functions in the nervous, gastrointestinal and cardiovascular systems. Despite such importance, 5-HT signaling pathways are not entirely clear. We demonstrated previously that 4-aminopyridine (4-AP)-sensitive voltage-gated K+ (Kv) channels determine the resting membrane potential of arterial smooth muscle cells and that the Kv channels are inhibited by 5-HT, which depolarizes the membranes. Therefore, we hypothesized that 5-HT contracts arteries by inhibiting Kv channels. Here we studied 5-HT signaling and the detailed role of Kv currents in rat mesenteric arteries using patch-clamp and isometric tension measurements. Our data showed that inhibiting 4-AP-sensitive Kv channels contracted arterial rings, whereas inhibiting Ca2+-activated K+, inward rectifier K+ and ATP-sensitive K+ channels had little effect on arterial contraction, indicating a central role of Kv channels in the regulation of resting arterial tone. 5-HT-induced arterial contraction decreased significantly in the presence of high KCl or the voltage-gated Ca2+ channel (VGCC) inhibitor nifedipine, indicating that membrane depolarization and the consequent activation of VGCCs mediate the 5-HT-induced vasoconstriction. The effects of 5-HT on Kv currents and arterial contraction were markedly prevented by the 5-HT2A receptor antagonists ketanserin and spiperone. Consistently, alpha-methyl 5-HT, a 5-HT2 receptor agonist, mimicked the 5-HT action on Kv channels. Pretreatment with a Src tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, prevented both the 5-HT-mediated vasoconstriction and Kv current inhibition. Our data suggest that 4-AP-sensitive Kv channels are the primary regulator of the resting tone in rat mesenteric arteries. 5-HT constricts the arteries by inhibiting Kv channels via the 5-HT2A receptor and Src tyrosine kinase pathway.
4-Aminopyridine/pharmacology ; Action Potentials ; Animals ; Calcium Channel Blockers/pharmacology ; Calcium Channels/metabolism ; Cells, Cultured ; Ketanserin/pharmacology ; Male ; Mesenteric Arteries/drug effects/*metabolism/physiology ; Muscle Contraction ; Muscle, Smooth, Vascular/cytology/drug effects/metabolism/physiology ; Myocytes, Smooth Muscle/drug effects/metabolism/physiology ; Nifedipine/pharmacology ; Potassium Channel Blockers/pharmacology ; Potassium Channels, Voltage-Gated/antagonists & inhibitors/*metabolism ; Protein Kinase Inhibitors/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptor, Serotonin, 5-HT2A/*metabolism ; Serotonin/*pharmacology ; Serotonin 5-HT2 Receptor Antagonists/pharmacology ; Spiperone/pharmacology ; *Vasoconstriction ; src-Family Kinases/antagonists & inhibitors/*metabolism

OBJECTIVE: Gene variants within the serotonin pathway have been associated with major depressive disorder (MDD) treatment outcomes, however a possible different modulation on pharmacological or psychological treatments has never been investigated. METHODS: One hundred sixty MDD patients were partially randomized to either inter-personal counseling (IPC) or antidepressants. The primary outcome was remission at week 8. Five serotonergic polymorphisms were investigated (COMT rs4680, HTR1A rs6295, HTR2A rs2224721, HTR2A rs7997012 and SLC6A4 rs421417). RESULTS: IPC (n=43) and antidepressant (n=117) treated patients did not show any difference in remission rates at week 8 (corrected for baseline severity, age and center). None of the studied gene variants impacted on response and remission rates at week 8 neither in the IPC nor in the antidepressant group. An analysis of the whole sample showed a trend of association between rs7997012 AA genotype and a better treatment outcome. CONCLUSION: Our study confirms that IPC is an effective psychological intervention comparable to antidepressants in mild-moderate MDD. Polymorphisms related to the serotonin system did not exert a major effect on clinical outcomes in none of the treatment groups.
Antidepressive Agents ; Counseling ; Depression ; Depressive Disorder, Major ; Genotype ; Humans ; Psychotherapy ; Receptor, Serotonin, 5-HT1A ; Receptor, Serotonin, 5-HT2A ; Serotonin ; Serotonin Plasma Membrane Transport Proteins

OBJECTIVE: The purpose of this study was to investigate the association between the T102C polymorphism in the serotonin 2A receptor gene and attention-deficit/hyperactivity disorder (ADHD) in Korean patients. METHODS: A total of 189 Korean children with ADHD as well as both parents of the ADHD children and 150 normal children participated in this study. DNA was extracted from blood samples from all of the subjects, and genotyping was conducted. Based on the allele and genotype information obtained, case-control analyses were performed to compare the ADHD and normal children, and Transmission disequilibrium tests (TDTs) were used for family-based association testing (number of trios=113). Finally, according to the significant finding which was showed in the case-control analyses, the results of behavioral characterastics and neuropsychological test were compared between ADHD children with and without the C allele. RESULTS: In the case-control analyses, statistically significant differences were detected in the frequencies of genotypes containing the C allele (chi2=4.73, p=0.030). In the family-based association study, TDTs failed to detect linkage disequilibrium of the T102C polymorphism associated with ADHD children. In the ADHD children, both the mean reaction time and the standard deviation of the reaction time in the auditory continuous performance test were longer in the group with the C allele compared to the group without the C allele. CONCLUSION: The results of this study suggest that there is a significant genetic association between the T102C polymorphism in the serotonin 2A receptor gene and ADHD in Korean children.
Alleles ; Case-Control Studies ; Child ; DNA ; Genotype ; Humans ; Linkage Disequilibrium ; Neuropsychological Tests ; Parents ; Reaction Time ; Receptor, Serotonin, 5-HT2A ; Serotonin

Schizophrenia is a psychiatric disease which requires a long term treatment. Thus, patient's therapeutic compliance can be very crucial to the disease's prognosis. Moreover, the adverse effects of drugs are also important to determine the patient's therapeutic compliance. The atypical antipsychotic drugs have been improved in the way to strengthen therapeutic effects and to reduce adverse effects. Blonanserin, an atypical antipsychotic, is a selective serotonin-dopamine agonist which blocks the dopamine D2/D3 receptors and serotonin 5-HT2A receptor. Blonanserin is well known to include parkinsonism, akathisia and insomnia. In this case report, Blonanserin treatment was given to patients who admitted to the closed ward due to psychotic symptoms such as idea of reference, persecutory delusion, auditory hallucination and blunted affect. The patients showed manic symptoms including elated mood, talkativeness, hyperactivity after the increase of Blonanserin dose up to 24 mg. Such manic symptoms were improved after Blonanserin dose was decreased to 16 mg. Many researches have reported newly-evoked manic/hypomanic episodes in schizophrenic patients after the use of atypical antipsychotics such as Risperidone, Olanzapine and Ziprasidone. However, there is no report of Blonanserin-induced manic/hypomanic episode. Therefore, further study is necessary to evaluate the manic/hypomanic episodes which are thought to be the adverse effects of Blonanserin.
Antipsychotic Agents ; Benzodiazepines ; Bipolar Disorder ; Compliance ; Delusions ; Dopamine ; Hallucinations ; Humans ; Parkinsonian Disorders ; Piperazines ; Piperidines ; Prognosis ; Psychomotor Agitation ; Receptor, Serotonin, 5-HT2A ; Risperidone ; Schizophrenia ; Serotonin ; Sleep Initiation and Maintenance Disorders ; Thiazoles

Schizophrenia is a psychiatric disease which requires a long term treatment. Thus, patient's therapeutic compliance can be very crucial to the disease's prognosis. Moreover, the adverse effects of drugs are also important to determine the patient's therapeutic compliance. The atypical antipsychotic drugs have been improved in the way to strengthen therapeutic effects and to reduce adverse effects. Blonanserin, an atypical antipsychotic, is a selective serotonin-dopamine agonist which blocks the dopamine D2/D3 receptors and serotonin 5-HT2A receptor. Blonanserin is well known to include parkinsonism, akathisia and insomnia. In this case report, Blonanserin treatment was given to patients who admitted to the closed ward due to psychotic symptoms such as idea of reference, persecutory delusion, auditory hallucination and blunted affect. The patients showed manic symptoms including elated mood, talkativeness, hyperactivity after the increase of Blonanserin dose up to 24 mg. Such manic symptoms were improved after Blonanserin dose was decreased to 16 mg. Many researches have reported newly-evoked manic/hypomanic episodes in schizophrenic patients after the use of atypical antipsychotics such as Risperidone, Olanzapine and Ziprasidone. However, there is no report of Blonanserin-induced manic/hypomanic episode. Therefore, further study is necessary to evaluate the manic/hypomanic episodes which are thought to be the adverse effects of Blonanserin.
Antipsychotic Agents ; Benzodiazepines ; Bipolar Disorder ; Compliance ; Delusions ; Dopamine ; Hallucinations ; Humans ; Parkinsonian Disorders ; Piperazines ; Piperidines ; Prognosis ; Psychomotor Agitation ; Receptor, Serotonin, 5-HT2A ; Risperidone ; Schizophrenia ; Serotonin ; Sleep Initiation and Maintenance Disorders ; Thiazoles