Hiroaki Jitsuiki

Manic/hypomanic switch during acute antidepressant treatment for unipolar depression.

Abstract: A significant proportion of patients with unipolar depression clinically develop manic or hypomanic switch during acute antidepressant treatment. Elucidation of its prevalence and predicting factors is of clinical relevance during acute antidepressant treatment of such patients. We retrospectively studied patients with unipolar depression who were admitted to our department during the 6-year period from 1997 to 2002 and who had fewer than 3 previous episodes before admission. The clinical background of the consecutive patients with manic/hypomanic switch (n = 37) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria was compared with that of patients without manic/hypomanic switch (n = 245). The prevalence rate of manic/hypomanic switch was 13.1%. The switch group was composed of 23 men and 14 women, whose average age was 48.8 ± 12.3 years (range, 26-78 years). Manic/hypomanic switch was most frequently observed between 2 and 3 weeks after the antidepressant was increased to the ongoing dose. Antidepressants were decreased in 13 patients and discontinued in 23. Manic/hypomanic episodes lasted from 1 to 8 weeks. The patients in the switch group included a greater proportion of male subjects and had a higher frequency of family history of bipolar disorders than those in the nonswitch group. The mean doses of antidepressants were not significantly different between these groups. The higher frequency of manic/hypomanic switch occurring around the period when antidepressants begin to show clinical effects and the higher frequency of family history of bipolar disorders might suggest a biological susceptibility to antidepressants in patients of the switch group.

Effects of Antidepressants on γ-Aminobutyric Acid- and N-Methyl-D-Aspartate-Induced Intracellular Ca2+ Concentration Increases in Primary Cultured Rat Cortical Neurons

We investigated the effects of antidepressants on the intracellular Ca²⁺ concentration ([Ca²⁺]_i) increases induced by γ-aminobutyric acid (GABA) or N-methyl-D-aspartate (NMDA) in primary cultured rat cortical neurons using fluorescence imaging. Acute treatment with imipramine inhibited GABA- and NMDA-induced increases in [Ca²⁺]_i in a concentration-dependent manner. Doses of 30 μM clomipramine, desipramine, amoxapine and maprotiline also inhibited both the GABA- and NMDA-induced [Ca²⁺]_i increases significantly. Both inhibitory effects of the five major antidepressants on the GABA- or the NMDA-induced [Ca²⁺]_i increases were well-correlated. Imipramine could inhibit significantly high-K⁺-induced [Ca²⁺]_i increases. Our previous study has already shown that the GABA-induced [Ca²⁺]_i increase involves a similar pathway to high-K⁺-induced Ca²⁺ influx. In conclusion, imipramine and several other antidepressants have acute inhibitory effects on the GABA-, NMDA- and high-K⁺-induced [Ca²⁺]_i increases, suggesting that these inhibitory effects are not related to specific receptors. One possibility is that these effects may be commonly mediated via part of the high-K⁺-induced [Ca²⁺]_i pathway.

Effect of lithium carbonate on the enhancement of serotonin 2A receptor elicited by dexamethasone

The purpose of this study was to investigate whether chronic dexamethasone (Dex) administration induces serotonin (5-HT) 2A receptor supersensitivity and if chronic lithium carbonate (Li) administration contributes to the normalization of 5-HT2A receptor supersensitivity induced by Dex in rat brain. We investigated the effects of a 14-day administration of Dex and/or Li on changes in body weight (BW), on plasma corticosterone levels, on plasma lithium levels, on 5-HT2A receptor binding sites, and on (±)-1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI)-induced wet dog shake (WDS), which is mediated by 5-HT2A receptor in rats. Dex significantly reduced the BW of rats. Li did not have any effect on BW gain and did not prevent the BW loss induced by Dex. The plasma corticosterone levels of rats treated with Dex were too low to be detected. Li did not have any effect on corticosterone levels and did not prevent the decrease in the corticosterone levels induced by Dex. Six hours after the last treatment, the plasma lithium levels of rats treated with Li were significantly higher than those of rats treated with Dex/Li. Chronic Dex administration resulted in a significant increase in the density (Bmax) of the 5-HT2A receptor without a significant change in the affinity (Kd). The increase in the Bmax induced by Dex was not prevented by chronic combined treatment with Dex and Li. Chronic Dex administration potentiated the WDS, and this increase was prevented by chronic combined treatment with Dex and Li. Chronic Li administration did not have any effect on WDS. These results indicate that chronic Li administration may improve the supersensitivity of the 5-HT2A receptor elicited by chronic Dex administration without decreasing the density of the 5-HT2A receptor, and the effect of Li was also independent of hypothalamo-pituitary-adrenal axis function.

Lithium chloride inhibits thrombin-induced intracellular calcium mobilization in C6 rat glioma cells.

In this study, the authors have demonstrated the effect of lithium, a typical mood stabilizer, on thrombin-evoked Ca2+ mobilization in C6 cells to elucidate the action mechanisms of the drug. Thrombin-induced Ca2 mobilization was reduced 24 hr after 1 or 10 mM lithium chloride (LiCl) pretreatment. The Ca2+ rise was reduced in a time-dependent manner, and the significant inhibition was observed 9 hr pretreatment with 10 mM LiCl. On the other hand, pretreatment of the cells with 10 mM LiCl for 24 hr did not alter the amount of Galphaq/11 significantly. Pretreatment with 10 mM LiCl for 24 hr failed to reduce the 5-HT-induced Ca2+ mobilization or to affect the desensitization of the 5-HT signal. Finally, thrombin-elicited Ca2+ rise was markedly inhibited in the presence of 0.05 U/ml plasmin, however, the Ca2+ rise was not further attenuated in the presence of plasmin in C6 cells pretreated with LiCl for 24 hr. These results indicate that pretreatment with LiCl attenuated thrombin-evoked intracellular Ca2+ mobilization in plasmin sensitive manner in C6 rat glioma cells. Thus, it is important to investigate the effect of lithium on thrombin-induced cellular responses to clarify the action mechanism of lithium in relation to some abnormality in thrombin-evoked Ca2+ rise observed in bipolar disorders.

Effect of heat stress on serotonin-2A receptor-mediated intracellular calcium mobilization in rat C6 glioma cells

Summary. This study was conducted to investigate an effect of heat stress at 44°C for 30 min on intracellular Ca2+ signaling system and on heat shock protein (HSP)-70 expression. 5-HT-induced Ca2+ mobilization was reduced 1, 3 and 6 hrs after heat stress, and recovered to the control level 12 and 24 hrs after heat stress. One hr after heat stress, Ca2+ rise was significantly decreased when the cells were stimulated by any concentration of 5-HT. Thrombin-induced Ca2+ increase was also markedly reduced 1 hr after heat stress. HSP-70 level was increased 6 and 9 hr after heat stress. In HSP synthesis inhibitor quercetin-treated cells, HSP-70 expression was not enhanced after heat stress, and Ca2+ rise in response to 5-HT did not return to the control level. However, the Ca2+ rise induced by 5-HT was not restored to the control level after stress in Ac-Asp-Glu-Val-Asp-H (DEVD)-exposed cells while DEVD had little effect on heat stress-induced synthesis of HSP-70. Dexamethasone did not alter the change in HSP-70 expression or Ca2+ response after heat stress. These results indicate that heat stress attenuated 5-HT-induced Ca2+ mobilization and that HSP-70 expression played an important role in recovery from Ca2+ impairment, possibly via protease activity in C6 cells.

Disrupted Brain Activation and Deactivation Pattern during Semantic Verbal Fluency Task in Patients with Major Depression

Background: Patients with major depressive disorder (MDD) exhibit cognitive impairment, and evidence suggests that the semantic version of the verbal fluency task is a reliable cognitive marker of the disorder. Here, using functional magnetic resonance imaging (fMRI), we investigated the dysfunction of neural processing in acute depression and examined the effects of a 6-week pharmacological intervention. Methods: Sixteen patients with MDD participated in 2 fMRI sessions, and 16 healthy control (HC) subjects participated in 1 fMRI session. During each fMRI session, the participants performed a semantic verbal fluency task. Brain activity during the task was compared between groups (MDD 1st fMRI vs. HC) and times (MDD 1st fMRI vs. 2nd fMRI). Results: Significant brain hypoactivation was observed in MDD patients at the prefrontal, lateral parietal, and limbic regions compared to HC, and MDD patients exhibited hyperactivation at the left precuneus compared to HC. Hypoactivity of the left dorsolateral prefrontal cortex (DLPFC) and hyperactivity of the precuneus were normalized with treatment. Conclusions: Hypoactivation of the left DLPFC and hyperactivation of the precuneus should be considered as dysregulation of anticorrelated brain networks during a cognitive demanding task. This failure of network regulation may be an important factor in the pathophysiology of MDD.

One-year outcomes of unipolar depression patients with manic or hypomanic switch during acute antidepressant treatment

Abstract Objective. The aim of the study was to investigate one-year outcomes of unipolar depression patients with manic or hypomanic switch during acute antidepressant treatment. Methods. A review of medical records revealed 37 consecutive patients admitted from 1997 to 2002 who underwent an antidepressant-induced manic or hypomanic switch fulfilling DSM-IV criteria. Their clinical courses were retrospectively investigated after discharge. Results. Of the 37 patients, 33 (89.2%) were followed up for 1 year after discharge. None developed a manic episode, while seven developed a hypomanic episode, including 1 patient who was lost after emerging from a hypomanic episode within 6 months after discharge. Only one of those seven patients developed hypomania during acute antidepressant treatment for a recurrent depressive episode under maintenance mood stabilizer treatment. Furthermore, bipolar conversion occurred in four patients within the first 6 months and in another two patients, including 1 with rapid cycling, over the subsequent 6 months after discharge. Of these 33 patients, 28 received continuous maintenance treatment with mood stabilizers for the one-year period after discharge. Conclusions. The subjects were considered to have a bipolar nature according to the prevalence rate of bipolar conversion over a one-year period. Longer follow-up studies appear warranted determine the diagnostic issues of antidepressant-induced switch in unipolar depression.

Effect of repeated treatment with lamotrigine on locomotor activity and on DOI-elicited wet dog shakes in rats

Lamotrigine is a new anticonvulsant, and it is also effective for bipolar disorder, especially for bipolar depression. In this study, we have investigated the effect of single or repeated treatment with lamotrigine on some behavioral response in rats to understand its action mechanisms on mood disorder. As for acute effect of lamotrigine, single treatment with lamotrigine (5, 10 and 20 mg/kg) did not change the intensity of 8-OH-DPAT-induced flat body posture, the frequency of DOI-elicited wet dog shakes (WDSs), or spontaneous locomotor activity in rats. As for chronic effect of lamotrigine, rats were subcutaneously injected with dexamethasone (1 mg/kg) and/or lamotrigine (10 mg/kg) intraperitoneally for 14 days. One day after the last administration, spontaneous locomotor activity of the rats was measured, and subsequently DOIinduced WDSs were observed. Repeated treatment with lamotrigine (10 mg/kg) itself facilitated spontaneous locomotor activity. Repeated dexamethasone injection significantly enhanced DOIproduced WDSs, and the enhancement declined with repeated treatment with lamotrigine (10 mg/kg). These findings are similar to the effect of some antidepressants and mood stabilizers on these behaviors, and can explain some action mechanisms of lamotrigine on mood disorder.