Clinical efficacy of tandospirone augmentation in patients with major depressive disorder: a randomized controlled trial

The purpose of the present paper was to investigate the efficacy of augmentation of clomipramine (CMI) by tandospirone in 36 untreated outpatients with major depressive disorder. Twelve patients were treated with CMI and tandospirone (T group), 12 with CMI and diazepam (D group) and 12 with CMI alone (C group) for 6 weeks. No statistically significant differences in the percentage improvement of the Hamilton Depression Rating Scale (17 items; HDRS-17) and the Hamilton Anxiety Rating Scale (14 items; HARS-14) scores were shown among the three treatment groups. However, at 2 weeks, the percentage improvement of HDRS-17 score in the T group tended to be higher than that in the D and C groups, although there was no statistically significant difference among the three treatment groups. No change in plasma prolactin level or adverse events was induced by the addition of tandospirone. These results suggest that 6 weeks of treatment with tandospirone or diazepam was not effective for augmentation of CMI in major depressive disorder patients. However, augmentation of antidepressants by tandospirone administration for a few weeks might induce early expression of antidepressive effects.     

Effects of tandospirone citrate on frozen gait in patients with early stage of progressive supranuclear palsy, investigated by walk-induced activation single photon emission computed tomography method]

We reported a 64-year-old woman in the early stage of progressive supranuclear palsy presenting as pure akinesia syndrome who showed marked improvement with tandospirone citrate. She revealed bradykinesia, severe frozen gait and disturbance of postural reflex without rigidity or tremor. Treatment with L-dopa and L-threo DOPS was not effective, but tandospirone citrate at a daily dosage of 30 mg significantly lessened the severity of frozen gait. Activation single photon emission computed tomography study with 99mTc-ethyl cysteinate dimer during gait revealed a significant increase in brain activity in the right cingulate cortex after tandospirone citrate treatment. The effect lasted ten months until neck rigidity and ventricular supranuclear palsy were evident.     

Inhibitory effects of tandospirone, a 5-HT1A agonist, on medial vestibular nucleus neurons responding to lateral roll tilt stimulation in rats

An electrophysiological study was performed using chloral hydrate-anesthetized rats to determine whether tandospirone, a 5-HT_1A agonist, affects neuronal activities of the medial vestibular nucleus (MVN), since serotonergic innervation and 5-HT_1A receptors are present in this nucleus. Tandospirone applied microiontophoretically at a current of 20–60 nA caused an inhibition of tilt-induced firing of -type neurons, which showed increased and decreased firing with lateral tilt ipsilateral and contralateral to the recording site, respectively, along with that of β-type neurons which exhibited the reverse responses to ipsilateral and contralateral tilt stimulation. The inhibition was antagonized during simultaneous, iontophoretic application of WAY-100635 (20–60 nA), a 5-HT_1A receptor antagonist, although WAY-100635 alone rarely affected spontaneous or tilt-induced firing in either type of neurons. These results suggest that tandospirone acts on a 5-HT_1A receptor to inhibit transmission of otolith information to - and β-type MVN neurons.     

Inhibitory effects of tandospirone, a 5-HT1A agonist, on medial vestibular nucleus neurons responding to lateral roll tilt stimulation in rats

An electrophysiological study was performed using chloral hydrate-anesthetized rats to determine whether tandospirone, a 5-HT_1A agonist, affects neuronal activities of the medial vestibular nucleus (MVN), since serotonergic innervation and 5-HT_1A receptors are present in this nucleus. Tandospirone applied microiontophoretically at a current of 20–60 nA caused an inhibition of tilt-induced firing of α-type neurons, which showed increased and decreased firing with lateral tilt ipsilateral and contralateral to the recording site, respectively, along with that of β-type neurons which exhibited the reverse responses to ipsilateral and contralateral tilt stimulation. The inhibition was antagonized during simultaneous, iontophoretic application of WAY-100635 (20–60 nA), a 5-HT_1A receptor antagonist, although WAY-100635 alone rarely affected spontaneous or tilt-induced firing in either type of neurons. These results suggest that tandospirone acts on a 5-HT_1A receptor to inhibit transmission of otolith information to α- and β-type MVN neurons.     

Effects of cytochrome P450 (CYP) 3A4 inhibitors on the anxiolytic action of tandospirone in rat contextual conditioned fear

The azapirone derivatives, including tandospirone and buspirone, are anxiolytics with 5-HT(1A) receptor agonistic action. Previous in vitro studies have suggested these azapirone derivatives are mainly metabolized by the cytochrome P450 (CYP) 3A4 isoform. The purpose of this study was to clarify the effects CYP3A4 inhibitors have on the anxiolytic action of tandospirone in a conditioned fear stress rat model. One day after fear conditioning, the orally administered tandospirone (30-100 mg/kg) significantly inhibited conditioned freezing in a dose-dependent manner. Co-administration of oral tandospirone and CYP3A4 inhibitors [ketoconazole (10 mg/kg, i.p.) and cimetidine (200 mg/kg, p.o.)] markedly inhibited conditioned freezing. Ketoconazole significantly increased the anxiolytic effect of buspirone similar to tandospirone. As with freezing behavior, the plasma concentrations of tandospirone and buspirone were increased by CYP3A4 inhibitors. This suggests the CYP3A4 isoform is involved in the metabolism of tandospirone, in vivo. Therefore, drugs with CYP3A4 inhibitory property may facilitate the anxiolytic effect of tandospirone when treating human anxiety disorders.     

The effect of tandospirone, a serotonin(1A) agonist, on memory function in schizophrenia.

BACKGROUND: The purpose of this study was to test the hypothesis that the addition of tandospirone, a 5-HT(1A) partial agonist, to ongoing treatment with typical antipsychotic drugs, would improve memory function in patients with schizophrenia. METHODS: Eleven outpatients (male/female = 7/4) with schizophrenia who had been on stable doses of haloperidol and biperiden were given tandospirone, 30 mg/day, for 4 weeks. The Wechsler Memory Scale-Revised (WMS-R) was administered at baseline and 4 weeks after the addition of tandospirone. The Brief Psychiatric Rating Scale (BPRS; Total, Positive, and Negative subscale scores) and the Simpson-Angus Scale for Extrapyramidal Symptoms (SAS) were also completed on the two occasions. To exclude the possibility of a practice effect on the WMS-R test, 11 age-matched patients with schizophrenia (M/F = 7/4) were tested at baseline and after a 4-week interval. RESULTS: Repeated measures analysis of variance revealed a significant time by group (patients with or without tandospirone) effect for the Verbal-, but not the Visual Memory composite scores of the WMS-R test; no significant change was observed in patients without tandospirone, whereas improvement in the Verbal Memory score was noted in patients receiving tandospirone. Moreover, there was improvement in the Inclusion score, an index of memory organization as measured by the Logical Memory subtest of WMS-R, only in patients with tandospirone. Scores on the BPRS and SAS were improved during treatment with tandospirone, but the effects did not reach statistical significance. CONCLUSIONS: The results suggest that adjunctive treatment with 5-HT(1A) agonists may improve some types of memory function in schizophrenia.     

Pharmacokinetic interaction between tandospirone and fluvoxamine in the rat contextual conditioned fear stress model and its functional consequence: Involvement of cytochrome P450 3A4

Aims: In a previous study it was demonstrated that the anxiolytic action of tandospirone, a 5‐hydroxytryptamine (5‐HT)_1A receptor agonist, is facilitated by cytochrome P450 (CYP) 3A4 inhibitors, such as ketoconazole and cimetidine. It is also known that fluvoxamine, a selective serotonin re‐uptake inhibitor (SSRI), inhibits CYP3A4. The purpose of the present study was to clarify the pharmacokinetic interaction between tandospirone and fluvoxamine and to evaluate their combined effect in the rat anxiety model. Methods: The anxiolytic action of co‐administration of tandospirone and fluvoxamine was examined using the rat contextual conditioned fear stress model. After testing the conditioned fear, plasma concentrations of tandospirone and its major metabolite 1‐(2‐pyrimidyl) piperazine were determined. Results: One day after fear conditioning, both tandospirone (60 mg/kg, p.o.) and fluvoxamine (60 mg/kg, p.o.) significantly inhibited conditioned freezing and their combination effect was additive. In addition, plasma concentration of tandospirone was increased by fluvoxamine. Conclusions: There is a CYP3A4‐related drug–drug interaction between tandospirone and fluvoxamine. Therefore, fluvoxamine may facilitate the anxiolytic effect of tandospirone via CYP3A4 inhibition.     

Beneficial effects of tandospirone on ataxia of a patient with Machado-Joseph disease

Tandospirone citrate (tandospirone) is an anti-anxiety drug that acts by combining with serotonin receptor (5-hydroxytryptamine-1 A [5-HT1A]). Recently, there have been a few reports of its potential role in the treatment of cerebellar ataxia. We report the first case of a patient with Machado-Joseph disease in which we successfully treated cerebellar ataxia. In addition, his leg pain, insomnia, anorexia, and depression, which are thought to be related to 5-HT1A receptors, were also remarkably alleviated by treatment with tandospirone.     

The locus coeruleus and memory: a study of chronic alcoholics with and without the memory impairment of Korsakoff's psychosis.

The loss of noradrenergic locus coeruleus neurons has been identified as the possible critical lesion inducing amnesia in alcoholic patients with the Wernicke-Korsakoff syndrome. The present study aims to test this hypothesis by quantifying the number of pigmented locus coeruleus neurons in 4 alcoholics with the Wernicke-Korsakoff syndrome, 5 alcoholics with Wernicke's encephalopathy alone but no amnesia, and 1 alcoholic and 5 age-matched controls with no neurological disorders. Apart from an increased vascularity in the locus coeruleus of alcoholics, no significant differences in the number, morphology or distribution of pigmented locus coeruleus neurons was noted between any of the groups analysed. There was a significant correlation between the number of locus coeruleus neurons and brain weight. These data demonstrate that neither alcohol neurotoxicity nor thiamine deficiency result in a reduction in the number of pigmented cells in the locus coeruleus and refute the hypothesis that locus coeruleus cell loss is critical for the amnesia in the Wernicke-Korsakoff syndrome.     

Autoradiographic localization and pharmacological characterization of [3H]tandospirone binding sites in the rat brain.

The regional distribution and pharmacological properties of [3H]tandospirone binding sites in the rat brain were investigated using quantitative autoradiography. [3H]Tandospirone binding was notably high in the dentate gyrus and CA1 area of the hippocampus, lateral septum, entorhinal cortex, interpeduncular nucleus and dorsal raphe nucleus. The distribution profiles of [3H]tandospirone binding sites significantly correlated with that of serotonin (5-HT)1A receptors identified using [3H]8-OH-DPAT. In competitive binding studies, [3H]tandospirone binding was inhibited by 5-HT, 8-OH-DPAT, pindolol, buspirone and N-(a,a,a-trifluoro-m-tolyl)-piperazine. The potencies of these ligands correlated with their affinities for 5-HT1A receptors. In addition, there was no significant difference in the dissociation constant of [3H]tandospirone binding between the dentate gyrus, CA1 area, dorsal raphe nucleus, lateral septum and entorhinal cortex (about 10 nM) suggesting that [3H]tandospirone binds to 5-HT1A receptors with same affinities in these brain structures. The distribution pattern of binding sites for [3H]tandospirone was also compared with that of benzodiazepine receptors identified using [3H]fludiazepam to find common effector sites for different types of anxiolytics. Some similarities were observed. It is evident in the hippocampal formation that an overlap of intense binding occurred. 5-HT1A receptors in the hippocampus may participate in the anxiolytic effects of tandospirone.     

Effects of tandospirone on "5-HT1A receptor-associated symptoms" in patients with Machado-Josephe disease: an open-label study

BACKGROUND: We investigated the frequencies of the symptoms such as "ataxia, depression, insomnia, anorexia, and pain," that have been reported to be associated with 5-HT1A receptor, and the effect of tandospirone citrate (tandospirone: 5-HT1A agonist) in patients with Machado-Joseph disease (MJD). METHODS: Ten MJD patients received tandospirone (15-30 mg/d) for seven weeks. During that time, they were evaluated weekly using the Ataxia Rating Scale (ARS) and Total Length Traveled (TLT) by Stabilimetry tests, the Self-rating Depression Scale (SDS), which in addition to evaluating their level of depression, also evaluated their degree of insomnia and anorexia, and a pain questionnaire. RESULTS: Before tandospirone therapy, all patients displayed cerebellar ataxia, while insomnia, and leg pain was observed in 7 patients, depression in 6 patients, and anorexia was observed in 2 patients. In response to treatment, 7 of the 10 patients who were ataxic showed a reduction in their ARS, while 3 of 6 patients showed a reduction in their SDS, and 5 of 7 patients showed an alleviation of their insomnia and leg pain. Both of the affected patients showed a marked improvement in their anorexia. A stabilimetry test could be performed in 7 patients, 5 of whom showed a reduction in TLT. CONCLUSIONS: Our data indicate that the patients with MJD are prone to manifest 5-HT1A receptor-associated symptoms, and tandospirone is a useful drug for these symptoms in patients with MJD, though a double-blind study is needed.     

Tandospirone, a 5-HT1A agonist, ameliorates movement disorder via non-dopaminergic systems in rats with unilateral 6-hydroxydopamine-generated lesions

Serotonin 1A (5-HT1A) receptors are distributed throughout the brain with their highest concentrations in the frontal cortex, subthalamic nucleus and entopeduncular nucleus as well as the dorsal and median raphe nucleus. There is growing evidence that 5-HT1A receptor agonists have an antidepressant effect in individuals with major depressive disorders. Recent clinical studies suggest that tandospirone, a highly potent and selective 5-HT1A receptor agonist used clinically as an antidepressant in Japan and China, may act as an antiparkinsonian drug. In the present study, we investigated the effect of tandospirone on contralateral rotational behavior in a unilateral hemiparkinsonian rat model produced with 6-hydroxydopamine (6-OHDA). Tandospirone, as well as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), significantly increased contralateral turnings in a dose-dependent manner (0.5-10 mg/kg). Tandospirone also remarkably potentiated the contralateral turning induced by 0.025 mg/kg of apomorphine. Pretreatment with WAY-100635, a 5-HT1A receptor antagonist, almost completely blocked the contralateral turning behavior evoked by tandospirone and 8-OHDPAT, but not that by apomorphine. SCH-23390, a selective dopamine D1 receptor antagonist, did not affect on the tandospirone-induced rotational behavior. These results suggested that tandospirone could act on postsynaptic 5-HT1A receptors and modulate excitatory amino acid pathways in the basal ganglia. Thus, tandospirone could have therapeutic potential for the treatment of Parkinson's disease by modulating neuronal activities of non-dopaminergic pathways.     

Acute axonal polyneuropathy in chronic alcoholism and malnutrition.

In contrast to the classic, slowly progressive polyneuropathy in alcoholic patients, acute forms, clinically mimicking Guillain-Barré syndrome, are rare. We present a patient who developed motor weakness and sensory loss in all four limbs within four days. Laboratory data were consistent with long-term alcohol abuse and documented thiamine deficiency. Repeated cerebrospinal fluid examinations were normal. Electrophysiological studies showed an acute sensorimotor polyneuropathy with predominantly axonal involvement. We conclude that acute alcoholic neuropathy has to be distinguished from Guillain-Barré syndrome and other forms of acute polyneuropathy by using clinical, laboratory, and electrophysiological data. Both ethanol toxicity and vitamin deficiency could play a role in the pathogenesis.     

坦度螺酮与多虑平治疗焦虑症对照研究

目的：比较坦度螺酮与多虑平治疗焦虑症的疗效和不良反应。方法：60例焦虑症患者随机分为坦度螺酮组和多虑平组，每组各30例;分别给予坦度螺酮和多虑平治疗。疗程4周。于治疗前及治疗1、2、4周采用汉密尔顿焦虑量表（HAMA）和治疗中出现的症状量表（TESS）评定临床疗效和不良反应。结果：坦度螺酮组总有效率和显效率分别为83.3%和46.7%，明显高于多虑平组的60.0%和36.7%（P〈0.05）;坦度螺酮组和多虑平组HAMA评分治疗前分别为（28.3±6.1）分和（29.2±5.7）分，治疗4周，分别下降至（10.9±4.6）分和（15.8±5.1）分，两组均有效但以坦度螺酮组显著为好（P〈0.05）。两组不良反应发生率以坦度螺酮组较多虑平组少而轻。结论：坦度螺酮治疗焦虑症疗效明显好于多虑平，显效快，不良反应少。     

A case of progressive supranuclear palsy improved with tandospirone citrate]

We reported a 74-year-old male case of progressive supranuclear palsy (PSP) who responded to tandospirone citrate, a serotonin receptor (5-HT1A) agonist. The patient manifested postural instability and gait disturbance at 71 years. Additionally, he showed vertical gaze paresis, regidity of the neck, extremities and trunk, bradykinesia and mild cognitive impairment. A brain MRI revealed moderate atrophy of bilateral frontal/temporal lobes and of midbrain tegmentum one year after the onset. The patient had been diagnosed as PSP and treated with L-DOPA. However, L-DOPA therapy showed only transient response for a few months. His symptoms deteriorated gradually, and he became unable to sit, stand up or walk by himself. Tandospirone citrate was additionally administered at 30 mg/day. Rigidity and bradykinesia were remarkably improved in two weeks after the start of tandospirone treatment. He became able to stand up and walk a short distance with supports in four weeks. Cognitive disturbance was also slightly improved. Tandospirone citrate was effective on our case of PSP, especially on rigidity. Our findings suggest that combination of levodopa and tandospirone citrate is a useful therapy for PSP.     

Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment

OBJECTIVE: The goal of this study was to evaluate the effects of the addition of tandospirone, a serotonin-1A (5-HT(1A)) agonist, to ongoing treatment with typical antipsychotic drugs, on two cognitive domains that are relevant to functional outcome in patients with schizophrenia. METHOD: Twenty-six patients with schizophrenia who were receiving stable doses of typical antipsychotics were randomly assigned to adjunctive treatment with 30 mg/day of tandospirone or placebo for 6 weeks. Executive function and verbal memory as well as psychopathology were assessed at baseline and after 6 weeks. RESULTS: Both cognitive measures improved significantly in the patients who received tandospirone; subjects who did not receive tandospirone showed no change. There was no significant change in psychopathology ratings in either group. CONCLUSIONS: The results suggest the usefulness of 5-HT(1A) agonists for enhancing some types of cognitive performance and possibly social and work function in patients with schizophrenia.     

坦度螺酮治疗癫痫伴焦虑、抑郁效果的系统评价

目的 系统评价坦度螺酮治疗癫痫伴焦虑、抑郁的临床效果及安全性。方法 计算机检索PubMed、Cochrane、Science Direct、Embase、维普、万方和中国知网等数据库，检索时间为从建库至 2018年8月，收集坦度螺酮治疗癫痫合并焦虑抑郁的随机对照试验，应用Rev Man 5.3软件进行Meta分析。结果 共纳入6个随机对照试验，包含462例。Meta分析结果显示:坦度螺酮显著降低汉密尔顿焦虑 量表评分（SMD=-1.01；95% CI:-1.91~-0.11；P=0.03），显著降低汉密尔顿抑郁量表评分（SMD=-1.57；95% CI:-2.42~-0.72；P=0.001），显著降低副反应发生率（OR=0.43；95% CI:0.22~0.82； P=0.01），显著增加有效率（OR=3.31；95% CI:1.97~5.56；P<0.001）。结论 坦度螺酮治疗癫痫伴焦虑抑郁具有显著的临床效果及较好的药物安全性。     

Brain stem auditory evoked responses in chronic alcoholics.

Brain stem auditory evoked responses (BAERs) were performed on 25 alcoholic patients with Wernicke-Korsakoff syndrome, 56 alcoholic patients without Wernicke-Korsakoff syndrome, 24 of whom had cerebellar ataxia, and 37 control subjects. Abnormal BAERs were found in 48% of patients with Wernicke-Korsakoff syndrome, in 25% of alcoholic patients without Wernicke-Korsakoff syndrome but with cerebellar ataxia, and in 13% of alcoholic patients without Wernicke-Korsakoff syndrome or ataxia. The mean value of the I-V interval was prolonged in all patient groups. There were more patients with prolonged I-V and I-III intervals in the Wernicke-Korsakoff syndrome group than in the group without the syndrome. The I-III interval was prolonged in 32% of those with Wernicke-Korsakoff syndrome but in only 6% of alcoholics without the syndrome. These abnormalities improved following thiamine treatment and abstinence from alcohol. The presence of prolonged I-III interval in an alcoholic should raise the possibility of Wernicke's encephalopathy.     

Treatment of cerebellar ataxia with 5-HT1A agonist

Effective, pharmacologic approaches to the treatment of cerebellar ataxia are lacking or inadequate. We recently reported preliminary evidence that tandospirone citrate (tandospirone), a 5-HT1A agonist, improved cerebellar ataxia in patients with Machado-Joseph disease (MJD). In the course of that study, we found that such treatment also alleviated the pain associated with cold sensations in the legs, insomnia, anorexia, and depression, all of which are thought to be mediated through activation of the 5-HT1A receptor. In this paper, we reviewed the few published clinical trials that involved the use of 5-HT1A receptor agonists for the treatment of cerebellar ataxia, and discussed the current theories regarding their mechanism of action. Cortical cerebellar atrophy (CCA) was reported, in a double-blind study, to be amenable to treatment with tandospirone. Other types of spinocerebellar degeneration (SCD) i.e., olivopontocerebellar atrophy (OPCA) and Machado-Joseph disease (MJD) have also been reported to respond to the drug, but these have been small studies. Responsive patients exhibited only mild ataxia. The doses of 5-HT1A agonists that have been used successfully ranged from 12.5 mg/day to 60 mg/day (or 1 mg/kg), and were well tolerated by most patients.     

九味镇心颗粒与坦度螺酮治疗老年期广泛性焦虑障碍患者的对照研究

目的:比较九味镇心颗粒及坦度螺酮治疗老年期广泛性焦虑障碍的临床疗效及安全性。方法:采用随机临床对照研究,将广泛性焦虑障碍的老年期患者85例随机分成九味镇心颗粒组和坦度螺酮组治疗4周,用汉密尔顿焦虑量表(HAMA)进行疗效评估,用治疗中出现的症状量表(TESS)评估,结合心电图、血生化及生命体征评估治疗的安全性。结果:经4周治疗,两组的有效率相当,不良反应发生率差异有统计学意义;九味镇心颗粒主要为口干,坦度螺酮组为嗜睡、乏力、口干、肝功能及心电图异常等。结论:九味镇心颗粒对老年期广泛性焦虑障碍患者的疗效与坦度螺酮相当,而安全性更好。