Modeling the pharmacokinetics and pharmacodynamics of dexamethasone in depressed patients

Summary Changes in time course effected by cortisol suppression and the relationship of these changes to the plasma dexamethasone concentration of suppressor and non-suppressor patients are described in this report on a combined pharmacokinetic-pharmacodynamic model.Thirteen depressed patients (8 suppressors and 5 non-suppressors) received an intravenous dose (1.5 mg) of dexamethasone. The drug-induced effect changes are found to lag behind, in time, the plasma drug level changes. To accurately relate the temporal relationship of effect changes to plasma dexamethasone levels, a pharmacodynamic model (sigmoid-Emax) was combined with a pharmacokinetic model that incorporated an effect compartment. The magnitude of the time-lag was quantified by the half-time of equilibration between concentrations in the hypothetical effect compartment and the plasma dexamethasone levels (t_&frac;k_eo).The t_&frac;k_eo of the nonsuppressing group was about 50 of that of the suppressing group, indicating that for a given plasma level the onset and termination of effect for the nonsuppressing group is about two times more rapid than for the suppressing group. Moreover, the model can estimate the effect-site concentration that causes one-half of the maximal predicted effect (EC₅₀), a measure of an individual's sensitivity to dexamethasone. The receptor sensitivity (as determined from the EC₅₀ ratio) of the suppressing group was about twice that of the nonsuppressing group.     

Self-inflicted orbital and intracranial injury with a retained foreign body, associated with psychotic depression: Case report and review

Reports of intracranial self-multilation by psychotic individuals are associated with severe mental disorders, criminality, or both. We describe a psychotically depressed male who drove a ballpoint pen through his right medial canthus and into his intracranial compartment. The patient developed a cavernous sinus syndrome and a traumatic dissection of the cavernous portion of the carotid artery. The pen was removed intraoperatively. Postoperatively, the patient was placed on a course of broad-spectrum antibiotics, antidepressants, and antipsychotic medications, and he has received long-term psychiatric follow-up. The literature related to these unusual cases is reviewed, and relevant surgical, medical, and psychiatric aspects of treatment are discussed.     

5-HT1A receptor agonists: recent developments and controversial issues

During the last decade, serotonin (5-HT)_1A receptors have been a major target for neurobiological research and drug development. 5-HT_1A receptors have been cloned and a variety of selective agonists, such as the aminotetraline 8-OH-DPAT and the pyrimidinylpiperazine ipsapirone, have become available. Demonstrations of apparent intrinsic activity of these ligands at 5-HT_1A receptors, however, depend highly on the particular assay system. This may be due to the possible existence of receptor subtypes and to assay (or brain region)-dependent differences in receptor reserve and the nature of receptor-effector coupling. Nevertheless, the apparent intrinsic activity of 8-OH-DPAT seems to be higher (although possibly not yet maximal) than that of the pyrimidinylpiperazines. In the brain, 5-HT_1A receptors are located presynaptically as somatodendritic receptors on 5-HT neurons and postsynaptically in particular limbic and cortical regions. Although it is generally accepted that presynaptic 5-HT_1A receptors control 5-HT neuronal activity, recent evidence suggests an additional role of postsynaptic 5-HT_1A receptors in cortex as part of a negative feedback loop. Anxiolytic and antidepressive properties of selective 5-HT_1A receptor agonists have now been confirmed by clinical studies. Although it is well established that the latter properties depend on theagonistic activity of these compounds, theoptimal level of intrinsic activity is still a matter of debate and may be dependent on the clinical indication. Such compounds may also have antiaggressive effects, and possibly anticraving effects (manifested by their alcohol intake-reducing effects in dependent animals), but the specificity of these so-called anti-impulsivity effects is still controversial and not yet tested clinically. Anticataleptic, antiemetic and neuroprotective properties have been demonstrated in different species. Behavioral studies on the mechanisms underlying the anxiolytic and antidepressive effects have examined the relative contribution of pre-and postsynaptic 5-HT_1A receptors by means of local cerebral application and lesion techniques. Most evidence points towards a critical involvement of presynaptic receptors in the anxiolytic effects of 5-HT_1A receptor agonists (although a possible contribution of postsynaptic receptors cannot be excluded). With regard to the antidepressive properties, a case can be made for the reverse; i.e., a strong involvement of postsynaptic receptors and a questionable contribution of presynaptic receptors. However, as the therapeutic effects of those 5-HT_1A receptor (partial) agonists which have been tested clinically require repeated administration, attention has been directed increasingly towards chronic studies. These studies have shown that a number of electrophysiological, biochemical, behavioral and endocrinological 5-HT_1A receptor-related events adapt differentially to repeated or sustained administration. Thus, several hypotheses accounting for the delayed onset of action have been advanced. Among these, time-dependent downregulation /desensitization of eitherpre- orpostsynaptic 5-HT_1A receptors, or cortical 5-HT₂ receptors have received much attention. However, these hypotheses have their weaknesses, and it is argued thatfunctional sensitization of particular postsynaptic 5-HT_1A receptor-mediated events remains a valuable alternate hypothesis. Basic research on the role of 5-HT_1A receptors in psychopathology and in the therapeutic effects of clinically effective therapeutics, as well as on the mechanism of action of 5-HT_1A receptor ligands, will enable rational design of ligands with particular profiles of intrinsic activity at different 5-HT_1A receptor populations, and may contribute to a more efficient treatment of a multiplicity of brain disorders.     

曲唑酮治疗抑郁症的疗效观察

目的：观察曲唑酮治疗抑郁症的疗效。方法：对31例抑郁症患者给予每日50～250mg曲唑酮治疗，不合用其它精神药物，并用汉密尔顿抑郁量表(HAMD)，不良反应症状量表(TESS)进行治疗前后对照。结果：痊愈20例，显著进步6例，进步2例，无效3例，总有效率90．3％。结论：曲唑酮是一种强效而安全的抗抑郁药。     

急性脑卒中后抑郁症25例临床分析

目的 :观察分析急性脑卒中后抑郁症的病理过程及治疗效果。方法 :统计分析 2 5例脑卒中病人的临床资料 ,特别对汉密顿抑郁量表的结果进行评价。结果 :2 5例病人中 ,脑出血 10人 ,脑梗塞 15人 ,汉密顿抑郁量表平均总分 2 4分± 5分 ,其中重度 4例 ,中度 15例 ,轻度 6例。经赛乐特治疗后 ,平均总分下降至 13分± 5分 ,其治愈率为 75 % ,显效 2 5 %。结论 :急性脑卒中后抑郁症的临床表现较功能性者轻 ,早期发现与正确治疗后 ,疗效满意     

Tender points, depressive and functional symptoms: Comparison between fibromyalgia and major depression

Summary The degree of symptomatic overlap between fibromyalgia and major depression should be estimated by assessing the amount of local tenderness and the frequency and severity of depressive and functional symptoms. Tender points were assessed by palpation and symptoms by psychometric scales in 30 patients with fibromyalgia and 26 patients with major depression. The patients with fibromyalgia had markedly more tender points (16.5) than the depressive patients (1.3). In contrast, depressive and functional symptoms were present in both groups of patients, and some depressive patients (26%) also suffered from clinical pain. An increased sensitivity to pressure pain clearly distinguishes fibromyalgia from depression even if there is an overlap of other symptoms.     

Platelet-rich plasma serotonin levels in tension-type headache and depression

We measured platelet-rich plasma (PRP) serotonin in patients suffering from tension-type headache, before and after treatment with amitriptyline, comparing them with a healthy control group and patients with untreated depression. We evaluated the severity of headache and depression in each group. PRP serotonin levels were higher in patients with headache than in controls and depressed patients. We observed a fall of PRP serotonin in patients with tension-type headache to similar levels after treatment as the depressed group. This fall was correlated with the improvement of headache but not with depression scales. Our data suggest that the rise of platelet serotonin levels in tension-type headache is related to pain and not depression.     

抑郁症的基础与认知激活脑SPECT显像

目的通过抑郁症患者基础和认知激活局部脑血流（ｒＣＢＦ）灌注显像的半定量分析，评估抑郁症患者的脑血流灌注异常。方法选择２７例未经抗抑郁治疗、ＩＣＤ１０分类为中度抑郁发作伴躯体症状的患者，１５例年龄匹配的健康人作正常对照。２７例患者中２１例、１５例健康人中１３例行双日法基础与认知激活脑ｒＣＢＦ显像；另６例患者及２例健康人仅行基础脑ＳＰＥＣＴ显像。认知激活采用Ｗｉｓｃｏｎｓｉｎ卡片分类试验。半定量分析在横断面图像７～１１帧上进行，将各ＲＯＩ的平均计数与同侧小脑的最高计数相除，得到各ＲＯＩ的ｒＣＢＦ比值。结果抑郁症左额叶和左颞叶的基础ｒＣＢＦ值均为０７２０，明显低于对照组（０７６４和０７５０，Ｐ＜００５）；左额、左颞、左顶叶的认知激活ｒＣＢＦ值分别为０７１９、０６９０及０７０１，明显低于对照组（０７８２、０７５２和０７６６，Ｐ＜００１和Ｐ＜００５）。结论①抑郁症患者存在左额叶、左颞叶的局部血流低灌注。②额叶、颞叶皮层低灌注可能是引起抑郁症认知障碍、心境低落的原因。③Ｗｉｓｃｏｎｓｉｎ卡片分类试验认知激活脑ＳＰＥＣＴ显像有助于提高抑郁症的诊断准确性     

Advances in development of medications for alcoholism treatment

 Over the past decade, research on medications to treat alcohol problem has flourished. Naltrexone and acamprosate are tangible fruits of such endeavors and each has now earned approval in a large number of countries. Recent studies on naltrexone indicate that patient compliance is important if full benefits are to be achieved. Several laboratory studies with human subjects are beginning to elucidate the mechanisms underlying efficacy of naltrexone, as well as explaining variability of response among subpopulations of drinkers. In addition to these two agents, recent investigations have also demonstrated that the antidepressants desipramine, imipramine, and fluoxetine reduce mood-related symptoms and, to some extent, drinking itself in alcoholics who are depressed. Research to date suggests that opioid antagonists and selective serotonin reuptake inhibitors are more effective in reducing alcohol intake when used in combination. Clinical issues, methodology, and directions for future research are also reviewed in this article. In particular, issues addressed include alternative dosage regimens, necessary duration of treatment, employment of medications in combination, integration of pharmacologic agents with behavioral interventions, enhancement of patient compliance, and concurrent treatment of psychiatric comorbidity. Received: 16 December 1997 / Final version: 15 April 1998     

Comorbid disorders in hospitalized bipolar adolescents compared with unipolar depressed adolescents

This study examined comorbid psychiatric disorders in adolescents with bipolar disorder. Hospitalized bipolar adolescents (N=10) were compared to hospitalized adolescents with unipolar depression (N=33), and to adolescents with nonaffective psychiatric disorders (N=11). Results showed conduct disorder, attention-deficit hyperactivity disorder, psychosis, and having any DSM-III-R psychoactive substance use disorder were all significantly more common in the bipolar group than the unipolar depressed group. Comorbid anxiety disorder was present in 40–45% of the subjects in the unipolar and bipolar groups, but in none of the control group subjects. This study is supported in part by a grant to Dr. Borchardt from the University of Minnesota Graduate School.