Imipramine in panic disorder. 1. Clinical response and pharmacological changes

Clinical and biochemical variables were monitored in 18 patients with panic disorder before and during treatment with imipramine over 16 weeks. Imipramine dosage was slowly increased from a starting dose of 10 mg daily, to prevent early treatment drop-outs. All patients were effectively treated for at least 6 weeks, and only two patients dropped out before the end of the study. There were substantial reductions in panic attack frequency, ratings of depression and avoidance behaviour, but only small reductions in ratings of state and general anxiety. Plasma levels of the noradrenaline metabolite 3-methoxy-4-hydroxyphenyl- ethylene glycol initially fell after starting imipramine, but returned to pre-treatment levels by week 8 of treatment. Plasma imipramine and/or desipramine concentrations were very variable and did not correlate with either psychological or biochemical changes during treatment.     

Imipramine in panic disorder. 2. Effects on α2-adrenoceptor function

Untreated patients with panic disorder have been shown to have altered α(2)-adrenoceptor sensitivity, as assessed by clonidine challenge testing. We investigated clonidine-induced biochemical, physiological, hor monal and psychological responses in six panic patients, before and after treatment with imipramine. Comparison of the clonidine-induced fall in plasma MHPG pre- and post-treatment showed it to be sig nificantly reduced after imipramine. Significantly smaller clonidine-induced falls in diastolic blood pressure and heart rate occurred after imipramine treatment. However, growth hormone and sedation responses were not altered. These data suggest that reduced sensitivity of some central α(2)-adrenoceptors occurs during treatment of panic disorder with imipramine. However, these changes do not fully explain the therapeutic actions of antidepressants in this condition.     

The effects and after effects of the α2-adrenoceptor antagonist idazoxan on mood, memory and attention in normal volunteers

Idazoxan, an α( 2)-adrenoceptor antagonist, is an effective antidepressant with a mode of action different from that of conventional antidepressants. As it is used as an antidepressant it is important to know whether there are any unwanted CNS side effects. Study of its effects will also provide information on the relationship between noradrenergic function and mood and performance. Twelve normal male volunteers who were given the drug (40 mg orally three times daily for 21 days) were compared with 12 matched controls. A computerized test battery was used to assess mood and various aspects of memory and attention. Many of the tests of memory and attention in the battery have been widely used over the last 20 years, and in addition two new selective attention tasks were included. The subjects were tested 3 days before starting the drug, on days 3 and 17 while on the drug, and after they had stopped taking the drug (4 days after and 24 days after). Control subjects followed a similar testing schedule. The results showed that the drug had no effect on mood, logical reasoning, retrieval from semantic memory or sustained attention. However, the drug did improve one aspect of selective attention (the place repetition effect), although this effect was only observed on the third day on the drug. Overall, the results suggest that idazoxan produces selective performance improvements, and that the measures of selective attention used here may be more sensitive indicators of drug effects than some of the traditional tasks currently in use.     

Systematic review of cognitive development across childhood in Down syndrome: implications for treatment interventions

Background There is conjecture regarding the profile of cognitive development over time in children with Down syndrome (DS). Characterising this profile would be valuable for the planning and assessment of intervention studies. Method A systematic search of the literature from 1990 to the present was conducted to identify longitudinal data on cognitive trajectories in children with DS. Results Thirteen studies were identified: six assessed overall cognitive performance and seven assessed specific cognitive domains. Studies assessing IQ reported a decline across time. Studies assessing change in cognitive domains were, for the most part, not interpretable because of large age ranges in samples obscuring age‐specific data. Conclusion The current literature has only begun to describe typical cognitive developmental trajectories in children with DS; additional research is needed to clarify this topic.     

Progesterone loading as a strategy for treating postpartum depression

Postpartum depression (PPD) is a severe disorder that adversely impacts both mothers and infants. It is associated with significant morbidity and mortality and reported prevalence is 11.5% (Ko, Rockhill, Tong, Morrow, & Farr. (2017). MMWR Morbidity and Mortality Weekly Report, 66(6), 153–158). Although PPD's fundamental pathophysiology remains to be fully illuminated, the influence of changes in perinatal hormones such as allopregnanolone (an endogenous progesterone metabolite) are most promising avenues of research. Conventional treatments for PPD are aligned with treatment strategies for depressive disorders. Brexanolone is a small molecule, neuroactive steroid GABA_A receptor allosteric modulator consisting of synthetic allopregnanolone and a solubilizing agent. In early 2019, brexanolone received approval in the United States for the treatment of PPD. Brexanolone is only available through a restricted program and is costly. Animal models demonstrate that progesterone prevents depression-like behaviors. However, studies of progesterone's effects in women suffering from PPD are few and inconclusive. We hypothesize that orally dosed progesterone will increase concentrations of allopregnanolone in the central nervous system, which should relieve symptoms of PPD.     

An eight-week trial investigating the efficacy and tolerability of atorvastatin for children and adolescents with heterozygous familial hypercholesterolemia

This study aimed to assess the efficacy and tolerability of atorvastatin in Tanner stage (TS) 1 patients ages 6 to 10?years and TS ??2 patients ages 10 to <18?years with genetically confirmed heterozygous familial hypercholesterolemia (HeFH) and a low density lipoprotein cholesterol (LDL-C) level of 4?mmol/l (155?mg/dl) or higher. In this open-label, 8-week study, 15 TS 1 children were treated initially with atorvastatin 5?mg/day and 24 TS ??2 children with 10?mg/day. Doses were doubled at week 4 if the LDL-C target (<3.35?mmol/l [130?mg/dl]) was not achieved. The efficacy variables were the percentage change from baseline in LDL-C, total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), and apolipoprotein (Apo) A-I and Apo B. Safety evaluations included clinical monitoring, subject-reported adverse events (AEs), vital signs, and clinical laboratory tests. The mean values for LDL-C, TC, VLDL-C, and Apo B decreased by week 2 among all TS 1 and TS ??2 patients, whereas TG, HDL-C, and Apo A-I varied considerably from week to week. After 8?weeks, the mean reduction in LDL-C was ?40.7%?±?8.4 for the TS 1 children and ?39.7%?±?10.3 for the TS ??2 children. For the TS 1 patients, the mean reductions were ?34.1%?±?6.9 for TC and ?6.0%?±?32.1 for TG. The corresponding changes for the TS ??2 patients were ?35.6%?±?9.5 for TC and ?21.1%?±?29.7 for TG. Four patients experienced mild to moderate treatment-related AEs. No serious AEs or discontinuations were reported. Overall, no difference in safety or tolerability was observed between the younger and older cohorts. Across the range of exposures after atorvastatin 5 to 10?mg (TS 1) or atorvastatin 10 to 20?mg (TS ??2) doses for 8?weeks, clinically meaningful reductions in LDL-C, TC, VLDL-C, and Apo were observed with atorvastatin in pediatric patients who had HeFH. Atorvastatin also was well tolerated in this population.     

Rapid cycling affective disorders in the mentally retarded

This article describes a group of 10 hospitalized, mentally retarded patients with rapid cycling affective disorders, including details of demography, pattern of illness, and response to an open trial of treatment with lithium and/or carbamazepine. Family histories of these patients revealed high rates of mental illness, including affective disorder and mental retardation. Men had an earlier onset of affective illness and rapid cycling than did women. Half of the patients showed partial or complete improvement on lithium alone or in combination with carbamazepine; those who responded to the combined treatment had more episodes of affective illness per year than those who did not. Rates of response to treatment and some clinical characteristics of these patients were similar to those of non-mentally retarded rapid cycling patients.     

The Effects of Spatial Selective Attention on the Somatosensory Event-Related Potential

Event-related potentials (ERPs) were recorded during a selective attention task involving weak or strong electrical stimuli delivered to the index fingers of the left and right hands. In an attend weak condition, subjects were asked to count the number of weak stimuli (targets) interspersed amongst strong stimuli (standards) delivered to a designated hand, whilst ignoring a similar set of stimuli delivered to the other hand. In an attend strong condition, subjects were asked to count the number of strong targets interspersed amongst weak stimuli. In both conditions, targets and standards occurred with probabilities of .10 and .40 respectively on each hand. Counting weak targets was found to be more difficult than counting strong targets. The latency of the earliest significant effect of selective attention on ERPs to standards was dependent on stimulus intensity: N80 in the case of weak standards, P105 for strong standards. There was no evidence of a later prolonged negative shift in attended standard ERPs. Rather, an enhanced N150 component post-centrally was followed by a prolonged positive shift of attended standard ERPs. This Late positive shift had a similar scalp distribution to the late positive component elicited by attended target stimuli.     

Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group

AIMS: The objectives of this study were to assess the safety, pharmacokinetic and pharmacodynamic profiles, and antiviral efficacy of pegylated interferon-alpha2b monotherapy in patients with chronic hepatitis C. METHODS: Fifty-eight patients (38 men, 20 women; age range, 25 to 65 years) with compensated chronic hepatitis C were enrolled in this open-label, randomized, active controlled study. Patients received 0.035 to 2.0 microg/kg pegylated interferon-alpha2b subcutaneously weekly or the active control, interferon-alpha2b 3 million IU subcutaneously three times/week, for 24 weeks. Safety and antiviral efficacy assessments were performed during treatment and in a subsequent 4-week follow-up period. Detailed pharmacokinetic assessments were performed at weeks 1 and 4. RESULTS: Pegylated interferon-alpha2b produced dose-related reductions in white blood cells, neutrophils, and platelets, and dose-related increases in oral temperature, serum neopterin, and serum 2'5'-oligoadenylate synthetase activity, which were qualitatively similar to those produced by nonpegylated interferon-alpha2b. Reported adverse events (flu-like symptoms, asthenia) were qualitatively similar in pegylated interferon-alpha2b- and nonpegylated interferon-alpha2b-treated groups. Dose-related antiviral activity, as measured by loss of detectable serum hepatitis C virus RNA (<100 copies/mL), was noted at the end of treatment and after 4 weeks of follow-up. Both pegylated and nonpegylated interferon-alpha2b were rapidly absorbed, with maximal concentrations occurring approximately 8 to 12 hours after dose administration. Pegylated interferon-alpha2b had sustained maximal serum concentrations for 48 to 72 hours after dose administration, whereas nonpegylated interferon-alpha2b concentrations declined rapidly. Volume of distribution for both compounds was similar (approximately 1 L/kg). Pegylated interferon-alpha2b elimination half-life was approximately 10-fold greater, and mean apparent clearance was one tenth that of nonpegylated interferon-alpha2b. CONCLUSIONS: Pegylated and nonpegylated interferon-alpha2b safety and pharmacodynamic profiles were comparable. Pegylated interferon-alpha2b demonstrated delayed clearance compared with nonpegylated interferon-alpha2b, consistent with once-weekly administration.