Results of phase II pharmacokinetic study of levetiracetam for prevention of post-traumatic epilepsy

Levetiracetam (LEV) has antiepileptogenic effects in animals and is a candidate for prevention of epilepsy after traumatic brain injury. Pharmacokinetics of LEV in TBI patients was unknown. We report pharmacokinetics of TBI subjects≥6years with high PTE risk treated with LEV 55mg/kg/day orally, nasogastrically or intravenously for 30days starting ≤8h after injury in a phase II safety and pharmacokinetic study. Forty-one subjects (26 adults and 15 children) were randomized to PK studies on treatment days 3 and 30. Thirty-six out of forty-one randomized subjects underwent PK study on treatment day 3, and 24/41 subjects underwent PK study on day 30. On day 3, mean T(max) was 2.2h, C(max) was 60.2μg/ml and AUC was 403.7μg/h/ml. T(max) was longer in the elderly than in children and non-elderly adults (5.96h vs. 1.5h and 1.8h; p=0.0001). AUC was non-significantly lower in children compared with adults and the elderly (317.4μg/h/ml vs. 461.4μg/h/ml and 450.2μg/h/ml; p=0.08). C(max) trended higher in i.v.- versus tablet- or n.g.-treated subjects (78.4μg/ml vs. 59μg/ml and 48.2μg/ml; p=0.07). AUC of n.g. and i.v. administrations was 79% and 88% of AUC of oral administration. There were no significant PK differences between days 3 and 30. Treatment of TBI patients with high PTE risk with 55mg/kg/day LEV, a dose with antiepileptogenic effect in animals, results in plasma LEV levels comparable to those in animal studies.     

Unusual stereospecificity of the potential antidepressant rolipram on the cyclic AMP generating system from rat brain cortex

Adrenoceptor sensitivity of central synapses is thought to be involved in regulation of mood. Persistent changes exceeding normal fluctuations conceivably could lead to disease states like manic-depressive illness. Several treatment regimens which affect mood in man reversibly alter the density of beta-adrenoceptors in animals in a time- and dose-dependent manner. Most prominently, many antidepressants which inhibit neurotransmitter uptake downregulate postsynaptic adrenoceptors, and thus diminish intracellular cyclic AMP formation elicited by noradrenaline. In addition, other modulations of presynaptic nerve activity, e.g. electroconvulsive shock or treatment with thyroid hormones, also cause adaptational responses at the postsynapse. In general, functional integrity of the pre/postsynaptic unit had to be maintained strictly to observe postsynaptic downregulation. Using a highly potent and stereospecific inhibitor of cyclic AMP hydrolysis we demonstrate that downregulation can also be elicited by postsynaptic mechanisms. Treatment of rats with rolipram, a phenylpyrrolidinone derivative, decreases adrenoceptor density in a time- and dose-dependent fashion. The ED50 for the racemate is 0.35 mg/kg, for the (-)-isomer 0.18 mg/kg. The (+)-isomer is inactive. This effect correlates with the drug's potency to inhibit a calmodulin/calcium-insensitive phosphodiesterase from brain cortex (ED50 racemate: 1.2 microM; (-)-isomer: 0.4 microM). Using methods of computer-assisted drug design to identify common stereochemical features of rolipram and the unrelated tricyclic antidepressants, we found that calculated low energy conformations fit onto a four-point model which specifies four hypothetical binding sites between a drug and its presumptive receptor site. These findings may indicate that all antidepressants share a common, hitherto unknown site of action irrespective of their known biochemical activities.     

Autoradiographic mapping of a selective cyclic adenosine monophosphate phosphodiesterase in rat brain with the antidepressant [3H]rolipram

Rolipram is a clinically effective antidepressant with selective cAMP phosphodiesterase (PDE) inhibiting properties. (+/-)-[3H]Rolipram binds with high affinity (Kd = 2.52 +/- 0.47 nM) to sections of rat brain (Hill number = 0.90 +/- 0.05). Binding is stereospecific. Association of (+/-) [3H]rolipram to sections is rapid (47% of specific binding in the first minute, kobs = 0.52 min-1). Dissociation of (+/-)-[3H]rolipram exhibits non first order kinetics (3 component model; t1/2 = 2.5 min, 50 min and 6 h, respectively). A number of PDE inhibitors reduce (+/-)-[3H]rolipram binding to the level of nonspecific binding ((-)-rolipram, IC50 = 0.9 nM; (+/-)-rolipram, IC50 = 1.5 nM; Ro 20-1724, IC50 = 11 nM; ICI 63.197, IC50 = 35 nM; medazepam, IC50 = 240 nM; diazepam, IC50 = 1200 nM; IBMX, IC50 = 3800 nM). In vitro autoradiography reveals high binding site densities in the cerebellum, olfactory bulb, lateral septal nucleus, frontal cortex, subiculum and CA1 of hippocampus. Most of the labeled structures are part of the limbic system. In vivo autoradiography of (+/-)-[3H]rolipram binding shows much more nonspecific binding than in vitro, nevertheless the distribution pattern of (+/-)-[3H]rolipram binding sites is similar. A comparison of the distribution pattern of (+/-)-[3H]rolipram binding sites with that of an antidepressant (monoamine oxidase inhibitor, monoamine uptake inhibitor) reveals no overlap. Limited, though significant correlations exist with the distribution of beta 1-adrenergic, adenosine1 and glutamate/quisqualate receptors as well as protein kinase C, but not with beta 2-adrenergic receptors and forskolin binding sites.     

The anti-koro effect of a tricyclic antidepressant

The authors are reporting a case of koro syndrome which was associated with major depression. Koro syndrome is a rare disease which manifests itself with a severe anxiety associated with the fear of having the penis shrinking and disappearing in the abdomen. The case reported was treated with trimipramine, a tricyclic antidepressant, at a dose of 150 mg/day associated with bromazepam, a benzodiazepine. In addition, the patient received psychotherapy, which allowed him to deal with the situation and to eliminate guilt feelings. It is hypothesized that the tricyclic antidepressant, by treating the depression, had a curative effect on the koro syndrome.     

Chronic treatment with the potential antidepressant drug rolipram: the effect on the behavioural responses to adrenergic and dopaminergic receptor agonists with some biochemical correlates

Summary We studied the effect of acute and chronic treatment with rolipram, a potential antidepressant drug, on the behavioural responses induced by adrenergic and dopaminergic receptor agonists in mice and rats, and on (³H)prazosin and (³H)dihydroalprenolol binding to cortical membranes and whole brain noradrenaline and dopamine utilization in rats. Chronic, but not acute, administration of rolipram potentiated a behavioural response mediated through central ₁-adrenoceptors, attenuated an ₂-adrenoceptormediated response and inhibited a-adrenoceptor-mediated response. Neither treatment affected the behavioural responses to dopaminergic stimulants. Repeated treatment with rolipram decreased the density of cortical (³H)dihydroalprenolol, but not (³H)prazosin bindings sites, and reduced brain noradrenaline, but not dopamine utilization. These results suggest that chronic administration of rolipram induces the down-regulation of the central- and ₂-adrenoceptors and enhances the responsiveness of the central ₁-adrenoceptors with no apparent changes in the ₁-adrenoceptor density.     

Absence of anticholinergic activity of rolipram, an antidepressant with a novel mechanism of action, in three different animal models in vivo

Rolipram, in contrast to the tricyclic antidepressants amitriptyline and imipramine or the acetylcholine receptor antagonist atropine, failed to antagonize the salivation, hypothermia, or tremor caused in mice by the muscarinic receptor agonists pilocarpine or oxotremorine. The absence of anticholinergic activity, the extremely low therapeutic dose, and the novel mechanism of antidepressant action suggest that rolipram may also be a well tolerable antidepressant suitable for the treatment of problematic subpopulations of depressives such as elderly patients.     

Triiodothyronine potentiation of the antidepressant effect of phenelzine

Two patients with depression that was refractory to tricyclic antidepressant therapy alone and in combination with lithium or triiodothyronine (T3) were treated with the monoamine oxidase inhibitor phenelzine. In both cases, the addition of T3 potentiated the antidepressant response to phenelzine. These observations suggest that thyroid hormone potentiation may not be specific to one class of antidepressant drugs.     

Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: a double-blind placebo-controlled study.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a noninvasive method to stimulate the cortex, and the treatment of depression is one of its potential therapeutic applications. Three recent meta analyses strongly suggest its benefits in the treatment of depression. The present study investigates whether repetitive TMS (rTMS) accelerates the onset of action and increases the therapeutic effects of amitriptyline. METHODS: Forty-six outpatients meeting DSM-IV criteria for nonpsychotic depressive episode were randomly assigned to receive rTMS (n = 22) or sham repetitive TMS (sham) (n = 24) during 4 weeks over dorsolateral prefrontal cortex (DLPFC) in this double-blind controlled trial. All patients were concomitantly taking amitriptyline (mean dose 110 mg/d). The rTMS group received 20 sessions (5 sections per week) of 5 Hz rTMS (120% of motor threshold and 1250 pulses per session). Sham stimulation followed the same schedule, however, using a sham coil. The efficacy variables were the Hamilton Depression Rating Scale-17 items (HAM-D/17), the Montgomery-Asberg Depression Rating Scale (MADRS), a Visual Analogue Scale (VAS), and the Clinical Global Impression (CGI). Tolerability was assessed by clinical examination and a safety screening of TMS side effects. RESULTS: Repetitive TMS had a significantly faster response to amitriptyline. There was a significant decrease in HAM-D/17 scores, already after the first week of treatment (p < .001 compared with baseline and p < .001 compared with sham). The decrease in HAM-D/17 scores in the rTMS group was significantly superior compared with the sham group throughout the study (p < .001 at fourth week). CONCLUSIONS: Repetitive TMS at 5 Hz accelerated the onset of action and augmented the response to amitriptyline.     

Cognitive behavior approach to loss of clinical effect during long-term antidepressant treatment: a pilot study

OBJECTIVE: The aims of this investigation were to explore the feasibility of a cognitive behavior approach to loss of clinical effect during long-term antidepressant therapy and to compare it with dose increase. METHOD: Ten patients with recurrent depression who relapsed while taking antidepressant drugs were randomly assigned to dose increase and clinical management or to cognitive behavior therapy and maintenance of the antidepressant drug at the same dose. RESULTS: Four of five patients responded to a larger dose, but all had relapsed again on that dose by the 1-year follow-up. Four of five patients responded to cognitive behavior therapy, and only one relapsed during follow-up. CONCLUSIONS: The data suggest that application of a cognitive behavior therapy approach is feasible when there is a loss of clinical effects during long-term antidepressant treatment and may carry long-term benefits. The results need to be confirmed with large-scale controlled studies.     

Acute antidepressant effect of lithium is associated with fluctuation of calcium and magnesium in plasma. A double-blind study on the antidepressant effect of lithium and clomipramine

In a double-blind study on 22 patients with major depressive disorder the effects of lithium and clomipramine on signs and symptoms and on calcium and magnesium in plasma were compared. Ratings of antidepressant and side effects were performed by 2 psychiatrists at the end of a placebo period of 5-7 days and after treatment for 2 and 4 weeks. Psychopathology was rated by 15 reported and 4 observed items from the Comprehensive Psychopathological Rating Scale (CPRS). Eleven items present in 72-100% of the patients were used to evaluate the effect of the two drugs. After 2 weeks of treatment the rated scores dropped for more than half of the CPRS items. After 4 weeks the scores for all but one item were reduced in both groups. The sums of scores were significantly reduced after 2 weeks in both groups and after 4 weeks global scores were reduced as well. The drugs had notable and similar antidepressant effects. Lithium treatment was associated with fluctuations in calcium and magnesium levels in plasma not seen during clomipramine treatment. Serum prolactin increased during clomipramine treatment but was unaffected by lithium treatment. No correlations were found between the sum of rating scores and blood levels of drugs, prolactin, calcium or magnesium.     

Long-term continuation antidepressant treatment: a comparison study

This retrospective study examined the clinical characteristics and the course of 26 patients with major affective disorders who repeatedly relapsed during or shortly after antidepressant tapering off at the usual 6-12-month intervals. The patients apparently required long-term antidepressant continuation therapy not preventive therapy, as they were unable to be successfully tapered off antidepressants over a mean of 36.6 months. In contrast with a group of 15 randomly selected patients with a more typical recurrent course of illness and successful tapers after 6-12 months of treatment, the long-term continuation therapy patients were younger, had a longer duration of depression before entering treatment, and were more likely to meet the DSM-III criteria for concomitant dysthymic, panic, or personality disorder or major depression with psychotic features. The findings suggest that secondary Axis I and Axis II diagnoses in antidepressant-responsive depressed patients are associated with the need for long-term continuation treatment.     

Predictors of antidepressant adherence: Results of a Japanese Internet‐based survey

Aim: The purpose of the present study was to identify the psychosocial/pharmacological predictors of antidepressant (AD) adherence. Methods: An Internet‐based survey was conducted among 1151 Japanese individuals with major depressive disorder. Subjects were asked to report their degree of non‐adherence for each AD taken using a 5‐point Likert scale: 0, never forget; 1, rarely forget; 2, occasionally forget; 3, sometimes forget; and 4, often forget. The highest number reported among each subject was assigned as their low adherence index (LAI). Individuals with an LAI ≥ 3 were defined as members of the low adherence (LA) group. Predictors of LA was analyzed using bivariate and multivariate models, both among the total number of subjects and single AD subgroup (n = 657). Results: Nearly one‐third of subjects (n = 381, 33.1%) reported LA. On bivariate analysis, LA was associated with lower age, worker or student status (vs unemployed or housewife), higher daily dosing frequency (DDF), low drug satisfaction, and a neutral/negative doctor–patient relationship (DPR; P < 0.001). In a multivariate model, LA was predicted by age (≤34 years: odds ratio [OR], 1.64), worker or student status (OR, 1.87), higher DDF (≥twice daily: OR, 1.61), and neutral/negative DPR (OR, 1.54; P < 0.01). Among the single‐AD subgroup, adherence was similar between those on selective serotonin reuptake inhibitors/serotonin‐noradrenaline reuptake inhibitors and tricyclics. Use of neither medication was associated with adherence in a multivariate model. Conclusion: LA was predicted by lower age, worker or student status, higher DDF, and neutral/negative DPR. Adherence was not significantly different between subjects on newer agents and tricyclics.