The effects of atomoxetine on emotional control in adults with ADHD: An integrated analysis of multicenter studies.

PURPOSE: To investigate the effects of atomoxetine on emotional control in adults with ADHD. METHODS: We performed an integrated analysis using individual patient data pooled from three Eli Lilly-sponsored studies. An integrated analysis can be viewed as a meta-analysis of individual patient-level data, rather than study-level summary data. RESULTS: Two populations were identified: a large sample of patients with pre-treatment baseline data (the "overall population"; n=2846); and a subset of these patients with placebo-controlled efficacy data from baseline to 10 or 12 weeks after initiating treatment (the "placebo-controlled population"; n=829). At baseline, in the overall population, ∼50% of ADHD patients had BRIEF-AS (Behavior Rating Inventory of Executive Function-Adult Version Self-Report) Emotional control subscores between 21 and 30, compared with ∼10% of normative subjects in the BRIEF-A manual. At endpoint, in the placebo-controlled population, atomoxetine led to a small (effect size 0.19) but significant (P=0.013) treatment effect for emotional control. The effect size was 0.32 in patients with BRIEF-AS Emotional control scores>20 at baseline. Improvements in emotional control correlated with improvements in the core ADHD symptoms and quality-of-life. DISCUSSION: As deficient emotional control is associated with impaired social, educational and occupational functioning over and above that explained by core ADHD symptoms alone, improvements in emotional control may be clinically relevant. CONCLUSION: At baseline, adults with ADHD were more likely to have impaired emotional control than normative subjects. In the adult ADHD patients, atomoxetine treatment was associated with improvements in emotional control, as well as in core ADHD symptoms and quality-of-life.

Effects of repeated treatment with MDMA on working memory and behavioural flexibility in mice.

Repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) produces dopaminergic neurotoxicity in mice. However, it is still not clear whether this exposure induces deficits in cognitive processing related to specific subsets of executive functioning. We evaluated the effects of neurotoxic and non-neurotoxic doses of MDMA (0, 3 and 30 mg/kg, twice daily for 4 days) on working memory and attentional set-shifting in mice, and changes in extracellular levels of dopamine (DA) in the striatum. Treatment with MDMA (30 mg/kg) disrupted performance of acquired operant alternation, and this impairment was still apparent 5 days after the last drug administration. Decreased alternation was not related to anhedonia because no differences were observed between groups in the saccharin preference test under similar experimental conditions. Correct responding on delayed alternation was increased 1 day after repeated treatment with MDMA (30 mg/kg), probably because of general behavioural quiescence. Notably, the high dose regimen of MDMA impaired attentional set-shifting related to an increase in total perseveration errors. Finally, basal extracellular levels of DA in the striatum were not modified in mice repeatedly treated with MDMA with respect to controls. However, an acute challenge with MDMA (10 mg/kg) failed to increase DA outflow in mice receiving the highest MDMA dose (30 mg/kg), corroborating a decrease in the functionality of DA transporters. Seven days after this treatment, the effects of MDMA on DA outflow were recovered. These results suggest that repeated neurotoxic doses of MDMA produce lasting impairments in recall of alternation behaviour and reduce cognitive flexibility in mice.

Disruption of prepulse inhibition by 3,4-methylenedioxymethamphetamine (MDMA): comparison between male and female wild-type and 5-HT(1A) receptor knockout mice.

The aim of this study was to investigate the involvement of serotonin-1A (5-HT(1A)) receptors in the effects of 3,4-methylenedioxymetamphetamine (MDMA) on prepulse inhibition of acoustic startle (PPI) by comparing male and female wild-type (WT) mice and 5-HT(1A) receptor knockout (1AKO) mice. MDMA dose-dependently decreased PPI in male and female mice although female mice were more sensitive at the 100-ms inter-stimulus interval (ISI). In male mice, 10 mg/kg MDMA disrupted PPI in 1AKO but not in WT controls. There was no genotype difference at higher or lower doses of MDMA. In female mice, there was no difference between genotypes at any dose of MDMA. Average startle was reduced by 10 mg/kg and 20 mg/kg MDMA similarly in male and female mice and all genotypes. These results show an involvement of 5-HT(1A) receptors in the effect of MDMA on PPI in male, but not female mice.

A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem. METHODS: Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. RESULTS: Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory (p = 0.053) and motor subscales (p = 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity. CONCLUSION: Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.

In vivo canine model comparison of cardiovascular effects of antidepressants milnacipran and imipramine.

Milnacipran is a specific serotonin and norepinephrine reuptake inhibitor, which has been widely used against major depressive episodes. In this study, cardiovascular effects of milnacipran were assessed in comparison with those of a typical tricyclic antidepressant imipramine using the halothane-anesthetized dogs. Milnacipran (n = 6) or imipramine (n = 6) was intravenously administrated in three escalating doses of 0.1, 1 and 10 mg/kg over 10 min with a pause of 20 min between the doses. Clinically relevant plasma concentrations were obtained after 0.1-1 mg/kg of milnacipran in this study, whereas therapeutic dose and plasma concentration of imipramine were reported to be similar to those of milnacipran. The low and middle doses of milnacipran hardly affected cardiohemodynamic or electrophysiological variables except that they slightly increased vascular tone and ventricular contraction, whereas same doses of imipramine delayed repolarization process without affecting the other variables. The high dose of both milnacipran and imipramine induced similar extent of negative chronotropic, inotropic and dromotropic effects together with vasoconstriction and repolarization delay. Thus, the effects of milnacipran may be more selective for cardiohemodynamics than for repolarization delay, whereas reverse will be true for imipramine, supporting lack of clinical report of patients with milnacipran-induced long QT syndrome unlike imipramine.

Effects of acute and sustained administration of the catecholamine reuptake inhibitor nomifensine on the firing activity of monoaminergic neurons.

Nomifensine potently inhibits the reuptake of norepinephrine and dopamine in vitro. It is one of few antidepressants with marked potency to block dopamine reuptake that has ever been used clinically. Acute and sustained administration of nomifensine was investigated on the firing of monoaminergic neurons to understand its mechanism of action. In vivo extracellular recordings of locus coeruleus, ventral tegmental area and dorsal raphe nucleus neurons were obtained from male Sprague-Dawley rats. The intravenous injection of nomifensine in the locus coeruleus and ventral tegmental area yielded ED(50) values of 40 +/- 1 and 450 +/- 41 microg/kg, respectively, suggesting that nomifensine directly acted upon dopamine and norepinephrine neurons, since these values are proportional to its affinities for norepinephrine and dopamine transporters. There was no effect on 5-HT neurons. Nomifensine (5 mg/kg/day, subcutaneous, using minipumps) potently and significantly inhibited dopamine neuronal firing in the ventral tegmental area after 2 days, with recovery to normal after the 14-day treatment due to D(2) autoreceptor desensitization. Norepinephrine neuronal firing in the locus coeruleus was significantly decreased after 2 and 14 days. A significant increase in dorsal raphe nucleus 5-HT neuronal firing was seen after a two-day regimen, and remained elevated after 14 days. Desensitization of the 5-HT(1A) receptor on 5-HT neurons of the dorsal raphe nucleus occurred after two days of nomifensine administration. Nomifensine likely treated depression by acting on dopamine, norepinephrine and 5-HT neurons, highlighting the importance of the functional connectivity between these three monoaminergic systems.

[My child is so restless]. / Wenn Kinder ständig stören: Erziehungsfehler oder Krankheit?

Hyperkinetic or attention deficit hyperactivity disorders (ADHD) are characterized by three symptoms: attention deficit, hyperactivity and impulsiveness. For some patients, intensive, continuous counselling or behaviour therapy leads to adequate success. If this is not effective, drug treatment using stimulants such as methylphenidate or the selective norepinephrine reuptake inhibitor atomoxetine is indicated.

Reboxetine in therapy-resistant enuresis: results and pathogenetic implications.

OBJECTIVE: To investigate whether the norepinephrine reuptake inhibitor reboxetine is effective as a non-cardiotoxic alternative to imipramine in the treatment of therapy-resistant enuresis. MATERIAL AND METHODS: Twenty-two children with severely socially handicapping enuresis resistant to urotherapy, the enuresis alarm, desmopressin and anticholinergics (all children had tried all these treatments) were given reboxetine, 4-8 mg at bed-time, for compassionate reasons. RESULTS: Thirteen of the children (59%) achieved complete dryness with reboxetine, either as monotherapy or combined with desmopressin. Side-effects were minor and did not lead to discontinuation of treatment. CONCLUSIONS: Although the results of this study need to be confirmed in randomized, placebo-controlled trials, reboxetine may prove to be a useful treatment for therapy-resistant nocturnal enuresis.

Effects of acute and chronic administration of selective monoamine re-uptake inhibitors in the rat forced swim test.

The rat forced swim test (FST) is a model that is used extensively as a screening test for antidepressant activity. It has previously been reported that thorough analysis of behaviour in this model reveals two distinct types of active response - climbing and swimming - and that these are separately evoked by re-uptake inhibitors selective for noradrenaline (NA) and serotonin (5-HT), respectively. In the present study, utilising re-uptake inhibitors selective for NA, talsupram, and 5-HT, 5-chloro-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)- phthalan (Lu 10-134-C), we examined if this scoring technique could detect the antidepressant potential of a selective serotonin re-uptake inhibitor (SSRI), and whether re-uptake inhibitors selective for distinct monoamine systems induce exclusive behavioural responses. We also analysed if chronic antidepressant administration for three weeks was more effective than acute treatment. We found Lu 10-134-C (40 mg/kg; PO) to be behaviourally active in this paradigm. Although treatment with talsupram (40 mg/kg; PO) resulted solely in climbing behaviour, Lu 10-134-C induced both climbing and swimming behaviour. However, chronic pre-treatment with either re-uptake inhibitor (20 mg/kg; twice daily; PO) failed to augment the response observed with acute treatment. Similarly, chronic administration of either compound was without effect on the basal, or stress-induced, serum corticosterone concentrations or anterior pituitary (AP) preproopiomelanocorticotropin (POMC) mRNA expression. These results suggest that selective monoamine re-uptake inhibition produces distinct, but not necessarily exclusive, behavioural responses in the forced swim test.

The impact of heterogeneity on the diagnosis and treatment of interstitial cystitis / O impacto da heterogeneidade no diagnóstico e tratamento da cistite intersticial

A cistite intersticial (CI) é uma doença cuja etiologia permanece desconhecida. A CI é um dos estados mais incômodos na prática urológica. Geralmente afeta mulheres, que apresenta sintomas de dor ao encherem a bexiga e freqüência urinária. A CI é uma síndrome heterogênea e é, freqüentemente, dividida em dois subtipos. Comparada à CI clássica, a do tipo näo-ulcerativa difere por apresentar aspectos sintomáticos, endoscópicos e histológicos diferentes, além da resposta aos vários tipos de tratamento. Esta revisäo é uma introduçäo à síndrome da CI, no que diz respeito a características clínicas e critérios de diagnóstico. Uma variedade de modalidades de tratamento têm sido sugeridas ao longo dos anos, e säo aqui revisadas e avaliadas, entre as quais estäo a hidrodistençäo da bexiga, a terapia de instilaçäo intravesical, a medicaçäo oral e a estimulaçäo elétrica transcutânea do nervo, a ressecçäo transuretral do tecido doente da bexiga, a cistectomia supratrigonal seguida de enterocistoplastia e derivaçäo urinário.

Effect of acute, short- and long-term milnacipran administration on rat locus coeruleus noradrenergic and dorsal raphe serotonergic neurons.

The effect of milnacipran on the firing activity of dorsal raphe serotonin (5-HT) neurons and locus coeruleus norepineprine (NE) neurons was assessed using extracellular unitary recording in chloral hydrate anesthetized rats. A 2-day treatment with milnacipran (20 or 60 mg/kg/day, s.c.) markedly decreased the firing rate of NE neurons, and it remained reduced after a 7- or a 14-day treatment. Although the suppressant effect of the alpha2-adrenergic agonist clonidine on the firing rate of NE neurons was markedly reduced following long-term milnacipran (60 mg/kg/day x 14 days, s.c.), that of NE remained unchanged. The firing rate of 5-HT neurons was reduced following a 2-day treatment with milnacipran (20 mg/kg/day, s.c.), but there was a partial recovery after a 7-day treatment (20 mg/kg/day, s.c.) and a complete one after a 14-day treatment (20, 40 or 60 mg/kg/day, s.c.). The suppressant effect of 5-HT and of the 5-HT1A agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) on the firing rate of 5-HT neurons was also unaltered after milnacipran (60 mg/kg/day x 14 days, s.c.). The latter milnacipran treatment did not affect the uptake of [3H]5-HT but it inhibited that of [3H]NE by 30% in hippocampal slices. The NE system was thus investigated in an attempt to explain the effects of milnacipran on the firing activity of 5-HT neurons. Acute injection of milnacipran suppressed the firing activity of 5-HT neurons (with an ED50 of 5.7+/-1.5 mg/kg, i.v.), but not in NE-denervated rats. Furthermore, the inhibitory effect of clonidine on 5-HT neuron firing activity was markedly reduced by the long-term milnacipran treatment, whereas the inhibition of electrically evoked release of [3H]NE as well as that of [3H]5-HT produced by the alpha2-adrenoceptor agonist UK 14.304 from preloaded mesencephalic slices containing the dorsal raphe was unaltered. The latter results indicate that the alpha2-adrenergic autoreceptor and heteroreceptor were unaffected in the raphe area by milnacipran. In conclusion, milnacipran had profound effects on the function of 5-HT and NE neurons, and the mechanism by which 5-HT neurons regained their normal firing during milnacipran treatment appeared to implicate the NE system.