This remarkable and immediate antidepressant modality has been recognized for 30 years, but is little used in everyday clinical practice. Perhaps it is the paradox of taking sleep away from the depressive insomniac that has a negative connotation for both patient and psychiatrist (“wake therapy” would be a more positive alternative name). Perhaps it is also the short-term nature of the response

that has hindered its use, though the magnitude of the clinical changes brought about by sleep deprivation still remain highly intriguing and may provide clues for understanding the pathophysiology of depression. Sleep deprivation Inhibitors,research,lifescience,medical is the paradigm par excellence for depression research: rapid, nonpharmacological, and short lasting. It may be the nonpharmacological Inhibitors,research,lifescience,medical nature of sleep deprivation (it cannot be patented) that has contributed to its status as an “orphan drug.”67 It is surprising that no pharmaceutical company has focused on this model to search for that much-needed rapid-acting antidepressant.8 This lack may be remedied in the future; new research reveals that, whereas Inhibitors,research,lifescience,medical sleep induces very few genes, wakefulness increases expression of several groups of genes,68 and here comparisons with

the effects of antidepressant drug treatment may narrow down the candidates. Some committed proponents of sleep deprivation have recognized its clinical usefulness to initiate rapid improvement, particularly in Inhibitors,research,lifescience,medical the most severely depressed

patients in whom time is of the essence. Sleep deprivation is effective in all diagnostic subgroups of depression. The problem is the relapse after recovery sleep, and new strategies have sought treatments to prevent this. Response appears to be well maintained by treatment with lithium, antidepressants (in particular SSRIs), or the 5-HT1A receptor antagonist pindolol, Inhibitors,research,lifescience,medical as well as nonpharmacological adjuvants such as repetitive transcranial magnetic stimulation (rTMS),69 light therapy, or phase advance of the sleep-wake cycle, or various combinations thereof (see, for example, reference 36 and 70, reviewed in reference 8; Table I). Light therapy Light therapy can be considered to be the most successful clinical application of circadian MycoClean Mycoplasma Removal Kit rhythm concepts in psychiatry to date. Light is the treatment of choice for SAD.71 The quality of recent SAD studies has been BYL719 datasheet exemplary, and the response rate is well above placebo (in fact, superior to analogous trials with antidepressant drugs).72 The success of this nonpharmacological treatment has been astonishing, but it has taken rather long for light therapy to be accepted by establishment psychiatry,72 and trials of other indications are still in the research phase. Its very success in SAD has limited use in other forms of depression (characterized as “it’s a chronobiological treatment for a chronobiological subset of depressive patients”).

31 The relatively favorable side-effect

profile of pregabalin makes it another useful treatment option in GAD.7 Current treatment guidelines recommend a dose range of 150 to 600 mg/day for adult patients.9 Antipsychotic agents have also been studied as monotherapy in GAD. There is evidence that the atypical antipsychotic quetiapine is more effective than placebo in improving Inhibitors,research,lifescience,medical clinical response and remission rates in patients with GAD.32,33 However, risk:benefit ratio remains a concern given the possibility of adverse events such as metabolic syndrome. On the other hand, these agents may have a role to play in treatment-selleck chemicals refractory patients, with evidence suggesting that various antipsychotic agents may be beneficial as augmentation strategies in those with treatment-refractory

GAD.34,35 Indeed, in clinical practice a significant proportion of patients with GAD fail either to receive appropriate therapy or to respond to first-line pharmacotherapy. An immediate Inhibitors,research,lifescience,medical step in the management of the latter group of patients is to ensure that diagnosis is correct, that psychiatric and medical comorbidity has not been overlooked, and that the trial is of sufficient duration and dosage.36 Next steps include switching to a different agent, or augmentation.8,9,16,37 There are few switch studies in GAD, but the literature on depression suggests that a different SSRI or an agent from a different class Inhibitors,research,lifescience,medical might be Inhibitors,research,lifescience,medical useful in refractory cases. Pharmacotherapy augmentation strategies include the addition to SSRI/SNRI treatment of buspirone,29 pregabalin,38 or low doses of atypical antipsychotics.35,34 Although data on the value of combined pharmacotherapy and psychotherapy in GAD is surprisingly limited,39 psychotherapy

augmentation strategies may also be considered. In addition to the glaring absence of data on how best to approach the treatment-refractory GAD patient, a number of other gaps in the literature deserve to be highlighted. First, most treatment data on GAD derive from trials of GAD patients without comorbidity recruited by academic centers; there are few data Inhibitors,research,lifescience,medical on effectiveness in real-world settings, where the vast majority of patients with GAD present, often with a range of comorbid psychiatric and medical ALOX15 disorders and symptoms. Second, there are relatively few data on “special” populations, including children and adolescents and geriatric patients with GAD,40,41 or on whether early pharmacotherapy of GAD is able to prevent subsequent onset of mood and substance-use disorders.42 Several promising future lines of investigation of GAD have, however, been opened up by ongoing work on the psychobiology of GAD. Work on the role of the glutamate system in fear extinction,43 on the role of neuropeptides in stress responses,44 and on a range of second messenger or other downstream systems,45,46 for example, may ultimately lead to new treatments for GAD.

Surgery Rats were anesthetized with urethane (1.5 g/kg, i.p.) and placed in a stereotaxic instrument in the skull flat position and body temperature was monitored and maintained at 37°C by a thermoregulated heating pad (FHC, Bowdoin, ME). Electrode placements were mapped according to the coordinates found in the Paxinos and Cisplatin solubility dmso Watson brain atlas (Paxinos and Watson 1998) for the perforant path (7.2 mm posterior and 4.1 mm

lateral from bregma) and for dentate gyrus (3.5 mm posterior and 2.0 mm lateral). A concentric bipolar stimulating electrode (NE-100; Kopf Instruments, Tujanga, CA) was lowered into the perforant path (~3.0 mm from brain surface). A conjoined Inhibitors,research,lifescience,medical electrode/cannula assembly was constructed of a single stainless steel recording electrode (0.5–1 MΩ; FHC Inc.) and a 22-gauge stainless steel guide cannula (Plastics One, Roanoke, VA). The cannula and electrode, secured together with regular epoxy, were aligned so that a 28 gauge injection cannula, when inserted into the guide cannula would sit, ~25 μm

lateral Inhibitors,research,lifescience,medical and 50 μm dorsal to the tip of the electrode. This ensured that the concentration delivered at the recording site was as close as possible to the concentration Inhibitors,research,lifescience,medical infused. The internal injection cannula (Plastics One) was attached to a solution-filled (ISO in aCSF or aCSF only) autoanalyzer tubing and a dH2O-filled 5 μL microsyringe. The total injection (guide and internal cannula) and recording assembly was then slowly lowered into the granule cell layer of the dentate gyrus (~2.5–3.5 mm from brain surface). The electrode placement was localized Inhibitors,research,lifescience,medical to the granule cell

layer by monitoring the response to 0.2 ms test pulses delivered to the perforant path and by maximizing the positive-going fEPSP and negative-going population spike. Stimulation and recording procedures Single monophasic square wave test pulses (0.2 ms) were delivered to the perforant path using an interstimulus interval of 30 sec (Neurodata Instruments, New York, NY). The evoked responses were amplified, filtered (0.3 Hz to 3 kHz; P5-11; Grass Instruments, West Warwick, Inhibitors,research,lifescience,medical RI), and digitized at a rate of 10 kHz and stored online for analysis. At the commencement, and at the termination of the recording period, an input–output current intensity series (I/O curve) was determined. Dichloromethane dehalogenase This consisted of sampling three evoked responses at interstimulus intervals (ISI) of 10 sec, at each current level from 100 to 1000 μA at 100 μA intervals. On the basis of the initial I/O curve, a current intensity for baseline current stimulation was chosen at the intensity that produced approximately 50% of the maximal population spike. DataWave software (DataWave Technologies; Loveland, CO) was used to collect waveforms and analysis was performed after the experiments (see Data Analysis and Statistics). Baseline-evoked responses were recorded every 30 sec for at least 1 h before ISO infusion began.

In case 2 valproic acid was not able to stop rapid recurrences due to selleck chemical lithium discontinuation. The rapid cycling was stopped with the addition of memantine. In case 3 the patient had a rapid cycling bipolar II disorder treated with lithium and lamotrigine with poor response. She had to discontinue both drugs because of adverse

reactions. The rapid cycling course was stopped with memantine and a small dose of valproic acid. Moreover, we previously observed that the drug might be effective Inhibitors,research,lifescience,medical also as monotherapy in the prevention of affective recurrences occurring after lithium discontinuation [Serra et al. 2013]. Although we observed a good response to memantine administration 4 months after lithium discontinuation (case 2), the mood-stabilizing effect of memantine seems to be more effective (as a monotherapy [Serra et al. 2013]) when it is administered before lithium discontinuation Inhibitors,research,lifescience,medical (case 3: 9 months before). In case 1 memantine was added immediately after lithium discontinuation and the stabilization of the rapid cycling bipolar course was

obtained with the reinstatement of a subtherapeutic dose of lithium (serum level 0.2 mmol/L). Although Inhibitors,research,lifescience,medical memantine is used in combination with another mood stabilizer, it does not diminish the clinical relevance of our observations. In our patients lithium discontinuation led to a malignant course that did not respond to valproic acid as monotherapy. We observed a potent mood-stabilizing action of the combination of memantine with lamotrigine or valproic acid, drugs that usually are not able to stop the rapid Inhibitors,research,lifescience,medical cycling course when used as monotherapy [Kemp et al. 2012]. Moreover, even lithium, before its discontinuation and the addition of memantine, was administered in combination with another mood stabilizer,

because of the severity of the bipolar disorder course. These case histories are consistent with our previous observations suggesting that memantine has a long-lasting Inhibitors,research,lifescience,medical mood-stabilizing effect. As to the mechanism of action, we have observed that memantine prevents the bipolar-like behaviour induced by antidepressants in rats [Demontis et al. 2012], and suggested that the prevention of dopamine antagonist receptor sensitization (mania) by memantine results in an antimanic effect, which, in turn, prevents the following desensitization associated PDK4 with depression [Serra, 2010]. Regardless of the mechanism of action, these case reports confirm our previous observations, and suggest that memantine may be considered a useful replacement for lithium in the prevention of affective recurrences observed in patients who have to discontinue long-term lithium prophylaxis because of severe medical complications. Acknowledgments The authors would like to thank Denis Greenan for his valuable contribution to the drafting of the paper.

Scores on the QLS and the SIP-modified version improved uniformly in the three groups after the switch. There were no significant differences between the three novel antipsychotics. In another comparative open-label study, Ho et al28 did not find differential effects of risperidone and olanzapine on patients’ quality of life. They included 42 schizophrenic (DSM-IV criteria42) inpatients; 21 of them were started on risperidone (mean baseline dose 5.7 mg/day) and the remaining 21 on olanzapine (mean baseline dose 14.4 mg/day) based on Inhibitors,research,lifescience,medical the treating psychiatrist’s decision.

Quality of life was assessed using the Psychiatric Status You Currently Have-Baseline version (PSYCH-BASE)50 and its longitudinal follow-up version, the PSYCH-UP. The PSYCH-BASE is a structured interview with eight quality of life indices: occupational impairment, financial Inhibitors,research,lifescience,medical dependence, impairment in performance of household duties, relationship impairment with family members and with friends, enjoyment of recreational activities, satisfaction, and overall psychosocial functioning. A total of 26 patients

(13 in each group) completed the 6-month followup interview. At follow-up there were no statistically differential effects between the two treatments on the eight quality of life indices. Significant Inhibitors,research,lifescience,medical improvements at time of follow-up were reported on overall psychosocial functioning in the risperidone group and on impairment in performance of household Brefeldin A duties in the olanzapine group. Tran et al29 compared olanzapine with risperidone in an international, 28-week, double-blind, randomized study. Three hundred and thirty Inhibitors,research,lifescience,medical nine (olanzapine n=172, risperidone n=167) schizophrenic, schizophreniform, or schizoaffective patients

(DSM-IV criteria42) were assessed using the QLS.35 In both treatment groups, statistically significant improvements were observed on the QLS total score and on the four subscales from baseline to end point. Olanzapine demonstrated significant greater improvement in QLS interpersonal relations subscale scores than risperidone. Risperidone Bobes et al31 studied Inhibitors,research,lifescience,medical the effect of risperidone monotherapy maintenance treatment on the quality of life of 318 schizophrenic outpatients (The ICD-10 Classification of Megestrol Acetate Mental and Behavioral Disorders, Clinical descriptions and diagnostic guidelines, ICD-1051 criteria) who had been previously treated with other neuroleptics. Quality of life was assessed employing the SF-36.48 At month 8, significant improvement was observed in all SF-36 scale scores and in the summary measures. The greatest improvement was observed in the role emotional scale, followed by the role physical and the social functioning. Hertling et al30 compared the impact of risperidone and flupenthixol upon the quality of life of schizophrenic inpatients and outpatients with mainly negative symptoms.

58,59 Over the last decade LTG was established as the major medication in women with see more epilepsy who plan pregnancies, due to its favorable safety profile, which will be discussed in a later section. If one considers this development, it is surprising that it took several years until a Danish group discovered the pronounced and clinically relevant influence of oral hormonal contraceptives on LTG60 This was soon confirmed by other studies.61-64 It has been claimed

that ethinyl estradiol, but not progestérones, are responsible for this reduction of the LTG serum concentration.65 In women on hormonal contraception Inhibitors,research,lifescience,medical and LTG it is therefore reasonable to intensify therapeutic drug monitoring and either to increase the overall dosage to overcome seizure relapses during the fall of the LTG serum concentration or to consider a continuous Inhibitors,research,lifescience,medical hormonal contraception without a placebo interval. Other methods of hormonal contraception It has been suggested that the intramuscular application of sex steroids that bypasses the hepatic first-pass metabolism may be a way to achieve a higher contraceptive safety in patients on enzyme-inducing AEDs. However, the data on this issue are controversial, and not

Inhibitors,research,lifescience,medical sufficient. It was shown that the efficacy of levonorgestrel is reduced.66,67 Data on medroxyprogesterone are not yet available.68 For safety reasons it was suggested that, the injection interval should be shortened from 12 to 10 weeks.54 Whether or not this is really effective is not absolutely sure.25 Pregnancy – the mother’s side The course of epilepsy during pregnancy There are no reliable predictors of the course of epilepsy Inhibitors,research,lifescience,medical during pregnancy.55 It has been reported that the

risk of seizure relapses corresponds to the seizure type, since an increase in seizure frequency was significantly more often found in patients with complex partial seizures than in cases with generalized tonic-clonic and absence seizures.69 However, this series of 79 pregnancies is certainly too small to draw reliable conclusions. Similarly, the observation Inhibitors,research,lifescience,medical that a high seizure frequency prior to the pregnancy or the duration of the disease correlate with a higher risk of increased seizure frequencies during pregnancy,70 result from statistically unconvincing sample and sizes, and have been questioned somewhat.71 Several prospective pregnancy registries are being maintained in order to generate more reliable data on the course of pregnancy in patients with epilepsy and on the impact of AEDs in epileptic and in nonepileptic women. In most instances the course of epilepsy does not change during pregnancy. According to several previously published surveys, the seizure frequency remains stable in 50% to 85% of pregnancies of epileptic women. 16,24,49,71,72 The assessment of 1956 pregnancies in 1882 patients revealed that 58.3% remained seizure-free throughout the whole period of pregnancy.