By I. Roy. Manhattanville College.

These simulation PSTHs are normalized for 100 trials buy epitol 100 mg fast delivery, as for the empiric data purchase 100 mg epitol amex. Note that coupling reduces tonic (baseline) LC activity but in- creases phasic (transient) response to target stimuli discount epitol 100 mg line, captur- ing the phasic mode of LC neurons in our recordings. The role of locus coeruleus in the regulation of cognitive performance. First, they support the view that the LChas an important role in attentional processes, and that pathol- ogy in LCfunction could contribute to mental disorders with attentional components [e. These results also indicate that alterations in coupling among widely projecting neurons can have profound mental and behavioral consequences, offering a new dimension for analyzing the function of highly divergent modulatory brain systems. Finally, these results, in view of other findings that electrotonic coupling can be rapidly modulated by neuro- FIGURE 4. Simulation of behavioral performance by modu- transmitter inputs (55), indicate that coupling may be a lated coupling among locus ceruleus (LC) neurons. Left: Graphs valuable new target for pharmaceutical development in neu- showing higher rate of false alarm errors (% FA) during epochs of poor versus good performance by monkeys in the visual dis- ropsychopharmacology. No differences were noted in the percent- age of hit responses during the various levels of performance, as misses were rare. Right: Graphs showing higher % FA in the Opiate Withdrawal simulated data from our model (33) during epochs of low versus high coupling among LC neurons. Note similarity to empiric data A long series of studies has implicated the LCsystem in at left. Recent work has Chapter 4: Norepinephrine 51 shed light on molecular and cellular changes that occur in way could be involved also in the psychiatric disorders asso- LCneurons during long-term opiate exposure that may un- ciated with sleep dysfunction (e. It is generally acknowledged that the bulk of this hyperactive LCresponse is mediated by glutamate inputs CorticalInfluences on LC Activity from the PGi (11,57,58). However, a possible intrinsic Tract-tracing studies have revealed that the prefrontal cortex source of withdrawal-induced hyperactivity in LCneurons may directly innervate LCneurons. Our retrograde and an- has been somewhat controversial. Although some studies terograde studies in rat find a projection from the medial find no evidence for withdrawal-induced activation of LC prefrontal cortex to the extranuclear peri-LCdendritic zone neurons in slices taken from morphine-dependent rats (59, (69). Another of our studies confirms a projection from the 60), others have presented evidence for such intrinsically cingulate cortex to the LCin the monkey (32). Our study with these findings, additional experiments have revealed of local intra-LCmicroinfusion of opiate antagonists in prominent effects of cortical stimulation on LCactivity. As morphine-dependent rats has confirmed the likelihood that shown in Fig. Different results were obtained with chemical stimulation (70). We studies have suggested different mechanisms for this locally also found this activation to be mediated by glutamate re- mediated withdrawal effect. In contrast, Sara experiments consistent with the possibility that long-term and Herve-Minvielle (72) reported that medial prefrontal morphine exposure causes a sustained increase in a tetro- stimulation in rats results in inhibition of LCactivity. Pro- dotoxin-insensitive Na current, linked to the increase in cedural differences may underlie the different results. In cAMP, adenylate cyclase activity, and cAMP response ele- particular, the study by Sara and Herve-Minvielle used keta- ment-binding protein (CREB) that occurs in the LC during mine anesthesia, a potent glutamate antagonist. In their view, this inward current causes LC results may indicate an underlying inhibitory effect of pre- hyperactivity when the inhibitory influence of morphine frontal activation on LCactivity when the more potent glu- is removed during withdrawal. Our recent in vitro studies tamate-mediated excitation is antagonized. These results indicate that results reveal that the prefrontal cortex can strongly influ- long-term opiate administration produces a decrease in K ence activity of LCneurons. The decreased K conductance during long-term morphine administration The proposed role of the NE–LCsystem in arousal was may be a direct compensatory response to the increased K confirmed by Berridge and Foote (73), who showed that conductance evoked by acute opiates (49). In either case, it local activation of LCneurons by microinjection of betha- seems clear that the local component of withdrawal-induced nechol produces EEG activation in the halothane-anesthe- activation of LCneurons is small compared with the strong tized rat. Similar studies demonstrated that LCinactivation excitation evoked by the increased glutamate input from by local microinfusion of clonidine decreases EEG arousal the PGi (see above). Additional experiments revealed that the arousing ef- fects of LCstimulation are mimicked by stimulation of adrenoceptors within the medial septum and are blocked Hypocretin/Orexin by -receptor antagonists infused into this area (75). Con- As discussed above, the hypothalamic neuropeptide hypo- tinuing studies along these lines confirmed that local LC cretin, which is strongly implicated in sleep regulation, stimulation in waking animals increases EEG and behav- densely innervates the LCin rat and monkey (21). Additional studies found, how- studies have revealed that this peptide activates LCneurons ever, that septal infusion of antagonists in unanesthetized both in vitro (21,67) and in vivo (68). The activation is animals does not decrease arousal (77). Thus, in the waking associated with a mild depolarization but is independent of rat, actions at other NE or non-NE receptors may also be tetrodotoxin and Ca2 (67). Together, these studies indicate that tentative conclusion that hypocretin activates LCneurons LCactivity is an important regulator of EEG arousal, and by decreasing a resting potassium conductance (67). Over- that these effects are mediated, at least in part, by receptors all, the results are important because they indicate a possible in the medial septum area. Additional studies are needed pathway and transmitter mechanism by which the LCbe- to determine the precise location of these actions and what comes activated during arousal from sleep, which may in other systems and receptors may be important for maintain- turn help to drive a sleep-to-waking transition. Activation of locus ceruleus (LC) neuron by stimulation of medial prefrontal cortex (PFC) in rat.

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The effective dose is usually in the range of 600-1200 mg/day cheap 100 mg epitol otc. The optimal therapeutic carbamazepine plasma concentration for mood stabilization is yet to be established discount epitol 100mg overnight delivery. Some psychiatrists use the levels recommended for epilepsy prophylaxis (17-50 micromol/L) purchase epitol 100mg with visa. Others increase the dose until side-effects intervene, and then reduce the dose such that the side-effects are tolerable. SODIUM VALPROATE Sodium valproate was initially marketed as an anti-convulsant. Following the success of carbamazepine as a mood stabilizer, sodium valproate was found to be effective. In both acute mania and long term maintenance, sodium valproate is as effective as lithium and carbamazepine (Macritchie et al, 2004; Cipriani et al, 2013). It may be superior to lithium in the treatment of rapid cycling and mixed mania. In comparison to lithium, sodium valproate treatment provides comparable medical costs, clinical and quality of life outcomes (Revicki et al, 2005), with generally fewer side effects. The mode of action is uncertain; as with other mood stabilizers, there is blocking of sodium channels. In addition, there is potentiation of gamma aminobutyric acid (GABA) and effects on intracellular protein regulation. Animal studies show sodium valproate is neuroprotective, protecting neurones against glutamate induced excitotoxicity (Chuang, 2005) and promotes neurogenesis and neurite growth (Chen & Manji, 2006). Psychiatric uses  Acute management of mania  Prophylactic management of mania  Schizoaffective disorder  Management of bipolar depression (No controlled studies) Side-effects Common  Nausea  Vomiting  Abdominal pain  Diarrhoea  Tremor  Somnolence  Dizziness  Weight gain  Hair loss (reversible on discontinuation of valproate) Pridmore S. Haemodialysis may be necessary to eliminate the drug. Sodium valproate is associated with a 1% risk of neural tube defects, such as spina bifida when taken during the first trimester of pregnancy. Other congenital malformations have been reported, and the overall risk may be as high as 11% (Ernst and Goldberg, 2002). Gentile (2012) states risk to the unborn is unacceptable. Sodium valproate passes into the breast milk at less than 10% of the serum concentration. The effects on the nursing child are uncertain, but the risk is considered to be very low. Drug interactions Amitriptyline (TCA) and fluoxetine (SSRI) may increase valproate concentration, possibly by inhibiting valproate metabolism. Aspirin may elevate the free fraction of valproate, by displacing from protein-binding sites, thereby increasing the effects on the central nervous system. Valproate can displace diazepam, carbamazepine and warfarin, thereby increasing the activity of these drugs. Dosage and monitoring Blood count, liver function tests, and if appropriate, pregnancy testing. The starting dose is 250-1000 mg per day, in two divided doses. Dose can be increased every 2-3 days, depending on response and tolerance. In acute mania, oral loading of 20mg/kg can be given on the first day, to achieve rapid therapeutic levels. Patients who are not acutely manic may have difficulty tolerating this load. The usual therapeutic concentration is 50-150 micrograms/mL (blood drawn 12 hours after the last dose). It appears (in contrast to the other mood stabilizers) to be more effective in preventing relapse into depression than relapse into mania (Calabrese et al, 2003; Gitlin and Frye 2012). Lamotrigine is a first line drug in the treatment of bipolar depression. A rash occurs in up to 6% of patients, and is a cause of discontinuation. Recent work suggests that the therapeutic response to lamotrigine is dependent on plasma concentration (Kagawa et al, 2014). Commence with caution: 25 mg/day for 2 weeks, at week 3 increase to 50 mg/day, at week 5, increase to 100 mg per day at week 6, 200 mg/day (maximum dose). ATYPICAL ANTIPSYCHOTICS AS MOOD STABILIZERS For as long as they have been available, the antipsychotics have been used to calm patients with acute mania. However, in recent times, many of the atypical antipsychotics have been used as mood stabilizers. Quetiapine Quetiapine has a favourable side-effect profile; sedation and weight gain being the main problems. Quetiapine as a monotherapy or as an adjunct to other agents is recommended by most guidelines as a first-line choice in both acute and maintenance therapy for bipolar depression (Suttaijt et al, 2014) and acute and maintenance therapy for mania. Olanzapine Olanzapine is widely used in the treatment of acute mania. It has been shown effective as a bipolar maintenance treatment (Tohen et al, 2005). Olanzapine is associated with significant weight gain (in most studies >50% of patients gain more than 5lb) and sedation. Other issues are increased risk of diabetes and hyperlipidemia.

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A over time as well as a tendency to intermittent rather than more recent 2-week double-blind placebo-controlled study consistent dosing (86) 100mg epitol for sale. This study showed improvements in subjective sleep latency and sleep duration with both active drugs best 100mg epitol, although there was some evidence for superiority of zolpidem during Antidepressant Drugs the second treatment week purchase 100mg epitol with amex. Finally, somnia include trazodone, tertiary tricyclic agents, and mir- a recent open-label trial of paroxetine for primary insomnia tazapine. These drugs clearly have diverse effects on neuro- in the elderly showed significant improvement in a multi- transmission, as reviewed in Chapter 79. In general, the variate measure of sleep quantity based on both diary and sedating properties of antidepressants are related to antago- polysomnographic sleep measures (96). For instance, fluvoxamine the treatment of insomnia. Some antidepressant drugs also has a relatively alerting effect relative to desipramine that can cause or exacerbate insomnia problems. Selective seroto- in turn is more alerting than amitriptyline (97,98). In addition, serotonergic specific antide- comparison of fluoxetine with trazodone showed that the pressants can lead to anomalous sleep stages characterized later drug was associated with more improvements in in- Chapter 133: Current and Experimental Therapeutics of Insomnia 1939 somnia symptoms, but also with a greater percentage of specific receptors in the suprachiasmatic nucleus of the hy- sedating events during the daytime (100). In addition, melatonin shifts circadian parisons between fluoxetine and nefazodone has consis- rhythms according to a phase response curve (110,111). Doses greater than 1 mg are likely to induce supraphysiologic concentrations. Clinical trials have Antihistamines employed doses ranging from. Antihistamines such as diphenhydramine and doxylamine During daytime administration, melatonin causes sleepi- are the most widely available over-the-counter preparations ness in fatigue and healthy subjects (112,113). The mechanism of action of these drugs in- ministered at night to healthy subjects, melatonin decreases volves inhibition of histamine H1 receptors. Histaminic sleep latency (114) and the number of awakenings, and neurons in the posterior hypothalamus promote wakeful- improves sleep efficiency in an experimental insomnia para- ness through interactions with ascending cholinergic nuclei digm (115). Inhibition Studies in insomnia patients have also yielded inconsis- of H1 receptors leads to decreased alertness and subjective tent findings. Single-night administration seems to produce sedation. The elimination half-life of diphenhydramine very little effect (116). Subjective sleep ratings showed no ranges from 3 to 5 hours, within increases in elderly persons. Trials of melatonin in elderly people have Despite their widespread use, a large body of well-docu- ranged from 1 to 21 days. The most consistent effect is mented research does not support the efficacy of antihista- reduced sleep latency with some evidence as well for reduced mines. Diphenhydramine 50 mg, improved subjective rat- nighttime wakefulness using sustained-released preparations ings of sleep quality, sleep time, sleep latency, and (119–122). In a carefully designed 14-day crossover trial, wakefulness after sleep onset in middle-aged subjects with immediate- and sustained-release melatonin were associated insomnia (103). Amore recent study comparing the effects with shortened sleep latency, but no change in sleep time, of lorazepam versus a combination of lorazepam plus di- sleep efficiency, wakefulness, or subjective sleep measures phenhydramine showed a slight advantage for the combina- (123). On most sleep measures, the two drug carefully evaluated. Melatonin has effects on reproductive preparations were fairly similar. Studies of antihistamines cycles in several mammalian species, and reports have indi- in elderly people demonstrate subjective sedative properties cated the potential for worsening of sleep apnea and im- comparable in magnitude to those of benzodiazepines and paired cognitive and psychomotor performance during day- confirmed by effects such as increased sleep time, decreased time administration. There are also some concerns regarding awakening, and shorter sleep latency (105,106). Adverse effects of antihistamines include a range of cog- nitive and performance impairments (107). The anticholin- Valerian Extract ergic effects of these medications may be of particular con- cern in elderly subjects. The relative safety and efficacy of Valerian extract is one of the most widely used herbal reme- antihistamines with more sustained use has not been exam- dies for insomnia. They contain a number of potentially active compounds, including sesquiterpenes and valepotriates. Data regarding its efficacy and safety have in these preparations (124,125). The study designs, doses, and outcome mea- cross the blood–brain barrier, so this is an unlikely mecha- sures used in melatonin trials have been quite variable and nism of action. Other potential actions include affinity for may contribute to inconsistent findings (108). In particular, four double-blind pla- on sleep and wakefulness may result from interaction with cebo-controlled studies have examined doses of 400 to 900 1940 Neuropsychopharmacology: The Fifth Generation of Progress mg of valerian extract over periods of time from 1 to 8 days, With regard to behavioral treatments, one of the major and in diverse subject populations ranging from healthy challenges is designing well manualized and 'exportable' young adults to elderly insomniacs (126–129). Subjective treatments that can be applied more readily in a variety of effects include decreased sleep latency and improved sleep treatment settings, including primary care settings. One study also reported decreased studies have begun to examine the optimal combination of subjectively rated awakenings (126). Findings from these studies are hampered by small be developed. These studies do not demonstrate the effi- from basic neuroscience sources. For instance, recent evi- cacy of valerian extract in most groups of individuals with dence has accumulated regarding the role of adenosine as primary insomnia. Relative underacti- Clinical studies have suggested a generally favorable side vity of adenosinergic neurotransmission could potentially effect profile for valerian extract; however, the sedative ef- result in reduced sleep drive.

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