2007; Kreuzer et al 2012b] In addition, many authors hypothesiz

2007; Kreuzer et al. 2012b]. In addition, many authors hypothesize that under normal conditions, dopaminergic

and serotonin receptor activity, which decrease and increase body temperature, sellekchem respectively, are balanced. Atypical antipsychotics block serotonergic receptors, thereby leading to unopposed activity of dopaminergic receptors and increasing the risk for developing hypothermia. In humans, atypical antipsychotics are linked with 55% of reported #http://www.selleckchem.com/products/FTY720.html keyword# hypothermia cases associated with antipsychotic medications [van Marum et al. 2007]. Olanzapine is an atypical antipsychotic primarily designed for the treatment of schizophrenia and bipolar disease, and is the most commonly prescribed antipsychotic for bipolar disease in the USA [Baldessarini et al. 2008]. There have been 44 cases of hypothermia linked to olanzapine in WHO’s adverse drug reaction database [van Inhibitors,research,lifescience,medical Marum et al. 2007], and a review of the available literature reveals 10 prior case reports of olanzapine-induced hypothermia, including 3 cases published in a series of antipsychotic-induced hypothermia (Table 1). Hypothermia related to olanzapine has been documented in patients from the age

of 0–90 years [van Marum et al. 2007: Table 2]. In the database, a diagnosis of schizophrenia is a risk factor for hypothermia and is a prevalent Inhibitors,research,lifescience,medical diagnosis among case reports [van Marum et al. 2007]. Other risk factors for hypothermia Inhibitors,research,lifescience,medical associated with antipsychotic use include medical conditions such as endocrine disease,

specifically hypothyroidism, and organic brain disease including developmental delay and epilepsy [Kreuzer et al. 2012b]. Combinations of antipsychotics as well as comedication with benzodiazepines or beta blockers may increase the risk, although it is unclear if the association is due to patients with more refractory illnesses being at higher risk of disordered thermoregulation Inhibitors,research,lifescience,medical [Kreuzer et al. 2012b]. Table 1. Comparison of published cases of olanzapine-induced hypothermia in the English literature. As with other antipsychotics, most of the cases of hypothermia AV-951 occur after initiation or dose increase of olanzapine, although no single unifying etiology has been identified. Of these case reports, only four patients had previously been taking olanzapine for at least a few weeks [Parris et al. 2001; Fukunishi, et al. 2003; Blass and Chuen, 2004; Rasnayake et al. 2011]. In one case, the patient had 1 day of the medication orally prior to developing hypothermia, but received an intramuscular dose prior to hypothermia [Hung et al. 2009]. In 5 out of the 10 cases, the patients received a one-time dose of olanzapine prior to developing hypothermia [Phan et al. 1998; Hägg et al. 2001; Kreuzer et al.

Four centers

participated in all or parts of the E-MOSAIC

Four centers

participated in all or parts of the E-MOSAIC-Feasibility-Study. Patients filled in the E-MOSAIC in a paper-pen and a palm version in random order. The compliance, time needed, and experiences of patients with the palm were assessed by a structured 2-page evaluation. 62 patients (median Inhibitors,research,lifescience,medical age 64y [30–85], 25 female) participated. 4 patients had visual impairment, 6 comprehension problems, and 1 pat was too tired. 3/62 patients did not complete E-MOSAIC. Median time to complete was 3minutes. 10 patients preferred paper and 28 palm, 16 had no preference; 50 patients agreed to continue using palm. Palm-based symptoms (VAS) were compared with a paper-based categorical symptom assessment (ESAS). Wilcoxon signed-rank tests showed no significant differences between palm and paper of 9 symptoms Inhibitors,research,lifescience,medical of element P (p-value: well-being 0.089, dyspnea 0.060, the remaining 7 symptoms 0.249-0.940), but for www.selleckchem.com/products/XL184.html nutritional intake different (a significant difference was found (.p=0.013). Test-retest (1hour, n=20) reliability of 9 symptoms and Inhibitors,research,lifescience,medical nutritional intake was satisfactory (Cronbach alpha 0.62 – 0.94). The E-MOSAIC intervention for this

6-week trial Although the E-MOSAIC incorporates a module offering the possibility for real-time measurement of clinical benefit response and showing it in the LoMoS the duration of this study of 6weeks treatment, classical clinical benefit

response will not be measured as an outcome, since it needs longer observation to fulfill the criteria. Patient population and Inhibitors,research,lifescience,medical setting Patients are eligible who receive anticancer treatment in palliative intention given weekly or biweekly or continuous in the outpatient setting, and routine care which typically includes weekly visits. The setting and routine processes Inhibitors,research,lifescience,medical of care include a personal professional nursing contact and a brief patient assessment before the patients visit at the selleckchem Tipifarnib oncologists. • The palliative intention of the anticancer Cilengitide treatment is defined as an expected tumor response rate≤20% according to literature. To operationalize this definition, a list of tumor types and treatment line was composed (e.g. second line non-small cell lung cancer). • Patients have to be symptomatic (symptoms measured by VAS: 0=best, 10=worst; average over last 24hours) by the cancer disease, defined as at least one ESAS symptom>= 3/10. • Patients have to be able to understand the language of the E-MOSAIC assessment and the study related information, written informed consent and the physician is able to communicate with the patient studied without major difficulties (i.e., culture, language, speech).

This is based on studies demonstrating that BDNF is increased by

This is based on studies demonstrating that BDNF is increased by stress in the mesolimbic dopamine system and has a depressive effect in the social

defeat model, and conversely, that ADT decreases BDNF in this reward pathway.79 These findings demonstrate that the expression and function of BDNF, and possibly other trophic factors, is circuitdependent and that findings in one region cannot be extrapolated to others. Antidepressants increase BDNF In contrast to the effects of stress, chronic, but not acute ADT increases the expression of BDNF Inhibitors,research,lifescience,medical in the hippocampus and frontal cortex.1,80-82 Induction of BDNF is observed with different classes of chemical antidepressants as well as electroconvulsive seizures.1,80,82,83 Other agents known to have antidepressant

efficacy also increase BDNF expression in the hippocampus, including a-amino-3-hydroxyl-5-methyl-4-isoxazole -propionic acid (AMPA) receptor potentiators, NMDA receptor antagonists, transcranial magnetic stimulation, and exercise,1 These Inhibitors,research,lifescience,medical findings indicate that increased expression of BDNF is a common target for different therapeutic strategies. Inhibitors,research,lifescience,medical Postmortem studies also demonstrate that BDNF levels are increased in the hippocampus of patients receiving antidepressant medication at the time of death, demonstrating the clinical relevance of ADT induction of BDNF.59 These effects are thought to occur via activation of cAMP and/or Ca2+-dependent BDNF Inhibitors,research,lifescience,medical gene transcription that are activated by ADT.8-186 Neuroprotective, neurogenic, and behavioral actions of BDNF The neuroprotective effects of BDNF have been well documented, primarily in cultured cell systems, but also in vivo. This includes studies demonstrating that BDNF increases survival and has neuroprotective actions in models of hypoxia, ischemia, selleck chem excitotoxicity, hypoclycemia, and inflammation87-91; for reviews Inhibitors,research,lifescience,medical see refs 92,93. As discussed above, hippocampal pyramidal cell dendrite complexity is decreased in BDNF Met allele or heterozygous deletion mutants.74

Similar effects have been observed in PFC pyramidal cells, and stress does not produce Anacetrapib further atrophy of apical dendrites in BDNF heterozygous deletion mutants, indicating that decreased BDNF underlies the effects of stress.73 These findings indicate that a full complement of functional BDNF is required for maintenance of normal dendritic arbor in both the hippocampus and PFC. BDNF has also been shown to AMN-107 influence hippocampal neurogenesis. Infusions of BDNF increase hippocampal neurogenesis,94,95 and BDNF is necessary for the survival of new neurons in response to ADT.96 The BDNF receptor, TrkB is also required for antidepressant induction of hippocampal neurogenesis, as well as the behavioral actions of antidepressants.97 BDNF has also been implicated in the behavioral actions of ADT.

64 The layer-specific changes in neuronal density and size ident

64 The layer-specific changes in neuronal density and size identified in mood disorders implies that both inhibitory local circuit selleck compound neurons and excitatory projection types of cortical neurons may be involved in the neuropathology of mood disorders. Nonpyramidal inhibitory neurons using GABA are localized mainly in cortical layer II and establish local cortico-cortical connections Calcitriol solubility within or between adjacent functional columns of cortical cells. In contrast, pyramidal glutamatergic excitatory Inhibitors,research,lifescience,medical neurons reside predominantly in cortical layers III, V, and VI and give rise to long projections

to other cortical associational regions (layer III), striatum (layer V), and thalamus (layer VI). Neuronal pathology detected in cortical layers III, V, and VI of the dorsolateral prefrontal cortex and anterior cingulate cortex in MDD may be associated Inhibitors,research,lifescience,medical with the pathology of excitatory

pyramidal neurons within these laminae that use glutamate as their neurotransmitter. Moreover, the density of pyramidal neurons Inhibitors,research,lifescience,medical is selectively reduced in the dorsolateral prefrontal cortex in subjects with BPD,4 further confirming the pathology of glutamatergic neurons in mood disorders. These findings in postmortem brain tissue coincide with an in vivo proton magnetic resonance spectroscopy study in the anterior cingulate cortex revealing a reduction in glutamate levels in depression.65 There is increasing preclinical and clinical evidence that antidepressant drugs directly or indirectly reduce the function

of N-methyl-D-aspartate Inhibitors,research,lifescience,medical (NMDA) glutamate receptors.66 Depression-related decreases in glutamate levels or the density of glutamatergic pyramidal neurons may alter in cortex and elsewhere the glutamatergic recognition site and its coupling to the NMDA receptor complex. One study of suicide victims, some of whom were diagnosed with MDD, reveals changes in the glutamatergic recognition site and its coupling to the NMDA Inhibitors,research,lifescience,medical receptor complex in the anterior prefrontal cortex.67 Interestingly, drugs that reduce glutamatergic activity or glutamate receptor-related signal transduction may also have antimanic effects.66 Reductions in size and density of layer II neurons in the orbitofrontal and dorsolateral prefrontal cortex, as well as reductions in the density of Batimastat nonpyramidal neurons in layer II of the anterior cingulate cortex suggest deficient GABAergic neurotransmission. Most nonpyramidal neurons in cortical layer II colocalize GABA and recent clinical evidence suggests that MDD is associated with decreased levels of cortical GABA.11 In summary, the localization of morphological abnormalities in the mood disorders occurs in prefrontolimbic circuits that arc likely to regulate emotional, cognitive, and somatic symptoms in depression.

If pain relief is not sufficient, or the patient

is resor

If pain relief is not sufficient, or the patient

is resorting to illicit opioid use to control it, transfer to methadone maintenance may be needed. Discontinuation of buprenorphine maintenance While there is no legal limit to the length of buprenorphine maintenance, many fairly Patients ask to be withdrawn a few months after being maintained. The usual reasons are desire to be off all narcotics or the cost. Patients often have an unrealistic expectation of how easy it will be to remain abstinent144,145 and many (perhaps most) will relapse within a short period. Patients should be encouraged to remain on maintenance and, when possible, alternative solutions sought for issues like cost, eg, reducing frequency of visits, or exploring insurance options. Inhibitors,research,lifescience,medical There is no adequate data on the optimal length of time; each patient must be judged individually using issues such as previous relapses, addiction history, and lifestyle stability. It is not uncommon to need a number Inhibitors,research,lifescience,medical of episodes of opioid maintenance or even long-term maintenance. There is no consensus on the best way to withdraw from buprenorphine maintenance other than to do it gradually, eg, 2 mg/week until 4 mg is reached and then 1 mg decreased every Inhibitors,research,lifescience,medical other week or monthly. Clonidine may be useful in the final weeks to deal with the withdrawal symptoms. Relapse back to illicit opioid use should be taken seriously and the dose raised until the use stops. Continued use should probably be

handled by resuming full-scale maintenance. As yet, there are no adequate controlled studies comparing the ease or severity of withdrawal from maintained buprenorphine vs methadone patients, although Inhibitors,research,lifescience,medical earlier studies suggested that buprenorphine withdrawal might be better tolerated.146,147 Once the patient has completed detoxification, use of naltrexone for at least 3 months may help prevent relapse. The 1 -month depot naltrexone is preferable, but may be too expensive unless covered by insurance. Naltrexone Naltrexone was approved by

the FDA as an opioid kinase inhibitor Crizotinib antagonist in 1984. It is effective orally and Inhibitors,research,lifescience,medical is long-acting, depending upon dose. While methadone blocks heroin effects by cross-tolerance, naltrexone blocks the effects by competitive antagonism at the u receptor. The degree of blockade is a function of the concentrations of agonist to antagonist, Cilengitide and their receptor affinity. Because of the blocking action of naltrexone, self-administration of opioids at usual doses produces no euphoria so that either individuals cease heroin use or cease taking the naltrexone.148 Its long duration of action means that naltrexone can be given two or three times per week, but daily administration is usually preferred, both because of developing a regular habit of use and of creating a higher blockade. Less frequent administration is usually employed when an individual is taking monitored doses. Tolerance does not develop to the opioid antagonism, even after almost 2 years of regular use.

While technological advances in capacity for sequencing analysis

While technological advances in capacity for sequencing analysis have exceeded the benchmark measure of computing

power, Moore’s Law, there is no doubt that this success has been largely tied to computational advances. The transfer of this knowledge from the laboratory to the health care setting faces a steep climb to establish Pacritinib phase 3 information management practices in the US. Improved clinical knowledge from research is highly dependent on recovering standardized, useful clinical information from medical practice. The delivery of knowledge in clinically useful formats to support decision-making processes is similarly critical. The information management needs to Inhibitors,research,lifescience,medical span these gaps is found in the electronic health information technology (health IT). The major components of a health IT system to support personalized Inhibitors,research,lifescience,medical medicine includes widely used electronic medical record systems and personal health records that consumers can use for recording their own health care information. A second component is a nationwide effort to enable health information exchange among health care providers Inhibitors,research,lifescience,medical and institutions that will enable portability of information to suit purposes on demand. A third element

includes electronic decision support capabilities that engage medical records systems to facilitate evidence-based health care choices by the health care provider. Collectively, these are dependent on data standards that Inhibitors,research,lifescience,medical enable semantic and syntactic interoperability of data across health IT systems. As a health care enterprise,

the US has a dearth of electronic information to support these needs, and it will take many years to achieve all of these steps to technical support benefit all patients. The inability to connect information sources is a major contributor to the high costs of clinical research, particularly clinical trials. Despite escalating health care costs and substantial service inefficiencies in the US, there has been little incentive until recently to make capital investments in information Inhibitors,research,lifescience,medical systems for the inpatient and ambulatory care setting. Brefeldin_A Today, less than 20% of all physicians use electronic health record systems, and far fewer have systems that provide decision support capabilities to aid personalized medicine. Some progress is being made on the requirement for electronic transmission of prescriptions from the health care provider to the pharmacy. Computerized physician order entry (CPOE) for ordering laboratory tests and other services has also been improving. As part of the American Recovery and Reinvestment Act of 2009, nearly $20 billion will be invested in the next several years to build health IT capacity through network capabilities, support acquisition of electronic systems by practice groups and health care institutions, and provide fiscal incentives for adoption and use of health IT systems.

When the animals showed convulsive SE for more than half an hour,

When the animals showed convulsive SE for more than half an hour, diazepam was administered (5 mg/kg, i.p.) to control inhibitor Volasertib seizure severity. During each injection, an injection needle was connected via tube to a 1 μL Hamilton syringe (Bonaduz, Switzerland) and was lowered into the guide cannula. The length of the injection needle was predetermined Inhibitors,research,lifescience,medical and the

distance between the needle tip and the cannula tip was 0.5 mm. An amount of 0.1 μL KA (0.05 μg/0.1 μL; 0.1 μL/min) was injected from the syringe and then the needle was left in the cannula for another minute. Afterward, the needle was removed and a dummy was used to close the cannula. HFS HFS was delivered at 125 Hz, bipolar, biphasic, square wave with a width of 100 μsec. The stimulation intensity was determined for each rat before the first KA injection. Starting with 100 μA, the intensity was step-wisely increased by 100 μA until motor effects (twitching, head nodding, rearing etc.) or EEG abnormalities were observed. Then Inhibitors,research,lifescience,medical the intensity was reduced by 200 μA and was kept at that level for the rest of the experiment. HFS parameters and the protocol to determine stimulation intensity were similar to what was used in previous studies (Velasco et al. 2001a,b, 2001; Vonck et al. 2002). HFS was triggered when epileptic activities on EEG were identified by visual inspection (interictal spikes increased

with frequency Inhibitors,research,lifescience,medical and the amplitude surpassed twice the baseline EEG) without using any seizure detection algorithm and HFS lasted until EEG came back to the normal level (Fig. 1). The animals were continuously stimulated during seizures as well Inhibitors,research,lifescience,medical as during SE periods until the recording session was over. On average the delay between seizure start point and start of stimulation was 4.1 ± 0.3 sec (mean ± SEM). Figure 1 An example of seizure event on EEG. Epileptiform activity started on the CA3 channel with increasing amplitudes and frequency, and developed into high voltage spikes. Epileptic activity also occurred on the Inhibitors,research,lifescience,medical motorcortex channel with a delay. HFS was given … Histology At the end of

the experiment, the animals were anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and later a DC Drug_discovery current (25 μA, 15 sec) was delivered through the electrodes to create a lesion around the electrode tips. Afterward, the animals were perfused transcardially with 2% potassium ferrocyanide in a figure 1 solution of 4% formaldehyde in 0.04 mol/L phosphate buffer (pH = 7.3). The brains were removed and post-fixed in the same solution overnight at 4°C. After post-fixation, the brains were placed into a 30% sucrose solution and remained there until they sank 3 or 4 days later. Then coronal sections (50 μm) were cut by a microtome (HM 440E; Microm, Waldorf, Germany) and the slices containing the track of the cannula and electrodes were stained with cresyl violet.

The reference electrode was placed distally In the A series (Fig

The reference electrode was placed distally. In the A Ponatinib clinical series (Fig. 1), the active and reference electrodes for channel 1 were plastic-mounted bipolar electrodes (surface disks 3 cm apart); the active recording electrode was placed at the apex of the “V” between the first and second metacarpal bones, and the reference electrode was placed distally. In the B series (Fig. 2), the active and reference electrodes for channel 1 were rings mounted on the thumb, with

the active electrode proximal and the reference electrode 3 cm distal. Inhibitors,research,lifescience,medical Figure 1 Assembly for the realization of the A series. The image was made with the forearm pronated for better visualization. The nerve conduction data were selleck chemicals Ruxolitinib obtained with the forearm supinated. Figure 2 Assembly for the realization of the B series.

We considered the measurement to be positive for variation in the Inhibitors,research,lifescience,medical upper limbs when a SNAP was obtained on channel 1, whereas channel 2 showed a clear LACN SNAP (Fig. 3, ​,4).4). We believe that the SNAP captured on channel 1, an area normally Inhibitors,research,lifescience,medical supplied by the RSN, originates from the variant LACN. Figure 3 An example of an upper limb positive in the A series. The upper curve represents the channel 1, with the SNAP obtained in the dorsum of the hand. The lower curve represents the channel 2 with the LACN SNAP obtained by standard technique. Figure 4 An example of an upper limb positive in the B series. The upper curve represents the channel 1, with Inhibitors,research,lifescience,medical the SNAP obtained in the first finger. The lower curve represents the channel 2 with the LACN SNAP obtained by standard technique. Even with the precautions taken in the stimulation and in the exclusion of patients with motor artifact,

costimulation of RN remains as a possible pitfall of this technique. Results Of the 50 patients in the A series, 10 were male (20%) and 40 female (80%). We found six patients (12%) who tested positive for the RSN–LACN anatomic variation; all of them were females. We found two patients (4%) who tested positive for the variation in both upper limbs. Of Inhibitors,research,lifescience,medical the 100 upper limbs studied, we observed eight (8%) that were positive for the variation. All the four patients with unilateral variation showed variation on the left side. The SNAP amplitude obtained in channel 1 in the eight positive limbs ranged from 0.74 to 10.6 μV, with an average of 5.2 μV. Of the 50 Anacetrapib patients in the B series, 10 were male (20%) and 40 female (80%). We found 11 patients (22%) who tested positive for the RSN–LACN anatomic variation; all of them were females. We did not find bilateral variation in the B series. Of the 100 upper limbs studied, we observed 11 (11%) that were positive for the variation. In 11 patients with unilateral variation, six (54.5%) showed the variation on the left side, and five (45.5%) had the variation on the right side. The SNAP amplitude obtained in channel 1 in the 11 positive limbs ranged from 0.70 to 6.

2 1 FiatFlux-Headless In order to prepare FiatFlux for use from

2.1. FiatFlux-Headless In order to prepare FiatFlux for use from within a workflow environment, we developed a “headless” version of the software, which Tivantinib comprised three major aspects: (1) Enabling programmatic access: Being developed as interactive software, the code has not been designed for invocation from the outside. FiatFlux-Headless makes the functionality of the FiatFlux code base accessible for external invocation (without using Inhibitors,research,lifescience,medical the graphical user interfaces (GUIs)). (2) Emulation of user interaction: As the abstract 13C flux analysis process depicted in Figure 1 shows, the computations require several

user interactions via the GUIs. In FiatFlux-Headless the user interactions that are http://www.selleckchem.com/products/BAY-73-4506.html required at specific points of the original software Inhibitors,research,lifescience,medical are emulated by purpose-built methods. (3) Visualization support: FiatFlux comprises functionality for exporting the flux analysis results in different textual formats. As graphical presentations of metabolic flux distributions inside network diagrams are more accessible, FiatFlux-Headless furthermore exports the results in a format that can later be used in network visualization software. Details on the development of FiatFlux-Headless are given in the following sections. 2.2. Enabling Programmatic Access FiatFlux consists of the two main modules ratio and netto containing the GUI for steering the flux Inhibitors,research,lifescience,medical ratio and the

net flux distribution computation, respectively. Some other Inhibitors,research,lifescience,medical modules provide additional GUI components, for instance for the setting of different experimental parameters, for editing the weights of amino acid fragments that are considered in the flux ratio computation, or for writing the analysis results into text files. Basically, inactivation of the GUI in these

modules was achieved by rigorously removing all code Inhibitors,research,lifescience,medical for graphical components and replacing invocations from the GUI with (parameterized) functions. These changes made it possible to access the basic FiatFlux functions from external program code and to transfer data between the different analysis steps, which are prerequisites for integration into a workflow environment. Carfilzomib Another useful functionality that we adopted from FiatFlux is the possibility to upload custom network models instead of using the standard networks provided by the system. The required information has to be provided as a text file following a defined syntax. Also within this file, the user can specify new metabolic flux ratios complementary to those calculated in the ratio module. The values of such additional ratios have to be provided together with the analytical equations in the model file. Furthermore we extended the FiatFlux outputs with some additional information on the analysis procedure: Initially, results could be exported to text files that contain the data in tab-separated format and can thus be directly imported into spreadsheet programs like MS Excel or OpenOffice Calc.

SD showed synergistic interactions with drugs that increase the a

SD showed synergistic interactions with drugs that increase the activity of brain 5-HT,42,43,85 NA,118 and DA46 systems; conversely, DA antagonists block the behavioral119 and antidepressant120 effects of SD. Similar synergistic effects have been described for light therapy, which significantly potentiates serotonergic antidepressants,59,66 is influenced by genotypes influencing the density of the 5-HT transporter,112

and can prevent the mood-lowering effect of acute tryptophan depletion, which reduces brain 5-HT.121 Finally, an increasing interest on glutamatergic neurotransmission in depression stemmed from trials reporting antidepressant effects of the NMDA antagonists ketamine122 Inhibitors,research,lifescience,medical and the glutamatergic Inhibitors,research,lifescience,medical modulator riluzole.123 Glutamatergic neurotransmission follows a strict circadian rhythm, and in animal models

it is first enhanced and then markedly depressed during SD.124 In vivo single proton magnetic resonance spectroscopy (1H-MRS) indicated that glutamatergic transmission is altered by SD, as shown Inhibitors,research,lifescience,medical by reduced glutamate concentrations, the 17-DMAG Phase 2 changes being proportional to both perceived and observed mood amelioration in bipolar depression.125 Remarkably, these effects were observed in the anterior cingulate cortex, a brain area which has been widely implicated in providing a neural basis for mood-congruent cognitive biases in depression,126 and where chronotherapeutics was shown to profoundly change metabolism127,128 and neural reactivity to stimulus selleck chemicals words48 in responders to treatment. Biological clock and long-lasting effects on biological rhythms Inhibitors,research,lifescience,medical The hypothesis that several psychiatric conditions may involve primary or secondary changes in biological Inhibitors,research,lifescience,medical clocks,129 and the observations that biological rhythms show a range of abnormalities in mood disorders,130 make the biological clock a primary candidate to explain the mechanism of action of chronotherapeutic techniques. The molecular

machinery which constitutes the biological master clock in the suprachiasmatic nuclei (SCN) is being elucidated,131 but the systematic study of the relationship between clock and therapeutic GSK-3 interventions in psychiatry is just beginning.132 Growing evidence supports the hypothesis that changes in brain monoaminergic functioning influence the function of the biological clock molecular machinery, and the clock and the control of biological rhythms are emerging targets for antidepressant drug treatment.133,134 New animal models have been used to test the interactions between circadian genes and mood-related neurotransmitter systems, and, conversely, to explore the effects of light on brain circuitries and of antidepressant and mood-stabilizing drugs on the clock.