205 Intensive research is ongoing in an attempt to develop disease-modifying drugs by targeting the key neuropathological processes in AD such as β-amyloid protein.206 Summary Alzheimer’s disease represents an increasing challenge to public health and the health care system, and has had tremendous impact at both the individual and the societal levels. Epidemiologic research has provided sufficient

evidence that vascular risk factors in middle-aged and older adults play Inhibitors,research,lifescience,medical a significant role in the development and progression of dementia and AD, whereas extensive social network and active engagement in mental, social, and physical activities may postpone the onset of the dementing disorder. Multidomain community intervention trials are warranted to determine to what GDC-941 extent preventive strategies toward optimal control of multiple vascular factors and disorders, as well as the

maintenance of an active lifestyle, are effective against Inhibitors,research,lifescience,medical dementia and AD. Acknowledgments This work was supported in part by grants from the Swedish Research Council in Medicine, the Swedish Council for Working Life and Social Research (FAS), the Future Leader of Aging Research in Europe (FLARE)-FAS Program (CQ), the Alzheimer Foundation Sweden, and the Gamla Tjànarinnor Foundation. Selected abbreviations and acronyms AD Alzheimer’s disease Inhibitors,research,lifescience,medical APOE apolipotrotein E BMI body mass index ELF-EMF extremely-low-frequency electromagnetic fields HYVET-COG Hypertension

in the Very Elderly Trial-Cognitive Function Assessment MCI mild Inhibitors,research,lifescience,medical cognitive impairment PROGRESS Perindopril Protection Against Recurrent Stroke Study SCOPE Study on Cognition and Prognosis in the Elderly SHEP Systolic Hypertension in the Elderly Program Syst-Eur Systolic Hypertension in Europe Trial WHI-MS Women’s Health Initiative-Memory Inhibitors,research,lifescience,medical Study
Mild cognitive impairment (MCI) represents a clinical construct that identifies an intermediate state of cognitive function between that of healthy aging and memory and cognitive deficits associated with frank dementia. In most cases, the definition of MCI STK38 is intended to be applicable to those persons in the intermediate state of memory and cognitive impairment who are destined, if they live long enough, to meet criteria, at least clinically, for dementia or Alzheimer’s disease (AD). Although the causes of dementia and therefore MCI can vary widely, we will limit the discussion of the neuropathology of MCI to the role of postmortem neuropathological and neurobiological features that are commonly associated with AD. The criteria and definitions for MCI as initially described by the Canadian Study of Health and Aging,1,2 Reisberg et al,3-7 and Flicker8 in the late 1980s were relatively broad and permissive. Subsequent clinical studies suggested that some individuals with MCI remain in this intermediate stage of cognitive function for longer periods of time than expected.

7–17 In medicinal use, these adverse effects may be prevented or mitigated by avoiding THC entirely in favor of other non-psychoactive cannabinoids.18 For instance, prolonged exposure to the non-psychoactive phytocannabinoid, cannabidiol (CBD), at doses of 3–4 mg/kg/d, both in human volunteers and those with epilepsy, revealed no adverse effects or evidence of

toxicity.19 However, adequate precaution must be taken when CBD is used in conjunction with many other drugs due to its inhibition of several cytochrome P450 isoenzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2D6, and Inhibitors,research,lifescience,medical CYP3A4. This is especially important in the management of chronic pain, since many conventionally used analgesics (opioids and non-opioids) are metabolized via these pathways (most notable CYP2D6 and CYP3A4).20 Therefore, the key relevant clinical issues for practitioners dealing Inhibitors,research,lifescience,medical with populations of Liver X Receptor agonist patients in pain have to do with questions about effects of specific cannabinoids, their various modes of delivery and absorption, Inhibitors,research,lifescience,medical potential indications, and their respective risks and tolerability.21 Based on relatively new but limited scientifically based literature, it is now only possible to speculate about mechanisms of action and what the future may hold for phytocannabinoids as effective analgesics across the vast and

varied cohorts of people living with chronic pain. With that in mind, this review will proceed

with a summary of what is known about Inhibitors,research,lifescience,medical different cannabinoid congeners on various types of pain (efficacy and tolerability) and the putative role of commonly available “generally regarded as safe” (GRAS) ingredients that may enhance the effectiveness of certain phytocannabinoids. CANNABIS AND CANNABINOIDS: PAST Inhibitors,research,lifescience,medical TO PRESENT Cannabinoid refers to a pharmacological class of about 60 naturally occurring compounds (phytocannabinoids) found in plants of the genus Cannabis (i.e. marijuana and hemp) and structurally related synthetic analogues (e.g. Δ3,4-tetrahydrocannabinol and HU-210, which is 100–800 times more potent psychoactively than natural THC22). This classification has been generalized to include a wide range of exogenous and endogenously produced compounds that exhibit similar pharmacodynamic properties as the phytocannabinoids or demonstrate activity at the same receptor binding sites. over Cannabis sativa has two subspecies, indica and sativa. A variety of the former, hemp, has industrially and nutritionally useful qualities. Hemp has a very low amount of the psychoactive constituent Δ9-tetrahydrocannabinol (THC) but higher quantities of cannabidiol (CBD) which may offer a range of medicinal benefits without the cognitive effects and abuse potential associated with THC.23 Cannabis has a long and storied social and medicinal history dating back thousands of years.

Twenty-four hours of EEG is monitored for patients with suspected epilepsy. Description of common sleep disorders It is beyond the scope of this review to describe the entire gamut of sleep disorders. We will focus on the following common or severe sleep disorders: insomnia, circadian rhythm disorders, disorders of excessive somnolence (sleep apnea, narcolepsy, RLS/PLMD), and parasomnias. Inhibitors,research,lifescience,medical Insomnia Insomnia refers to almost

nightly complaints of insufficient amounts of sleep or not feeling rested after the habitual sleep episode. As the most common sleepwake-related disorder, it is more common in women and has a prevalence ranging from 10% to 30%.23 It can be classified based on severity (mild, moderate, severe) or duration (acute, subacute, chronic).4 Transient insomnia can occur in adjustment sleep disorders triggered by acute stress, travel, or sleeping in an unfamiliar environment.7 Symptoms usually resolve once the stress is reduced or removed, or the individual’s adaptation to the stressor increases. Inhibitors,research,lifescience,medical For transient insomnia, treatment consists of education and advice about healthy sleep practices. If these are insufficient, short-term treatment with hypnotics can be undertaken.

Chronic insomnia may be primary, or secondary to circadian rhythm, environmental, Inhibitors,research,lifescience,medical behavioral, medical, neurological, and psychiatric disorders. Vgontzas et al and Rodenback and Hajak reported nyctohemeral activation of the hypothalamic-pituitary-adrenal axis (HPA) in patients with chronic insomnia consistent with the arousal theory of insomnia.30,31 Vgontzas et al demonstrated a shift in interleukin-6 (IL-6) and tumor necrosis factor (TNF) secretion from nighttime to daytime in chronic Inhibitors,research,lifescience,medical insomniacs, and postulated that these could explain the daytime fatigue and performance decrements associated with

insomnia.32,33 The diagnosis of primary insomnia requires exclusion of the direct physiological effects of a substance or general medical condition. It does not occur exclusively during the course of a mental disorder or other sleep disorder. Among the primary insomnias, idiopathic insomnia represents a lifelong sleep disturbance associated Inhibitors,research,lifescience,medical with reduction in daytime alertness and performance, increased sleep latency, and decreased sleep efficiency on PSG.4 Other primary insomnias include psychophysiological insomnia and sleep-state misperccption. Psychophysiological insomnia refers to maladaptive from sleep-preventing behaviors, which perpetuate the sleep disturbance. Typically, these patients sleep better in any place other than their own bedroom. PSG shows increased sleep latency, increased number of awakenings, and poor sleep efficiency. Sleep-state misperccption refers to complaints of sleep difficulties with no PSG evidence of significant sleep disturbance; the sleep latency, quality, and architecture arc normal. this website Inadequate sleep hygiene and behavioral disorders can also produce chronic insomnia.

This multinational study randomized 325 men over age 45 with IPSS ≥ 13 to either tadalafil, 5 mg, daily or placebo for 12 weeks. This followed a 4-week wash-out period and 4-week placebo lead-in period. Compared with placebo, tadalafil significantly improved IPSS voiding and storage subscores (P = .02 and .002, respectively). The QoL index also improved (P = .013) but no difference was observed with the nocturia question (P = .233). IPSS questions for frequency (question 2) and urgency (question 3) improved significantly compared with placebo (P < .001 and P = .035, respectively). Tadalafil improved IIEF-EF domain at 12 weeks (least

squares treatment difference [95% CI, 2.5–6.9], Inhibitors,research,lifescience,medical P < .001). Few treatment Inhibitors,research,lifescience,medical emergent adverse events (TEAEs) were reported and the proportion of reporting at least one TEAE was similar between the placebo and treatment groups (tadalafil 26% vs placebo 22%). For tadalafil, most TEAEs were mild to

moderate in severity with the most common being headache (3.7%) and back pain (3.1%). Small increases in Qmax (tadalafil Inhibitors,research,lifescience,medical 1.6 mL/s [4.6] vs placebo 1.1 mL/s [4.6]; P = .30) and in postvoid residual volume (PVR) (tadalafil 8.8 mL [56.4] vs placebo 4.5 mL [66.7]; P = .50) were observed in both treatment groups.27 Several other studies assessing tadalafil administered once daily in men with LUTS and ED have demonstrated significantly improved ED and BPH outcomes with sustained benefits and excellent tolerability.29,30 Based on these randomized, placebo-controlled, double-blind trials, the US Food and Drug Administration (FDA) Inhibitors,research,lifescience,medical approved tadalafil in October 2011 for the treatment of LUTS secondary to BPH, as well as for the treatment of concurrent LUTS and ED. Combination α-Blocker and PDE5-I α1-Adrenergic blockers (α-blockers) are considered the Epigenetic pathway inhibitor first-line monotherapy for LUTS secondary to BPH. Concerns regarding the coadministration of α-blockers and PDE5-I are related to potential drug-drug interactions leading to hemodynamic Inhibitors,research,lifescience,medical changes and significant lowering of

blood pressure. Kloner and many colleagues assessed the safety of combining tadalafil with two different α-blockers. In the first study, healthy volunteers took doxazosin, 8 mg, for 7 days, followed by coadministration of either tadalafil, 20 mg, or placebo for a single dose. Although there was a greater decrease in mean maximal systolic blood pressure in the doxazosin plus tadalafil group, symptoms of dizziness experienced by three patients did not correlate to measurable changes in blood pressure. The second study had healthy subjects take tamsulosin, 0.4 mg, for 7 days, followed by a single dose of tadalafil (10 or 20 mg) or placebo given 2 hours after the α-blocker. There were no statistically significant differences seen in standing systolic blood pressure between groups.

7,86 These findings in drug addiction and OCD beg an important question; if both conditions can be explained, at least in part, by an enhancement

of habit-like learning or a dysregulation of the balance between learning systems, then why are they so manifestly different from a clinical perspective? This is an important question for further study. #trans-isomer mouse keyword# Conclusion In this brief review, we have sought to illustrate several instances in which dysregulation of mnemonic processes and the mechanisms of neuroplasticity contribute to prevalent neuropsychiatric diseases. As illustrated in the foregoing discussion, reduced, enhanced, and unbalanced plasticity can all potentially lead to psychopathology. This discussion has by no means been comprehensive—there are other disorders that might be chosen to illustrate the

connections between neuroplasticity Inhibitors,research,lifescience,medical and psychopathology, and each of the individual topics sketched above could be an ample focus for a lengthy review in its own Inhibitors,research,lifescience,medical right. The reader is directed to the various recent references provided for more detail. However, these examples serve to illustrate that advances in the basic science of synaptic plasticity, neurogenesis, memory systems, and related processes may lead very directly to new insight into a number of psychiatric diseases and, potentially, to new therapeutic strategies.
Drug addiction, which Inhibitors,research,lifescience,medical can be defined as the compulsive seeking and taking of drugs despite horrendous consequences or loss of control over drug use, is caused by long-lasting drug-induced changes that occur in certain brain regions.1 Only some individuals, however, succumb to addiction in the face of repeated drug exposure, while Inhibitors,research,lifescience,medical others are capable of using a drug casually and escaping an addiction syndrome. Genetic factors account for roughly 50% of this individual variability in addiction vulnerability, and this degree of heritability holds true for all major classes of addictive drugs, including stimulants, opiates, alcohol, nicotine, and cannabinoids.2

It has not yet been possible to identify most of the genes that comprise this genetic Dichloromethane dehalogenase risk, likely due to the involvement of perhaps hundreds of genetic variations summating in a single individual to confer addiction vulnerability (or, in other individuals, resistance). The other 50% of the risk for addiction is due to a host of environmental factors, occurring throughout a lifetime, that interact with an individual’s genetic composition to render him or her vulnerable to addiction to a greater or lesser extent. Several types of environmental factors have been implicated in addiction, including psychosocial stresses, but by far the most powerful factor is exposure to a drug of abuse itself.

The diagnostic criteria for ACS generally applied at the hospital during the study period were those of the European Society of Cardiology, the American College of Cardiology and the American Heart Association [21,22]. In the study patients, discharge diagnoses were made by the responsible ED physician, or, if the patient was admitted to inpatient care, by the responsible specialist ward physician.

Statistical analysis To get an overview of how the diagnostic tools were used to determine ACS suspicion, we present simple associations between the physician’s ACS suspicion on one hand, and TnT levels, ECG changes and symptoms on the other (Tables 1 Inhibitors,research,lifescience,medical and ​and22). Table 1 The physician’s overall Inhibitors,research,lifescience,medical suspicion of ACS and the underlying assessments of the ECG, symptoms, and TnT Table 2 Combinations of assessments of ECG findings, symptoms and TnT for cases with any suspicion of ACS To further evaluate how the diagnostic tools simultaneously were used to determine the level of suspicion of ACS, two different logistic regression models were applied (Table 3). In the first model the binary response was any suspicion of ACS compared to no suspicion, while in the Selleck AZD0530 second model we evaluated obvious/strong suspicion

of ACS compared to vague/no suspicion. ECG changes (4 categories; normal, ischemic, with LBBB or Q-wave, or with AF, AFL or pacemaker), symptom category, TnT-level Inhibitors,research,lifescience,medical (≥0,05 or<0.05 μg/L), sex and dichotomized age (≥65 or<65 years) were included as covariates

in both models. The reference categories were normal ECG, symptoms raising no suspicion of ACS, TnT<0.05, male sex and age<65 years, respectively. Factors were considered significant if the P-value was below 0.05. Analyses were conducted Inhibitors,research,lifescience,medical with IBM SPSS Statistics 18 for Windows (IBM Corp., Somers NY, USA) software. Table 3 Logistic regression analysis Results As shown in Figure 1, Inhibitors,research,lifescience,medical out of 1222 consecutive chest pain patients, a total of 1151 patients were included in the study. Fifty-six patients were excluded because of incomplete study data. Six-hundred and twenty-one (54.0%) were hospitalized and 140 of those (22.5%) proved to have ACS as the discharge diagnosis. Characteristics for the included patients are given in Table 4. Mean age was 60.7±18.5 (SD) years. Table 4 Characteristics of the included patients Assessments of symptoms, ECG and TnT, and the overall likelihood of ACS Table 1 shows the association between the designated likelihood of ACS and Thymidine kinase the underlying assessments of ECG, symptoms and TnT levels. Twenty-one (1.8%) of the 1151 patients were deemed as obvious ACS, 250 (21.7%) as strong suspicion of ACS, 439 (38.1%) as vague suspicion of ACS and 441 (38.3%) as no suspicion of ACS. Of the patients with ST-elevation, almost 71% were considered as obvious ACS. In contrast, only 5.8% of patients with typical symptoms of ACS were assessed as obvious ACS, and only 10.3% of those with a positive TnT.

Futures directions This author believes that a fundamental rethinking of MCI is necessary. He doubts that more conferences alone will lead to consensus, since there have been many such conferences and the differences of opinion remain. At the 9th Conference on Alzheimer’s Disease and Related Disorders in Philadelphia, Pa, in July 2004, this author received the impression of a growing split between the USA and Europe. In fact, within the USA, the original

Mayo Clinic concept of the MCI (perhaps Inhibitors,research,lifescience,medical to be renamed Petersen’s syndrome) is still meeting resistance. The main issue that remains is the need to address more seriously the continuum of aging. Of course, such a reconsideration of the categories of age-related cognitive impairment would have implications for AD as well.30 Despite the work in genetics and neuroimaging, we are having a harder Inhibitors,research,lifescience,medical time differentiating the various

types of dementia from each other.11 This is most likely explained by Inhibitors,research,lifescience,medical the fact that the process of brain aging affects individuals in many different ways and our attempts to assign dementias into discrete categories are failing because of the overlap in biologies at work in our brain.31 Vascular and neurodegenerative processes interact. Neuronal loss selleck products occurs in multiple different systems to different degrees creating a wide spectrum of cognitive, affective, and motor symptoms. Is there a regulatory implication for the development of medications Inhibitors,research,lifescience,medical to treat cognitive impairment? As I have suggested previously,1 it may be possible to treat cognitive impairment as a nonspecific symptom rather than a feature of different discrete conditions. The biological substrate for such a claim is that overall loss occurs continuously in various brain nuclei as we age. For example,

loss of cells Inhibitors,research,lifescience,medical in the cholinergic basal forebrain occurs in a variety of dementias and with normal aging. Cholinesterase inhibitors appear to work, albeit in modest ways, in a variety of dementias characterized by cholinergic pathology, including not only AD, but also Parkinson’s disease, vascular dementia, Mannose-binding protein-associated serine protease and other overlapping conditions. Could we consider cognitive impairment like pain? Perhaps an analogy closer to home is the treatment of agitation in dementia. Psychosis, which may be considered a discrete category, exists in a variety of conditions; agitation occurs on a continuum. Drugs to treat agitation are being developed and submitted for approval based on finding positive effects in three or more conditions, like dementia and mental retardation.

14 From a neurobiological perspective, the phenomenal space is divided into two broad regions (left and right of the dotted vertical plane in Figure 2). The predominant brain activation associated with experiences to the left of the figure (perceived externally) lies within find more specialized visual areas. In contrast, the predominant brain activation associated with experiences to the right of the figure (in the mind’s eye) lies within frontal and parietal regions. Thus, a veridical percept of motion,56 an illusion of motion,63 and an afterimage of motion66 are all linked to activity

Inhibitors,research,lifescience,medical within motion-specialized cortex. In contrast, imagery of motion involves predominantly frontal activations.73 Synesthetic visual experience has also been linked to activity within specialized visual cortex,67 although it is not clear whether this is the case for both projectors and associators. Figure 2. The neurophenomenological Inhibitors,research,lifescience,medical classification of visual perceptual experience. A three-dimensional space is represented with axes:

(i) perceptual locus – external or in the mind’s eye; (ii) sense of agency or volitional control; (iii) vividness (also coded … Emerging visual perceptual syndromes The various Inhibitors,research,lifescience,medical visual phenomena illustrated in Figure 2 are classified within our current psychiatric and philosophical taxonomies as distinct entities, differences between them based on their relation to external objects and to insight, with little attention paid to their content. Thus, a face hallucination is considered a distinct class Inhibitors,research,lifescience,medical of experience from a face illusion in a cloud formation, but not from the hallucination

of a landscape. Yet, viewed from a neurophenomenological perspective, the same perceptual experiences are Inhibitors,research,lifescience,medical classified in an entirely different way. Here, the face illusion and hallucination are considered to be closely related, both involving the same cortical area, but are distinct from the landscape hallucination which involves a different area. In the neurophenomenological classification, the content of perceptual experience becomes of central importance while traditional distinctions between illusions and hallucinations are STK38 de-emphasized. This is not to say that veridical percepts, illusions, and hallucinations of a given visual attribute are identical in terms of the underlying neural circuitry within a specialized area. However, it is clear is that these traditionally distinct experiences are more closely related than previously suspected. The neurophenomenological perspective undermines key shifts in emphasis in the approach to visual hallucinations and their syndromes instituted in 1936. In neurobiological terms, visual hallucinations are not unitary phenomena, different contents pointing to different cortical loci, and are not distinct from illusions.

Preoperative chemotherapy is considered a standard option for resectable adenocarcinoma of the GEJ but remains controversial for the preoperative management of intrathoracic esophageal cancer. Preoperative chemoradiotherapy versus surgery alone Surgery is considered important in the management of esophageal cancers. The CALGB 9781 study randomized esophageal cancer patients (77% adenocarcinoma, 24% squamous cell carcinoma) to preoperative chemoradiation (cisplatin, 5-FU, and RT to 50.4 Gy) followed by surgery versus surgery alone (12). Despite poor accrual (56 out of a planned 475 patients), a significant survival advantage was seen in the trimodality group with 5-year survival of 39% versus 16%

Inhibitors,research,lifescience,medical with surgery alone and median survival of 4.5 years compared to 1.8 years with surgery alone (p=0.002). The addition of chemoradiation in this setting afforded a convincing survival benefit and provided justification for the existing de-facto standard of care in patients with clinical stage II-III disease. In an EORTC Inhibitors,research,lifescience,medical study reported by Bosset, 282 patients with squamous cell carcinoma were randomized to preoperative cisplatin with radiation therapy (split course 37 Gy using Inhibitors,research,lifescience,medical 3.7 Gy per fraction) followed by surgery versus surgery alone (13). Results showed significant

improvements in favor of preoperative therapy for disease-free survival, local control, cancer-related deaths, and curative resection Inhibitors,research,lifescience,medical rates; however, there was no difference in overall survival (18.6 months for both groups).

Significantly more postoperative deaths were seen in the group treated with preoperative CRT (12% versus 4% with surgery alone), mainly because of the higher number of patients with respiratory insufficiency, mediastinal infection or sepsis. The authors discussed that the increased number of postoperative deaths in the CRT could have been due to the “deleterious effects of high dose of radiation per fraction or of CRT on lung tissue.” They recommended future studies click here incorporate 2-Gy range fraction sizes, continuous radiation to overcome repopulation seen with Inhibitors,research,lifescience,medical split course therapy, and 5-FU chemotherapy. This trial therefore showed that preoperative CRT could prolong disease-free survival and local control but not overall survival although was likely limited Thiamine-diphosphate kinase by the radiation scheme. An Australian study by Burmeister et al evaluated 257 patients with both adenocarcinoma (63%) and squamous cell carcinoma (27%) of the esophagus (14). Patients were randomized to preoperative cisplatin and 5-FU with concurrent radiation therapy (35 Gy in 15 fractions) or immediate surgical resection. The CRT and surgery groups had significantly more complete resections with clear margins and fewer positive lymph nodes than the surgery alone group did. However, neither progression-free survival (16 months with CRT and surgery versus 12 months with surgery alone, HR=0.82, p=0.

The apoptotic pathway evolves over hours to weeks after injury, is an active process requiring energy, is more closely associated with the caspase proteases, and is less clearly linked to inflammatory responses. Primary substrates for the AZD0530 datasheet caspases also include cytoskeletal elements as well as the capacity

to activate other processes that can be toxic to the cell.25 Both families of proteases and hence both the necrotic and apoptotic pathways are under complex control of multiple modulators, the ultimate balance Inhibitors,research,lifescience,medical of which appear to determine cell survival.25 In addition to these processes, there is a growing appreciation for the role of other factors in the cytotoxic cascades such as the generation Inhibitors,research,lifescience,medical of free radicals, and the disruption of lysosomal membranes with the subsequent release of hydrolytic enzymes into the intracellular environment.24 Inhibitors,research,lifescience,medical The excessive release of neurotransmitters other than glutamate may also play a role

in the elaboration of neurotrauma. For example cholinergic excess may amplify the destructive effects of excitatory amino acid excesses, and may be particularly injurious to brain areas where acetylcholine and excitatory amino acids are densely colocated (ie, hippocampus and frontal cortices).27 The effects of cerebral monoaminergic excesses in the cytotoxic cascade are not understood fully, although in experimental injury models traumatically induced elevations Inhibitors,research,lifescience,medical of cerebral serotonin seem to decrease cerebral glucose use,28,29 and serotonin agonists are not particularly helpful in improving post-traumatic neurobehavioral status or TBI outcome.30,31 Administration

Inhibitors,research,lifescience,medical of catecholamine antagonists impedes recovery from brain injury32-34 and delay emergence from post-traumatic amnesia Tryptophan synthase in humans,35 suggesting that blocking catecholamine excesses is not an effective means by which to mitigate the cytotoxic cascade after TBI. Neurotransmitter excesses seem to wane over the first several weeks after TBI,36,37 although the time course of their resolution is not characterized fully. TBI in humans produces chronic cerebral cholinergic deficit via injury to ventral forebrain cholinergic nuclei38,39 and their cortical projections.39-41 It is possible that TBI also results in primary or secondary disturbances in monoaminergic systems,42 the effects of which may be amplified by individual genetically mediated variations in catecholamine metabolism.