Holistic Solution to Overcome Depression

Destroy Depression

Destroy Depression is written by James Gordon, a former sufferer of depression from the United Kingdom who was unhappy with the treatment he was being given by medical personnell to fight his illness. Apparently, he stopped All of his medication one day and began to search for answers on how to cure himself of depression in a 100% natural way. He spent every waking hour researching all he could on the subject, making notes and changing things along the way until he had totally cured his depression. Three years later, he put all of his findings into an eBook and the Destroy Depression System was born. The Destroy Depression System is a comprehensive system that will guide you to overcome your depression and to prevent it from injuring you mentally and physically. Continue reading...

Destroy Depression Summary

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Antidepressants

The most recent Report on Confidential Enquiries into Maternal Deaths Maternal and Child Health has highlighted the risk of postnatal depression and its potential to lead to postnatal psychosis and suicide. There are numerous case reports offering conflicting advice about the use of psychotropic drugs in lactating women. The tricyclic antidepressants amitriptyline, nortriptyline and desipramine are all excreted into breast milk, with the baby being exposed to approximately 1 of the maternal dose. This poses a theoretical risk for the infant, but there are no case reports of adverse effects, and the balance of risks is generally believed to favour continuing treatment of the mother and allowing breastfeeding. Information about the selective serotonin reuptake inhibitors (SSRIs) in lactation is limited. The drugs are excreted into breast milk, but there are no controlled

Anxiety and depression

While a causal link between mood disorders and a dysfunction of the nicotinic cholinergic system has not been definitively established, compelling evidence exists suggesting a relationship 32-35 . A number of antidepressants in clinical use have been identified as antagonists at nicotinic receptors 32 . Nicotine and mecamyla-mine (9) have been shown to potentiate the effects of both imipramine and citalo-pram in the mouse tail-suspension test 36 . Mecamylamine also potentiates the effects of amitriptyline in the mouse forced swim test 37 . The novel 2, 7-diazaspiro 4.4 nonane TC-2216 (10) is a highly selective modulator for a4p2

Monocyclic core CRFR1 antagonists

Two compounds were recently reported from a series of pyridine-based CRF-R1 antagonists for advancement into clinical trials. Compound 2 (CP-316,311) (rat CRF-R1 IC50 6.8 nM) was determined to be a CRF-R1 antagonist with activity in several behavioral models, including reversal of intracerebroventri-cular (i.c.v.) CRF-induced excitation of locus coerulus neurons (60 inhibition at 0.3mg kg, intravenous (i.v.) administration), reversal of startle potentiation induced by i.c.v. CRF (100 at 32 mg kg, oral (p.o.) administration), and activity in the defensive withdrawal model for situational anxiety at 10 mg kg, intraperitoneal (i.p.) administration 23 . No liver toxicity was observed in five-day rat toxicology studies with 2, and it was subsequently selected for advancement into Phase 2 clinical trials in a placebo-controlled study with depressed patients. Due to a significant food effect observed in dogs and humans with compound 2 resulting in variable oral bioavailability, compound 3...

Discuss the effects of ephedrine and review common doses of this medication Give some examples of medications that

Ephedrine produces norepinephrine release, stimulating mostly A1 and B1 receptors the effects resemble those of epinephrine although they are less intense. Increases in systolic blood pressure, diastolic blood pressure, heart rate, and cardiac output are noted. Usual intravenous doses of ephedrine are between 5 and 25 mg. Repeated doses demonstrate diminishing response known as tachyphylaxis, possibly because of exhaustion of norepinephrine supplies or receptor blockade. Similarly, an inadequate response to ephedrine may be the result of already depleted norepinephrine stores. Ephedrine should not be used when the patient is taking drugs that prevent reuptake of norepinephrine because of the risk of severe hypertension. Examples include tricyclic antidepressants, monoamine oxidase inhibitors, and acute cocaine intoxication. Chronic cocaine users may be catecholamine depleted and may not respond to ephedrine.

New Therapeutic Approaches 31 Monoamine reuptake inhibitors

There is strong evidence that DA and NE play an important role in the pathophysiology of ADHD. The widely used psychostimulants, methylphenidate and amphetamine, and the non-stimulants desipramine (4), imipramine (5), bupropion (6) and atomoxetine act through the common mechanism of enhancing monoaminergic neurotransmission 7,8 . The therapeutic effects of the stimulants have been attributed to their ability to block reuptake and facilitate release (amphetamine) of DA in the striatum. The antidepressant bupropion and GW320659 (7, structurally similar to the active hydroxyl metabolite of bupropion) inhibit both DA and NE reuptake 9 . Bupropion has been shown to be an effective treatment for ADHD especially in the presence of co-morbid depression and bipolar disorder 10 . An initial study indicates that GW320659 may have clinically relevant efficacy in pediatric ADHD 11 . The tricyclic antidepressants (TCAs)

Dopamine reuptake inhibitors

There are three approved drugs, venlafaxine (16), duloxetine (17) and milnacipran (18), in the serotonin-norepinephrine reuptake inhibitor (SNRI) class. Whereas milnacipran blocks 5-HT and NE reuptake with almost equal potency, venlafaxine and duloxetine block 5-HT reuptake preferentially 39-41 . Clinical evidence shows that SNRIs have comparable efficacy in the treatment of MDD compared with antidepressants in the SSRI class. An advantage with SNRIs appears to be the ability of alleviating chronic pain associated with, and independent of depression 42-44 .

The Politics Of Abortion Pose A Direct Threat To Womens Mental Health

Increasing women's confidence in their ability to cope with an abortion has been found to lower their depressive symptoms after having an abortion (Major et al., 1990). Conversely, constructions of abortion that increase its social stigma can affect women's psychological well-being by encouraging them to feel shame and guilt at their decision to terminate pregnancy. This can then be used as further evidence of abortion's harmful mental health effects. It is important to remember that the meaning of abortion is socially constructed and can be made to seem wrong and shameful, despite the fact that it may represent a courageous act of a women acting out of a desire to meet her responsibilities to others and do the best she can under stressful conditions (Russo & Denious, 2005). Indeed, 74 of women cite concern for or responsibility to other individuals as the reason for their abortion (Boonstra, et al., 2006).

Animal Models Transgenic Mice And Mutated Flies

Classical behavioral despair models (Porsolt swim test, tail suspension) remain reliable methods for identifying antidepressants. Newer paradigms, e.g. chronic mild stress, rat Flinders Sensitive Line (FSL), guinea - pig vocalization models have proven useful in identifying atypical antidepressants with mechanisms distinct from classical monoamine potentiators e.g. TCAs, SSRIs. (55-57)

New Therapeutic Approaches

Monoamine Reuptake Inhibitors - Tricyclic anti-depressants that inhibit the reuptake of norepinephrine, such as desipramine (2) and nortriptyline (3), have efficacy in treating ADHD (34,35). The same side effect issues that impair utility of these medicines in treating depression limit their use in treating ADHD, including anticholinergic and antihistaminergic side effects. Moreover, effects of these drugs on cardiac conduction is of concern, particularly regarding use of these medicines in fairly healthy children. Because of some documented cases of sudden death in children treated with tricyclic antidepressants, their use in treating ADHD has fallen into disfavor.

Monoamine Reuptake Inhibitors

Nearly all antidepressants currently in use act by increasing the concentrations of the monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE), and or dopamine (DA), primarily by inhibition of reuptake mechanisms (for a review, see Ref. 10 ). Selective serotonin reuptake inhibitors (SSRIs) were introduced in the 1980s and include fluoxetine, paroxetine, sertraline, and escitalopram. Serotonin and NE reuptake inhibitors (SNRIs) include venlafaxine and duloxetine. The atypical antidepressant buproprion has been reported to inhibit the NE transporter (NET) and the DA transporter (DAT). Although new SSRIs continue to be identified, only those possessing additional receptor modulating properties will be discussed in this review (see Section 3).

Triple reuptake inhibitors

Triple reuptake inhibitors (TRIs), which increase DA levels in addition to serotonin and NE, are expected to be as efficacious as monoamine oxidase inhibitors (MAOIs) without being limited by the same side effects and dietary restrictions that accompany MAOI use. The rationale for including DAT inhibition is partially based on the well-established role of dopaminergic systems in motivation and reward. Anhedonia and lack of interest, which are core symptoms of MDD, result from dopaminergic impairment in corticolimbic areas, and depressed patients have been shown to have decreased DA release by nerve terminals in the mesolimbic system

HT2C receptor modulators

Selective 5-HT2C agonists have shown antidepressant-like effects in several animal models of depression 5 . Of the recently identified 5-HT2C agonists, Ro 60-0175, WAY-161503, and WAY-163909 have been the most extensively characterized in depression models. Results in chronic mild stress and olfactory bulbectomy models of depression suggest a more rapid onset of antidepressant action typical antidepressants require 2-3 weeks of dosing to show effectiveness, while 5-HT2C agonists are active in less than one week in both models.

Confounding Problems Controlling Drug Costs And Best Drug Selection Owing To Pharmaceutical Company Activities

Direct-to-consumer advertising policy by industry has also indirectly become a problem for therapeutics committees. These advertisements often encourage consumers to demand pricey drugs over cheaper ones that work just as well. The clinicians on the hospital staff then often make similar demands to the therapeutics committee to add the more expensive agents to the formulary. The percentage of industry spending on direct-to-consumer advertising has increased dramatically in the past 10 years. A review of this activity in 2002 by Competitive Media Reporting showed that about 60 of a company's spending on a drug may come from this form of advertising. The major classes of drugs that use this form of advertisement include, in decreasing order, anti-inflammatories, antihistamines, antihyperlipidemics, antiasthmatics, antiulcer drugs, antidepressants, erectile dysfunction drugs, weight loss drugs, oral contraceptives, genital herpes drugs, toenail fungus agents, and hormones. It is...

HT7 receptor antagonists

The 5-HT7 receptor has been postulated to play a role in depression based partly on its distribution in the brain and also on the observation that chronic treatment with antidepressants results in downregulation of this receptor. Additional support for this hypothesis has been gained by a recent study showing that 5-HT7 receptor knockout mice demonstrate antidepressant-like profiles in forced swim and tail suspension tests 33 . The identification of selective antagonist tool compounds has helped add further evidence in support of the hypothesis. For example, SB-269970, 16, exhibits antidepressant-like activity, even though this compound has a rather poor PK profile. SB-656104-A, 17, has been identified as a 5-HT7 antagonist with better PK properties and has been shown to modulate REM sleep in rats in a manner consistent with potential antidepressant-like activity 34 .

Neuropeptide Receptor Modulation 51 Neurokinins

The potential for NK1 antagonists as antidepressants has been the subject of a tremendous amount of research effort over the last decade 35 . At least three compounds (aprepitant, L759274, and CP-122721) showed early evidence of anti-depressant effects in clinical studies. The failure of aprepitant to separate from placebo in Phase III studies was a great disappointment 6 . Nonetheless, NK1 antagonists continue to be of interest for depression therapy since they have been shown to potentiate the activity of SSRIs. The NK1 antagonist vestipitant is currently being evaluated in combination with paroxetine for anxiety and depression. Interestingly, both of these activities have been attained in a single compound, 18, which is both a potent SERT inhibitor (pIC50 8.0) and an NK1 antagonist (pIC50 8.5) 36 . This compound reportedly increased rat 5-HT levels up to 250 of baseline (measured by microdialysis), and was orally active in the isolation-induced guinea-pig pup vocalization test of...

H3 antagonists with a dual mechanism

Patients suffering from depression are frequently diagnosed as having cognitive impairment and fatigue. Marketed SSRIs address the mood aspects of depression but fail to improve the cognitive and fatigue issues, and in many cases actually contribute to these phenotypes. Wake-promoting drugs, e.g. modafinil, have been proposed for use in treating the excessive sleepiness characteristic of depression 79 . JNJ reported dual H3 and SERT activity in a series of tetrahydroisoquinolines for treating depression 80,81 . A 4-methoxy or thiomethyl aryl substituent was preferred. Compounds 32 and 33 displayed high affinity for both hH3 (Kj 5.6 and 4.0 nM) and hSERT (Ki 2.7 and 13 nM) and also had moderate activity for norepinephrine (NET) and dopamine transporters (DAT). Dual H3 and AChE

Non Peptide Ligands For Crf Receptors

In addition to the basic understanding of the CRFt binding SAR there has also been some recent work in the synthesis of potential positron emission tomography (PET) and single photon emission computed tomography (SPECT) CRFi ligands for noninvasive clinical neuroimaging. Fluorinated and iodinated analogs of the three most utilized pharmacological tools 1, CP-154526 and NBI-27914 (compounds 19 and 20, respectively) have been reported (50-52). The fluoro analogs 21 and 22 as well as iodo analogs 23 and 24 are all high affinity ligands. The use of all of these compounds in vivo was limited by their high lipophilicity, limited solubility and poor bioavailability. Radiotracer 22 was evaluated in vivo but due to the limited brain exposure of the compound, studies were limited only to imaging of the pituitary. Imaging studies showed an enlarged pituitary in rats with chronic peripheral administration of CRF (51). These observations are analogous to those seen in depressed patients through...

Other GABAa receptor modulators

Melatonin receptor agonists and their relevance for the treatment of sleep disorders and major depression have been previously reviewed in Ann. Rep. Med. Chem., volume 39 29 . Since then, ramelteon has been approved, representing an important milestone for the proof of concept of this target, and has opened new possibilities for research.

Clinical Opportunities For

From SAR studies in the pyrazolo 1,5-a pyrimidine series emerged NBI-30775 (R121919) as a potent (CRF1 K 2.8 nM), selective (CRF2 K, > 2000 nM) CRF, receptor antagonist which inhibits CRF-induced cAMP accumulation (IC50 26 nM) and CRF-stimulated ACTH release from cultured rat anterior pituitary cells (EC50 28 nM) and displayed an excellent pharmacokinetic profile in rat following oral administration (35,76). The effect of R121919 was also studied in the elevated plus maze in two complementary rat breeds that exhibit high- and low-anxiety related behavior (77). The compound reduced anxiety-related behavior in the former group in a dose dependent manner but was without effect in the low anxiety group suggesting that CRF antagonists should be measurably active in clinical situations where there is an exaggerated stress response. Based on this and other data, the compound was selected for clinical development and, in an open label study with 20 depressed patients, a significant...

MLT agonists in clinical development for insomnia

Agomelatine (13) represents an outsider within this group, because it is not in development for insomnia but for depression and anxiety. Although it is a MT1 MT2 receptor agonist in the picomolar range, it also displayed potent affinity for the 5HT2c receptor (IC50 270 nM). This compound was extensively reviewed in 2004 29,42 , and, since then, new phase III trials for major depressive disorder were completed. However, the European Medicines Agency (EMEA) refused authorization in July 2006 due to concerns about its effectiveness 43 .

Biological Target Validation

Non-selective sodium channel blockers developed as local anesthetics 26 , an-ticonvulsants, antidepressants, or antiarrhythmics have found application in the treatment of various pain conditions 27 . All of these agents have CNS penetration and have undesired effects and off-target activities. In spite of the fact that these agents are non-selective against Nav1.5, the heart sodium channel, they demonstrate few cardiovascular liabilities. The observed therapeutic index is thought to be a result of their use and voltage-dependent properties as neuronal firing frequencies are often 3-100 fold higher than that of cardiac myocytes.

Diagnostic Tests for BDD

Cosmetic surgery aims to improve a patient's body image and self-esteem (Fig. 18.3). Disturbances of body image are present in a wide variety of psychiatric illnesses, including hypochondria, eating disorders, social phobia and schizophrenia 1 . Psychological evaluation of patients is not standard in clinical plastic surgery practice. Questioning of motivation and interview techniques to ascertain how realistic a patient is, however, standard. Considering that 50 of patients presenting for cosmetic surgery are on psychotropic medications and 27 of those are taking antidepressants suggests that perhaps some standard psychological tests should be introduced into the initial cosmetic surgery consultation 9 . Only a few authors have suggested this as a routine 15 .

Definition And Identification Of Key Neuropsychiatry Symptoms

Apathy consists of lack of motivation with diminished goal-directed behavior, reduced goal-directed cognition, and decreased emotional engagement. Apathy may accompany depression, but it is often an independent syndrome without the sadness, despair, and intense suffering typically experienced by depressed patients (5). Apathy is commonly accompanied by evidence of executive dysfunction.

Neurobiological Theories Of Adhd

Recent work in human and animal studies also suggests the involvement of the adrenergic system in ADHD. In rodents, norepinephrine (NE) depletion results in increased distractibility and motor hyperactivity (38), and in nonhuman primates, stimulation of the noradrenergic system has been shown to improve cognitive function and distractibility (39). Noradrenergic projections are particularly dense in the frontal cortex and cingulate gyrus. These regions are involved in mood stabilization and sleep regulation, as well as attention and alertness (40,41). Animals and humans with lesions in the prefrontal cortex show poor attention regulation and disorganized, impulsive, and hyperactive behaviors, similar to those observed in ADHD. Pharmacological studies have demonstrated the clinical usefulness of NE inhibitors (such as desipramine, nortriptyline, and atomoxetine) in the treatment of ADHD (42,43). The mode of action of these antidepressants is to block the reuptake of dopamine and...

Epidemiology And Implications Of Neuropsychiatric Features In Parkinsonian Disorders

What are the clinical implications of neuropsychiatric symptoms in patients with parkinsonian disorders Again, most research has been performed on patients with PD, and it seems reasonable to extrapolate the findings from these studies to patients with atypical parkinsonian disorders. First, several studies have consistently demonstrated that neuropsychiatric symptoms have strong negative influences on the quality of life, including physical, social, and psychological well-being of patients with PD, even after controlling for motor, functional, and cognitive disturbances. For instance, depression has consistently, and irrespective of instruments used to assess depression, been found to be among the most important independent predictors of impaired quality of life in PD patients (29-31), and a longitudinal study reported that depression and insomnia were the most important factors associated with poor quality of life (32). Although there is overlap between the symptoms of depression...

The Role Of Neuropsychiatric Assessment In Diagnosis Of Parkinsonian Disorders

During the last decade an increasing number of studies describing the neuropsychiatric characteristics of patients with neurodegenerative disorders have been published. Among the group of movement disorders, however, the majority of studies have focused on patients with PD, and only few studies with a low number of participants have explored the pattern of neuropsychiatry symptoms in atypical parkinsonian disorders, and thus the knowledge of the neuropsychiatric characteristics of these disorders is still limited. In addition, there are several other methodological caveats to consider when comparing different studies of the neuropsychiatric profile of patients with parkinsonism. First, patients can be selected from different sources. Clinical and demographic characteristics of patients attending a specialized movement disorder clinic may differ from patients referred to a neuropsychi-atric unit or residing in the community with regard to age, education, duration of disease, cognitive...

Psychiatric Aspects Of Dementia With Lewy Bodies

DLB is characterized clinically by dementia, visual hallucinations, and fluctuating consciousness in addition to parkinsonism. Neuropathological characteristics include alpha-synucleinopathy, such as Lewy bodies and Lewy neurites in the brainstem, particularly the substantia nigra, subcortical structures, limbic cortex, and neocortex. Some amyloid deposition is also found in most patients. Neurochemically marked cholinergic deficits are reported in addition to a moderate nigro-striatal dopaminergic, and monoaminergic deficits have also been reported. It is estimated that at least 80 of DLB patients experience some form of neuropsychiatric symptoms (23), such as visual hallucinations, auditory hallucinations, delusions, delusional misidentification, and depression. These visual hallucinations are consistently reported to be more frequent in DLB than in AD, also in samples diagnosed at autopsy, and constitute one of the key diagnostic features of the disorder. Although rates vary from...

Management Of Neuropsychiatric Symptoms

To our knowledge, only nine randomized, placebo-controlled studies of neuropsychiatric symptoms in parkinsonian disorders have been reported four trials with cholinergic agents in DLB (rivastigmine) (113), PD (donepezil) (114), and PSP (donepezil and RS-86, a cholinergic agonist) (115,116), two trials with clozapine in PD (117,118), and three trials with antidepressants in PD (119-121). The studies have usually included few subjects, with a total number of 356 patients in the nine studies. Further details are provided in Table 2. In addition to the two studies showing efficacy of clozapine in PD with psychosis, rivastigmine improved neuropsychiatric symptoms in DLB (113),

Pharmacological Treatment Of

Few trials of neuropsychiatric symptoms have been reported in PSP. In a recent placebo-controlled trial, the cholinesterase inhibitor donepezil did not improve neuropsychiatric symptoms. A slight improvement in memory was noted, but because of worsening of motor symptoms, a worsening of ADL was found in patients receiving donepezil (116). Similarly, a small placebo-controlled trial with RS-86, a cholinergic agonist, did not improve cognition or mood in PSP patients with dementia (115). In a clinical survey, it was reported that some PSP patients responded to antidepressive drugs (77). In a chart review, 7 of 12 autopsy-diagnosed PSP patients responded to a dopaminergic drugs, and 1 of 3 to a tricyclic antidepressant. None of the patients responded markedly, however. The serotonergic agent trazodone, but not the neuroleptic drug thiotixine or carbamazepine, improved agitation in patients with PSP (130). Another case report suggested that electroconvulsive therapy (ECT) could improve...

Miscellaneous Approaches

In several examples, simple chemical modifications to existing clinical compounds provided new antiarrhythmic agents. For example, evidence exists that tricyclic antidepressants such as imipramine and chlorpromazine induce self-defibrillation. However, these effects are seen at high doses resulting in therapeutic indices that are too low for use as antiarrhythmic agents. Modification of the side chain of imipra-mine to an amide (e.g. 26) resulted in antiarrhythmic agents that were potent in a cat model of ventricular fibrillation (1-3 mg kg i.v.) 45 .

Neurotransmitters and Their Impact on Emotions

Research suggests that there are circuits that are formed by these various neurotransmitters that are guided by the DNA from each person's genetic material (Stahl, 2000). Difficulties with these circuits appear to occur simultaneous to expression of certain groups of emotions labeled as mental disorders. For example, mood disorders, which includes major depression, involves too little serotonin in the synaptic fluid. This is usually due to the inability of the body to provide enough serotonin at the synapse so that the nerve impulse is slowed down. It could be a deficiency in the manufacture of serotonin, too little stored or released at the synapse, or it could be that too much serotonin is removed from the synaptic

And Cardiac Autonomic Neuropathy

Polyneuropathy involving the somatic and autonomic nervous system is responsible for substantial morbidity and increased mortality among diabetic patients. Near normoglycemia is now generally accepted as the primary approach to prevention of diabetic neuropathy (1,2). However, in diabetic patients with advanced stages of peripheral neuropathy, relatively long periods of near-normal glycemic control for several months or even years may be needed to retard the progression of nerve dysfunction (3). Because normoglycemia is not achievable in most diabetic patients, the effects of several medical treatments derived from the pathogenetic concepts of diabetic neuropathy have been evaluated in numerous randomized clinical trials during the past two decades. However, due to various reasons, none of these compounds has been marketed as yet in the major European countries or in the United States. Nonetheless, in symptomatic diabetic neuropathy, additional pharmacological treatment of painful...

Differential diagnosis and stages in Alzheimers disease

Major catecholaminergic pathways that are involved in depression (Van Praag, 1982) are also involved in the pathogenesis of AD (Rossor, 1982). There may thus be a common cerebral substrate in both depression and dementia. Secondly, profoundly depressed patients frequently display overt signs of dementia such as slowness, general inertia, disorientation and memory disturbances. The differentiation of depression and dementia based on clinical observation alone thus appears very difficult. A thorough neuropsychological investigation may be of importance in this respect. Preliminary results presented in Jolles (1985) suggest that neuropsychological methods and theory may contribute to the differentiation of depression and dementia.

Other Factors Affecting PAS

Controlling for these factors is an important step in gaining an accurate understanding of what may cause undesirable effects after a woman has had an abortion. For example, in one study, Russo and Denious (2001) at first found greater depressive symptoms, diminished life satisfaction, and a greater likelihood of experiencing rape, child

Disorders of Arousal and Motivation

The chronic, low-grade depressive symptoms shown by Charles are characteristic of dysthymia, a less dramatic but significantly impairing form of depression that has been described by Hagop Akiskal (1997). Charles was able to do most of what he was required to do, but found virtually no pleasure or satisfaction in most of life.

Box 71 Factors That Increase the Probability of Difficult Coping After an Abortion

The goal of pre-abortion counseling is to reduce these risk factors by helping the woman to make a decision about her pregnancy with which she is comfortable and able to live. Most abortion centers will not go ahead with the procedure until it is clear that this is the woman's own choice, that she has not been pressured by anyone to make this decision, and that she has some emotional support afterward. Sometimes, the counseling can be accomplished during the initial visit, especially if the woman's ambivalence or fears are allayed by providing information about the actual procedure itself. We provide information about the most common procedures used in abortion clinics in Chapter 4 so that therapists and counselors may educate themselves if they are not familiar with what actually occurs when women seek to terminate a pregnancy. They can then pass on this information to their clients. Other times, especially if the woman discloses a diagnosable mental illness such as a major...

Recovery after a Stroke

After a stroke, many people experience feelings of depression (see page 345). They may feel frustrated or isolated, especially if they have not been able to return to their usual routine or if they are having problems communicating with others. Symptoms of depression include sleeplessness, indifference, and withdrawal. For most of these people, the depression is temporary. It may be helpful for the person to join a support group to share experiences and information with others who are in a similar situation. Talking with a psychiatrist or another mental health professional may help the person cope with and overcome his or her depression. To treat prolonged depression, a doctor may prescribe antidepressant medications such as tricyclic antidepressants, serotonin reuptake inhibitors, monoamine oxidase inhibitors, or bupropion.

Neuropsychiatry Disorders

Affective Disorders - Many patients with major depression are hypercortisolemic and exhibit an abnormal dexamethasone suppression test (23,24). Given the primary role of CRF in stimulating pituitary-adrenocortical secretion, the hypothesis has been put forth that hypersecretion hyperactivity of CRF in brain might underlie the hypercortisolemia and symptomatology seen in major depression. The concentration of CRF is significantly increased in the cerebrospinal fluid (CSF) of drug-free depressed individuals (25-27), and a significant positive correlation is observed between CRF concentrations in the CSF and the degree of post-dexamethasone suppression of plasma Cortisol (28). Furthermore, the observation of a decrease in CRF binding sites in the frontal cerebral cortex of suicide victims compared to controls is consistent with the hypothesis that CRF is hypersecreted in major depression (29). The increased CSF concentrations of CRF seen in depressed individuals are decreased following...

Vulval Pain Syndromes

Historically, there have been some links made between vulvodynia and sexual and physical abuse. Most relevant studies have failed to demonstrate this link (Edwards et al., 1997). Studies in which patients have more depressive symptoms and somatic complaints than controls do not differentiate between cause and effect (Lotery et al., 2004). James Aikens et al. (2003) showed that increased scores for somatic depressive symptoms were due to a lack of sexual interest and chronic pain, with no significant difference in cognitive affective symptoms or depressive history disorder. antidepressants

Reasons For Identifying Striatal Cholinergic Cell Loss As The Origin Of The Four Syndromes

Abnormal dyskinetic movements also occur in some patients with Parkinson's disease during L-DOPA therapy (Barbeau, 1969 Cotzias et al., 1969 Chase et al., 1973) and are commonly referred to as peak-dose dyskinesia. This is relatively rare after L-DOPA administration in patients with no preexisting parkinsonian disorder (Barbeau, 1969 Cotzias et al., 1967 Mones et al., 1971 Markham, 1971 Chase et al., 1973), or in normal monkeys (see Section 9.4). Likewise, when L-DOPA was used to treat depression, dyskinesia was rare (Bunney et al., 1969 Goodwin et al., 1970).* There has been debate about whether the occurrence of PDD depends on the duration of treatment with L-DOPA, or alternatively on the duration of the illness itself. However, L-DOPA given long term to nonparkinsonian patients does not lead to the appearance of dyskinesia (Arts et al., 1991). The longer the prior duration of illness, the more severe (Cotzias et al., 1969) or the more common (Mones et al., 1971) are the involuntary...

Extending the cellbrain analogy

When conditions exceed the capacity of the brain to tolerate them, individuals suffer clinical depression, or in some cases catalepsy. Many higher brain functions are down-regulated, though housekeeping activities remain intact. Stress hormones are released, ensuring a continuing glucose supply. This is necessary (though it is unlikely to be sufficient) for restoring normal brain function.

Management of Opioid Adverse Effects

Successful opioid therapy requires that the benefits of analgesia clearly outweigh treatment-related adverse effects. This implies that a detailed understanding of adverse opioid effects and the strategies used to prevent and manage them are essential skills for all involved in postoperative pain management. The pathophysiological mechanisms contributing to adverse opioid effects are incompletely understood. The appearance of these effects depends on a number of factors, including patient age, extent of disease, concurrent organ dysfunction, prior opioid exposure, the route of drug administration, and the adverse drug interactions. The potential for additive side effects and serious toxicity from drug combinations must be recognized. The sedative effect of an opioid may add to that produced by numerous other centrally acting drugs, such as anxiolytics, neuroleptics and antidepressants. Likewise, drugs with anticholinergic effects probably worsen the constipatory effects of opioids. As...

Lack of Adequate Resources for Assessment and Treatment

Clinicians tend to interpret each patient's presenting complaints within the framework of diagnoses they know well. If they have been trained to recognize and treat depression and anxiety, but lack adequate training to identify and treat ADHD, clinicians are likely to interpret pa

Do all types of pain respond equally to medication containing opioids

Not all types of pain respond equally to the same medication. Opioid analgesics are helpful in controlling somatic or visceral pain. Bone pain may be helped partially by opioids. However, NSAIDs and steroids are highly effective in treating bone pain. The combination of NSAIDs and opioids is synergistic in controlling pain. Neuropathic pain, often described as pain with a burning, hyperesthetic quality, responds to a diverse group of drugs, including antidepressants (amitriptyline), anticonvulsants (carbamazepine or gabapentin), antiarrhythmics (mexiletine), muscle relaxants (baclofen), and a-adrenergic agonists (clonidine). Opioids may also be helpful. Frequently pain control is improved after 1 to 2 days of using adjuvant drugs. Alternative medications may also help to control somatic or visceral pain. Drugs that control pain by different mechanisms may be synergistic when used together (such as NSAIDs and opioids). By using lower doses of two different agents, the patient may have...

How is pain of malignant origin treated

Pain of malignant origin should be aggressively treated with a multiple therapeutic approach. This approach should initially be pharmacologic with introduction of short- and long-acting opioid preparations and some adjuvants. Adjuvants should be chosen according to the symptomatology and their side-effect profile. For example, nonsteroidal antiinflammatory drugs (NSAIDs) and steroids are very useful in the treatment of bone pain from primary or metastatic disease anticonvulsants and tricyclic antidepressants (TCAs) can be used in the treatment of neuropathic pain from compression or from previous interventions such as chemotherapy or radiation therapy.

Thomas A Widiger And Stephanie Mullinssweatt

The question of whether mental disorders are discrete clinical conditions or arbitrary distinctions along dimensions of functioning is a long-standing issue (Kendell, 1975), but its significance is escalating with the growing recognition of the limitations of the categorical model (Widiger & Clark, 2000 Widiger & Samuel, 2005). Indeed, in the last 20 years, the categorical approach has been increasingly questioned as evidence has accumulated that the so-called categorical disorders like major depressive disorder and anxiety disorders, and schizophrenia and bipolar disorder seem to merge imperceptibly both into one another and into normality . . . with no demonstrable natural boundaries (First, 2003, p. 661). In 1999, a DSM-V Research Planning Conference was held under joint sponsorship of the APA and the National Institute of Mental Health (NIMH), the purpose of which was to set research priorities that would optimally inform future classifications. One impetus for this effort...

Rasagiline Parkinsons Disease [7987

Precursor, is a standard line of treatment for PD, many patients begin to experience motor complications after several years of artificial dopaminergic stimulation. As an adjunct therapy, rasagiline treats the fluctuations in motor symptoms. The R-enantiomer exhibits 4-times the potency of the S-enantiomer, so the synthetic method begins with the optical resolution of racemic N-benzyl-1-amino-indan using (R,R)-tartaric acid as the resolving agent. Once isolated, the enantiomerically-enriched salt is submitted to hydrogenolysis to afford 1(R)-aminoindane that is subsequently propargylated to provide rasagiline. It is formulated as its mesylate salt, and the recommended dosage of rasagiline is 1 mg day, with or without levodopa. As an irreversible inhibitor, frequent dosing is not necessary since the duration of action is not driven by half-life regeneration of MAO-B is the critical factor in the duration of action. Rasagiline is rapidly absorbed with a Tmax of approximately 0.5 h and a...

Clinical Findings With Crfr1 Antagonists

The first clinical efficacy results were reported in 2000 from an open-label study with R121919 NBI-30775 (36) in patients with major depressive disorder 88 . R121919 is a potent CRF-R1 antagonist, having a Ki of 3.5 nM (human CRF-R1) and efficacy in a number of preclinical animal models 89 . In the open-label trial, 10 patients were treated with 36 at an escalating dose of 5-40 mg day over 30 days, while 10 patients were treated with an escalating dose of 40-80 mg day over 30 days. R121919 was found to be safe and well-tolerated at all doses. Significant reductions in anxiety and depression scores were obtained using both patient and clinician ratings, with the group receiving the higher dose showing a better overall response. While these results were promising, progression of 36 was halted due to elevated liver enzymes in normal subjects in an extended Phase 1 study 7 . It was noted that these findings are unlikely to be CRF-R1 mediated since these receptors are absent in the liver....

Nonstimulant Medications for ADHD

Ety and depressive symptoms that often appear with ADHD and are less likely to be alleviated by stimulants. tified tricyclic antidepressants and buproprion as second-line agents for treatment of ADHD. Clinicians are advised to utilize second-line agents for ADHD only if an individual fails to respond adequately to adequate trials of at least two stimulants and ATX. Tricyclic Antidepressants Tricyclic antidepressants (TCAs) were introduced in the late 1950s as an effective treatment for major depression. Medications in this class include imipramine, desipramine, nortriptyline, and others all act primarily on the noradrenergic system. TCAs remained the primary agents for treatment of depression until the advent of selective serotonin reuptake inhibitors in 1987. Most of the research on use of TCAs for treatment of ADHD has focused on desipramine and nortriptyline.

Achieving Emotional Stability

If the woman has a diagnosable mood disorder, whether she is depressed all the time or her feelings are labile, moving among feeling happy, sad, angry, anxious, and depressed, it is important to help her gain some mastery over her feelings. There are several ways that this can be done using structured treatment modalities such as cognitive behavioral therapy or dialectical behavior therapy (DBT) or simply providing supportive treatment. Teaching women to label their feelings and thoughts accurately and to better understand how their feelings, thoughts, and behavior all interact together is a good initial step when working with women who seem to have little control over letting their emotions control their behavior. We described the impact of mood stabilizers and antidepressant medication on developing fetuses in Chapter 5. Pregnancy causes hormonal changes that in turn affect women's mood fluctuations so it is important for the therapist to understand how these normal mood...

Norepinephrine dopamine reuptake inhibitors NDRIs

Triple reuptake inhibitors (TRIs), which inhibit reuptake at all three transporters, have attracted considerable interest in recent years 77 . The involvement of dopamine reuptake in the etiology of depression and other CNS disorders has been recognized 29,30 . As a result, TRIs have been proposed to offer a faster onset of action and improved efficacy for depression over currently prescribed single or dual action monoamine reuptake inhibitors. Historically, the mesocorticolimbic dopamine pathway is thought to mediate the anhedonia and lack of motivation observed in depressed patients 78,79 . In addition, methylphenidate, both immediate release and extended release formula, has been found to be effective as an augmenting agent in treatment-resistant depression 4 . Furthermore, clinical studies using the combination of bupropion and an SSRI or SNRI have showed improved efficacy for the treatment of MDD in patients refractory to the treatment with SSRIs, SNRIs, or bupropion alone...

Application of Microarrays to Neuropsychiatry Disorders

Neuropsychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are complex diseases, whose exact etiology is unknown. Evidence suggests genetic, developmental, and environmental factors combine to create each disorder, with susceptibility loci for SZ, BD, and MDD identified throughout the genome. With an absence of clearly defined genetic factors on which cellular and animal models can be generated, to further the understanding of this spectrum of disorders, gene expression analysis of postmortem material has been utilized to distinguish 6.2. Major Depressive Disorder

Utility Of Snps In Medicine And The Pharmaceutical Industry

Safety diagnostics require very accurate and predictive markers whereas the utility of efficacy markers may not necessitate the same stringent criteria. The use of a SNP-based genetic marker to increase the probability of response in a clinical development setting could have direct impact on the sample size required for a clinical trial. However, while the marker may predict an increased probability of response within a population of subjects, the predictability may be lower for an individual. The treatment of major depression with selective serotonin reuptake inhibitors (SSRIs) is well established. The SSRI class of compounds all have high affinity for the serotonin transporter. This transporter contains a polymorphism in a regulatory region upstream from the gene that influences expression levels of the protein. The polymorphism consists of a long and short form, based on the number of a 44 basepair repetitive element. The long form is associated with increased expression. Subjects...

The Relationships Between Lipid Profile Levels Depression and Suicide Attempts

Depressive Symptoms or Depressive Disorders Most of the data that examined depressive symptoms and lipid profile levels have been from the community studies performed in different countries by the self-related depression scales. Most of these studies were performed by psychiatrists according to specifically clinical criteria in psychiatric inpatients or outpatients or in patients admitted for general health screening. 2.1.1. Depressive Symptoms and Lipid Profile Levels in the Community Lower cholesterol levels have been found in some patients with depressive symptoms 21, 22 , but not in others 23-26 . Troisi et al. also found no significant association in the younger age group (< 50 years of age) 27 . In contrast, in a subgroup of older women, serum cholesterol was negatively and significantly correlated to negative mood with the self-rated scales. Restricting analysis to the subjects in the highest quartile of the age distribution (> 60 years of age) yielded a much stronger...

Neuropsychiatric Symptoms In Corticobasal Degeneration

In 14 patients with a neuropathological diagnosis of CBD selected from the research and neuro-pathological files of seven medical centers, the presenting symptom was dementia in 21 , frontal behavior (i.e., apathy, disinhibition, and irritability) in 21 and depression in 7 . Subsequently, dementia and depression had developed in 30-40 , and at the last visit, 58 showed frontal behaviors (84). Dementia as a presenting symptom in CBD was also reported in another postmortem study (85). A high prevalence of frontal behaviors was also reported in one of the few prospective studies reported. Kertesz et al. followed 35 patients with a clinical diagnosis of CBD and included a structured evaluation of language, cognition, and personality changes (Frontal Behavioral Inventory or FBI see ref. 86), which was specifically designed to assess the spectrum of apathy and disinhibition in frontotemporal dementias (87). They found two groups of patients according to the initial presentation 15 (43 )...

Agomelatine and derivatives

Anti-depressant efficacy in human phase 2 clinical trials has been shown by agomelatine 65 . In a randomized placebo controlled trial, agomelatine (25 mg day) after 2 and 4 weeks of treatment was significantly more effective than placebo in treating depression (based on HAM-D scores). Additionally, agomelatine was significantly more effective than placebo at treating a subpopulation of severely depressed patients whereas paroxetine was not significantly different from placebo. Agomelatine also decreased the severity of anxiety associated with depression and was well tolerated with adverse effects similar to placebo.

Neuropsychiatric Symptoms In Multiple System Atrophy

Several reports have described depressive symptoms in MSA (16,92-95). In a study of 15 patients clinically diagnosed with Shy-Drager syndrome using the BDI, 86 scored in the depressed range (i.e., BDI score 10-15), and 29 scored in the moderately depressed range (BDI score 16-19). The mean BDI score was 14.4. This score is comparable to that reported in a community-based sample of patients with PD, who had a mean BDI score of 12.8, compared to 7.9 in patients with non-neurological chronic disease (diabetes mellitus) and 5.9 in healthy elderly controls (52). Severity of depression did not correlate with disability or ability to perform activities of daily living (ADL) (95). In another study using the BDI, 3 of 15 (20 ) patients had a score over 15, and MSA patients had similar severity of depression as PD patients (94). The importance of depression in MSA is underlined by reports showing that MSA patients may initially present with an affective disturbance (92,96). Fetoni et al....

Norepinephrine reuptake inhibitors NRIs

The neurotransmitter norepinephrine is believed to play an important role in the etiology of depression. Approved antidepressants that belong to monoamine oxidase inhibitor (MAOI), TCA, SNRI, NRI and NDRI drug classes influence central norepinephrine function 17 . The development of selective NRI compounds has resulted in considerably fewer FDA approved drugs compared with the SSRI drug class 18 . No NRIs have been approved for treatment of depression in the U.S. and only reboxetine (8) has been approved for use in Europe 19 . In a recently reported double-blind study of 357 patients with major depressive disorder comparing the efficacy and tolerability of reboxetine and citalopram, both treatments produced similar efficacy 20 . However, there was a higher prevalence of sexual dysfunction in the citalopram group in this study. In another recently reported clinical trial, the combination of reboxetine and an SSRI appeared to be effective in cases of SSRI-resistant depression 21 .

Corticotropinreleasing factor

Corticotropin-releasing factor (CRF) is a well-known regulator of the hypothalamic-pituitary-adrenal (HPA) axis, which is activated in response to stress. Hyperactivity of the HPA axis has been linked to depression in humans, and both the elevation of CRF concentrations in the cerebral spinal fluid (CSF) and an increase in the number of CRF-containing neurons in the paraventricular nucleus have been observed in depressed patients. In addition, some antidepressants (e.g., desipramine and fluoxe-tine) have been shown to decrease CRF levels in the CSF. Furthermore, a number of CRF1 antagonists exhibits anxiolytic and antidepressant activity in certain animal models 37,38 . For example, antalarmin (CP-154,526) produces antidepressant-like responses in the rat learned helplessness and mouse chronic mild stress models of depression. Several CRF1 antagonists have reached human clinical trials, but to date SSR125543, 23, was orally active in the rat forced swim test (30mg kg, p.o.), and...

Therapeutic Alternatives and Developping Treatments in Refractory Urge Incontinence and Idiopathic Bladder Overactivity

Conservative therapies such as pelvic floor exercises, bladder retraining, electrical stimulation of the pelvic floor and pharmacotherapy involving anticholinergics, antispasmodics and tricyclic antidepressants are primary discussed. The use of pelvic floor muscle training with or without biofeedback for overactive bladder is suggested to inhibit detrusor muscle contraction by voluntary contraction of the pelvic floor at the same time, and to prevent sudden falls in urethral pressure by change in pelvic floor muscle morphology, position and neuromuscular function 17 . Some promising results have been reported, and these treatments are widely used, but there is still a need for high quality randomized trials on the effect of pelvic floor exercises on the inhibition of detrusor contraction. Detrusor over-activity current pharmacological treatment involve use of muscarinic receptor antagonists, but their therapeutic activity is limited by side effects resulting in the non continuance of...

Competitive inhibitors

Tricyclic antidepressants such as imipramine (25), clomipramine (26), amitripty-line (27), and doxepine (28) were found to be weak inhibitors of GST P1-1 in vitro. Inhibition of GST P1-1 was enhanced with the introduction of a chloro group on the dibenzazepine ring (25 40 inhibition at 15 mM 26 70 inhibition at 10 mM). The same result was observed with the substitution of an oxygen for a carbon in the heptadiene ring (27 18 inhibition at 10 mM 28 48 inhibition at 15 mM) 35 .

Clinical Phenotypes in Depression and Molecular Levels

In clinical studies, major depressive disorder has had four specifiers, including melancholic feature, atypical feature, catatonic feature, and postpartum onset. In the future, we should investigate the distributions of the four specifiers of depression among patients with physical illness and discuss which biological markers could link the depressive disorder and the physical illness. 4.1. Lipid Profile Levels in Patients with Major Depression with Melancholic Feature, Atypical Feature, Catatonic Although there are papers that discuss the relationships between cholesterol, lipid profiles, and major depression 34-39 , there are few data that discuss the association between lipid profiles and depressive disorders with different phenotypes. Huang and Chen investigated the correlation between serum lipid, lipoprotein concentration, and major depressive disorder in patients evaluated for general health screening 41 . They found that analysis of covariance after age adjustment revealed...

Recent Advances in Development of Novel Analgesics

Introduction - Nonsteroidal anti-inflammatory drugs (NSAIDs, e.g. aspirin, ibuprofen and naproxen), opioids (e.g. morphine) and a variety of adjuvant agents (e.g. tricyclic antidepressants, lidocaine and certain anticonvulsant agents) have been mainstays of pain therapy for decades. All these agents suffer from drawbacks in clinical use. The NSAIDs are associated with gastrointestinal side effects, increased bleeding time and do not effectively ameliorate severe pain. The opioids can produce tolerance and dependence, constipation, respiratory depression and sedation. Adjuvant agents, which non-selectively block sodium channels, are associated with CNS and cardiovascular side effects. Currently available analgesics also have limited utility in treatment of neuropathic pain (pain arising from nerve injury). Thus, there is a significant unmet medical need for safer and more effective analgesic agents, and this need is likely to be met by identification of novel ligands for newly...

Labour and delivery

There is a need for a high level of awareness amongst all healthcare professionals involved in intrapartum and postnatal care. Symptoms and signs suggestive of depressive illness must be treated promptly. Tri- and tetracyclic antidepressants, the selective serotonin reuptake inhibitor group of antidepressants and MAOIs may all be necessary in the treatment of both non-pregnancy-related and postnatal depression. Electroconvulsive therapy may also be indicated.

Duloxetine Antidepressant [3038

Duloxetine is a selective serotonin (5-HT) and norepinephrine reuptake inhibitor (SSNRI) for oral administration, and it is currently approved in the US and in Europe for the treatment of major depressive disorder (MDD) and diabetic peripheral neuropathic pain (DPN). Additionally, it is indicated for the treatment of stress urinary incontinence (SUI) in Europe. However, the US approval for SUI is still pending, and Lilly recently withdrew the NDA for this indication. It is expected that additional clinical trials may be required to secure FDA approval for SUI treatment due to concern over the potential of duloxetine to prolong the QT interval in patients taking concomitant CYP2D6 or CYP1A2 inhibitors such as tri-cyclic antidepressants, type 1C antiarrhythmics and phenothiazines. Duloxetine is the second SSNRI to enter the market. Its predecessor, venlafaxine, has been available since 1994 for the treatment of depression. Duloxetine has a higher affinity for human norepinephrine (K 7.5...

Summary

Research on the role of CRF in stress-related disorders has continued at a vigorous pace over the past several years 1-10 . While much basic research supports the potential of CRF receptor antagonists for treatment of these disorders, clinical results testing this concept have been slow to emerge and are mixed in outcome. Studies such as the open-label trial with R121919 NBI-30775 suggest positive results, while the more recent trials with CP-316,311 and GW-876008 showed a lack of efficacy for depression and anxiety end points, respectively. With a number of trials ongoing for treatment of anxiety, depression, and IBS, the potential utility of these agents is expected to become clearer over the next few years, particularly as the newer compounds may have different in vivo profiles (e.g., pharmacokinetics and potency) than the compounds tested to date. Possible expansion of the utility of CRF-R1 antagonists into the areas of drug addiction and feeding disorders should further enhance...

Ht6 Receptor Family

The 5-HT6 receptor is another GCPR in the serotonin family that positively couples to adenylyl cyclase through the G-protein Gs 96-98 . By mRNA, antibody mapping and radioligand binding, the receptor distribution in the CNS of humans and rats is most evident in the striatum with densities also noted in several other important brain regions 99-101 . The localization of 5-HT6 receptors to limbic regions and the high affinity of therapeutic antipsychotics and antidepressants, have resulted in significant efforts to identify selective 5-HT6 ligands for use in bipolar disorders, Parkinson's disease, and other affective disorders 102,103 . Furthermore, there has been a plethora of reports in the last five years implicating 5-HT6 therapeutics in the modulation of cholinergic neurotransmission 104 . The application of these discoveries has led to significant effort in identifying selective 5-HT6 ligands as potential therapeutics for Alzheimer's disease and other cognitive disorders.

Conclusion

The search for new drugs based on monoamine reuptake inhibition continues in an effort to find more effective treatments for MDD as well as a variety of other diverse clinical indications. The movement toward novel monoamine reuptake inhibitors with broader transporter reuptake inhibitor profiles (SERT, DAT and NET) is driven by the substantial patient populations that do not respond to the drugs in the SSRI class as well as the need for drugs with faster onset of action. Results from clinical trials where SSRIs are augmented with drugs like methyl-phenidate or bupropion support the benefit of adding DA reuptake inhibition in the design of new monoamine reuptake inhibitors. Other studies of this kind are likely to further elucidate the factors important for making better antidepressants.

Biology Of Melatonin

Other effects of melatonin described in the literature include its neuroprotective, antiinflammatory, pain modulatory, retinal, vascular and antioxidant properties 3,14-20 . This chapter focuses on the use of melatonin and synthetic melatonin agonists for the treatment of sleep, major depression and anxiety.

Kainate Receptors

Signaling pathways (Burns et al. 1997 Niswender et al. 1999 Price et al. 2001). In addition, cells expressing more highly edited 5HT2C receptors (e.g. VSV and VGV) demonstrate considerably reduced (or absent) constitutive activation in the absence of ligand compared to cells expressing the non-edited isoform (Niswender et al. 1999). This reduction in coupling efficiency and constitutive activity derives from a difference in the ability of edited 5HT2C isoforms to spontaneously isomerize to the active R* conformation, a form of the receptor that interacts efficiently with G-proteins in the absence of agonist (Burns et al. 1997 Niswender et al. 1999). As a consequence, the observed potency of agonists with increased affinity for the R* state is disproportionately reduced (Werry et al. 2008) and the 'functional selectivity' of receptor stimulus may be lost (Berg et al. 2001). More recent studies have indicated that alterations in 5HT2C editing are observed in suicide victims with a...

Pathology

A limitation of this proposal, however, is the absence of consensus as to fundamental pathologies that should be required. Pathologies are not currently included within diagnostic criterion sets in part because there is insufficient empirical support favoring one particular cognitive, interpersonal, neurochemical, or psycho-dynamic model of pathology over another (Widiger, 2004). Wakefield (1997), for example, indicated that in order to provide a meaningful distinction between major depressive disorder and normal bereavement, it is necessary to formulate some account . . . of the evolutionary programming of the mechanisms with respect to what kinds of triggering circumstances are supposed to cause which kinds of responses (e.g., loss-response mechanisms are designed so that perceptions of major losses trigger roughly proportional sadness responses) (p. 647). Wakefield's (1992) conceptualization of mental disorder is tied to evolutionary theory. Evolutionary theory has enriched current...

Adherence

As with all medical treatment the adherence of the patient to the regime is vital to its success. Erratic drug intake results in subtherapeutic drug levels with treatment failure and resistance. In patients on short-term courses of antivirals for acute infections, such as primary herpes simplex, this is less of a concern. In HCV the patients require to undergo treatment with a combination of interferon and ribavirin for 6 months or more. The interferon is given by subcutaneous injection and most patients experience flu-like illness and lethargy, with a significant percentage suffering depressive symptoms. Especially as the patient may not have felt particularly unwell prior to treatment, the future benefits may be less obvious to them than the acute side effects. In HIV, regimes are complex with multiple drugs and significant side effects, particularly given the long-term nature of treatment. Adherence may be compromised by all these factors. It is important that regimes are kept as...

Cingulate Gyrus

Reduced blood flow (Bench et al., 1992) and tissue volume (Drevets et al., 1997) have been reported in the anterior cingulate gyrus of depressed patients as compared to controls. Drevets et al. (1997) have in particular drawn attention to decreased activity in the subgenual prefrontal cortex (ventral to the corpus callosum, corresponding to a part of the anterior cingulate gyrus), especially in untreated familial depression. Subsequently, a focus of increased metabolism centered within the area of decrease identified by Drevets et al. (1997) and associated with depressed mood was identified specifically in subgenual area 25 (Mayberg et al., 1999). High-frequency deep brain stimulation targeting area 25 has been shown in early trials to improve the clinical picture of some patients with chronic, treatment-resistant depression (Mayberg et al., 2005).

The lifespan

At the end of a year, when Terry and his wife returned, quite fit-looking and keen to get on with their various plans, Alan had been taking antidepressants for some months and was oddly sombre. For the first time that Terry could remember, he and Alan seemed to have nothing to say to each other, even though they tried. After an evening that the two couples spent together, Terry's wife commented, 'Don't you think that Alan's looking old He seems to have aged a lot since we were away.'

Hippocampus

More recent attention has been drawn to alteration of hippocampal size in the affective disorders and in some stress-related disorders such as post-traumatic stress disorder (PTSD). Adults with PTSD have been shown to have smaller hip-pocampal volumes bilaterally compared with trauma-exposed people without PTSD and non-traumatized controls (Kitayama et al., 2005), although whether this represents a biological predisposition from genetic and familial factors or secondary changes from the consequent metabolic changes of the stress itself is unclear. It seems established that apoptosis (cell death) occurs in the postnatal hippocampus, and that in animal models, psychotropic drugs such as antidepres-sants and electroconvulsive stimulation can lead to neurogenesis in the adult hippocampus. Thus, the plasticity within the structure is potentially substantial, and perhaps interlinked with its central role in the modulation of so many behaviors including memory. Steroids have been shown to...

Depression

Dixon et al. reported on 262 patients with depression who were studied before and up to 4 yr after weight-loss surgery. Before the procedure, patients fell evenly into each of four categories (major depressive illness, moderate depression, mild depression, and normal status) as measured by the Beck Depression Inventory. At 1 yr, there were major reductions in the proportion of patients in each of the depression groups, with 75 of patients assessed to be normal. Four years after the procedure, the beneficial effect persisted (40).

Bipolar Disorder

Bipolar disorder (BPD) is also among diagnoses classified by Pennington as disorders of motivation and arousal. Formerly known as manic-depressive disorder, this syndrome is characterized by episodes during which the individual manifests an intense increase in elation, grandiosity, and rapid or racing thoughts, usually with decreased need for sleep and often with hypersexuality or increased frequency of other activities that may be pleasurable, but are likely to create serious difficulties for the individual. Such episodes alternate in longer or shorter intervals with episodes of major depression. Switches between the manic and depressive moods may occur with no clear cause. Individuals with BPD also have elevated risk for substance abuse and suicide. It is not only the severity of irritability that differentiates these two disorders. Geller found that suicidal tendencies occurred in 25 percent of the BPD children psychosis was seen in 60 percent and mixed mania, a combination of...

Epidemiology

For example, nicotine is usually not considered a substance of abuse in dual diagnosis research, despite the high rates of use among individuals with both mental illness (Lasser et al., 2000) and substance abuse (Bien & Burge, 1990), as well as a growing literature that suggests that nicotine dependence has links, perhaps biological in nature, to both major depression (Quattrocki, Baird, & Yurgelun-Todd, 2000) and schizophrenia (Dalack & Meador-Woodruff, 1996 Ziedonis & George, 1997). Others have found elevated rates of psychiatric and substance use disorders in smokers (Keuthen et al., 2000). Taken together, factors such as the type of problematic substance use assessed, the measures that are used, and the specific substances that are included in an assessment all contribute to varying meanings of the term dual diagnosis.

Pde11 Inhibitors

A recent study examined the role of all PDEs and their potential genetic contribution to major depression disorder (MDD). Interestingly, variants in PDE9A and PDE11A were found to be associated with the diagnosis of MDD, while variants in PDE1A and PDE11A were associated with remission on antidepressants. This highlights a potential role for PDE11A in the pathophysiology of MDD. Two recent PDE11 inhibitors, 19 (PDE11A IC50 0.7 nM PDE5 selectivity > 1000-fold) and 20 (PDE11A IC50 3.5 nM > 1000-fold selectivity versus PDE 2, 3, 4, and 5) illustrate compounds structurally unrelated to tadalafil (21) that are active as PDE11 inhibitors 39,40 . Tadalafil has been shown to inhibit PDE11 with an IC50 of approximately 40 nM 41 . These compounds were studied as potential anti-diabetic agents. However, because of their selectivity profiles, they may be useful probes to explore PDE11A biology in the CNS.

Hirsutism In Abdomen

Weight gain that is primarily centripetal, especially if associated with extremity wasting, purple striae, easy bruisability, moon facies, and rubor, suggests the presence of Cushing's syndrome, and these patients should be appropriately screened using 24-hour urinary-free cortisol levels or a cortisol level following an overnight dexamethasone suppression test. Other information that should be sought includes the patient's awareness of her body fat distribution, as women with PCOS have a greater prevalence of abdominal obesity (29). Weight gain may also be associated with carbohydrate craving and evidence of postprandial reactive hypoglycemia, particularly in mid-afternoons. For example, Holte and colleagues found that although insulin resistance in obese women with PCOS was reduced by weight loss to similar levels as BMI-matched controls, these patients continued to demonstrate an increased early insulin response to glucose, which could stimulate appetite and persistent weight gain...

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