Depression Causes and Treatment

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. Read more here...

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Indirect Indicators Of Irs Activation In Major Depression

If there is an IRS activation in major depression, it was anticipated to find other indicators of IRS activation, such as lower serum zinc (Zn), and specific alterations in fatty acid metabolism and the erythron. Other hallmarks of IRS activation are lower serum total cholesterol, high-density-lipoprotein cholesterol (HDL-C), a lower esterified cholesterol total cholesterol ratio, decreased activity of lecithin cholesterol acyltransferase (LCAT EC 2.3.1.43), and specific changes in polyunsaturated fatty acids (PUFAs). There is now some evidence that alterations in fatty acid metabolism and the composition of phospholipids in serum and membranes are involved in the pathophysiology of major depression (Horrobin, 1990 Smith, 1991 Maes, Delanghe, Meltzer, D'Hondt, & Cosyns, 1994a Maes, Smith, Christophe, Cosyns, Desnyder, & Meltzer, 1996a Maes, Vandoolaeghe, Neels, Demedts, Wauters, & Desnyder, 1997c Hibbeln & Salem, 1995 Maes & Smith, 1998 Peet, Murphy, Shay, &...

Neuroendocrine Disorders In Major Depression And Irs Activation

Proinflammatory cytokines have profound effects on the peripheral and brain serotonergic systems. Peripherally and central administration of IL-lp, IFNy, and TNFa increase extracellular 5-HT concentrations in several brain areas such as the hypothalamus, the hippocampus, and the cortex (Clement, Buschmann, Rex, Grote, Opper, Gemsa, & Wesemann, 1997). IL-ip modulates the activity of the 5-HT transporter (Ramamoorthy, Ramamoorthy, Prasad, Bhat, Mahesh, Leibach, & Ganapathy, 1995), which plays a central role in serotonergic neurotransmi-sion by reuptake of 5-HT. Proinflammatory cytokines, such as IL-1 and IFNy may induce the activity of indoleamine-2,3-dioxygenase (IDO), the first enzyme of the kynurenine pathway, which converts tryptophan, the precursor of 5-HT, to kynurenic acid and quinolinic acid. Induction of IDO, which occurs in infection or inflammation, may be detrimental because it leads to depletion of the plasma concentrations of L-tryptophan and...

Indicators Of Immune Activation In Depressed Patients

An interaction of genetic factors with environmental factors, including stress and infectious agents, is assumed to play a causal role in the pathogenesis of major depression. Since the rate of major depression in genetically succeptible populations has continued to increase over the past years, the identification of these environmental factors would provide targets for more effective antidepressant agents. thalamic-pituitary-adrenal (HPA) axis that is associated with immune inflammatory reactions. Hypercortisolism is one of the most consistent findings in depression (Carroll et al., 1976 Nemeroff., 1996). There is substantial evidence from clinical studies that the hypercortisolemia seen in major depression is due to hypersecretion of corti-cotropin-releasing hormone (CRH) (Gold et al., 1994 Holsboer et al., 1984).

Immune Activation In Major Depression

The status of the immune system in major depression has been extensively studied over the last ten years and there is now some evidence that the acute episode of this illness may be accompanied by immune activation acute phase response (Maes., 1993 Sluzewska et al., 1996b). The acute phase response (apr) is a response of the organism to disturbances of its homeostasis due to factors such as, infection, tissue injury, neoplastic growth or immunological disorders (Heinrich et al., 1990). Within this systemic reaction, that involves the endocrine, immunologic and metabolic system (Kushner and Mackiewicz., 1993), there are also behavioural changes, which are expressed as sickness behaviour, characterised by psychomotor retardation, sleep disturbances, anorexia, anergy, and lethargy (Kent et al., 1992). Changes in immune response in major depression include activation of the monocytic and T-lymphocytic arm of cell-mediated immunity (CMI), the apr, and autoimmune response. The presence of...

Cytokines In Major Depression And

Among the immune-inflammatory markers studied in depression there are the pro-inflamatory cytokine IL-6, soluble IL-6 receptor (sIL-6R), and soluble interleukin-2 receptor (sIL-2R) as well as soluble transferrin receptor (sTfR). Maes et al. (1995a) and Sluzewska et al. (1995a, 1996b) found significantly elevated concentrations of all the above-mentioned cytokines and soluble receptors in acute depressive episodes. Furthermore, Maes et al. (1995a) observed this too in clinical remission patients in comparison with normal controls. The soluble form of the IL-6 receptor (sIL-6R) is the only soluble interleukin receptor which, after combining with IL-6, intensifies its bio-activity (Bock et al., 1992). As an index of the potentiating effects of plasma sIL-6R on IL-6, the product term sIL-6R x IL-6 is computed in clinical studies. In our previous study (Sluzewska et al., 1996b), we demonstrated that the value of the product term was three times higher in depressed patients than in healthy...

Tricyclic Antidepressants

Examples of least anticholinergic tricyclic antidepressants (TCAs) include amitriptyline 10-25 mg qhs and desipramine 10-25 mg qhs. Nontricyclic antidepressants that have both serotonin and norepinephrine reuptake inhibition effects (norepinephrine reuptake inhibition is necessary for pain modulation) are venlafaxine (Effexor , Pfizer, New York, NY) > 150 mg for norepinephrine, duloxetine (Cymbalta , Eli Lily, Indianapolis, IN) 30 mg day advancing to 60-120 mg day, bupropion (Wellbutrin , Glaxo-Smith-Kline, Philadelphia, PA) SR 150-300 mg day, and trazadone (Deseryl , Bristol-Myers-Squibb, New York, NY) 50-300 mg day (avoid in men due to risk of priapism) (Management of Chronic Pain Syndromes 2005). Bupropion lowers seizure threshold, but at the recommended dose the risk of seizures is comparable to that observed for other antidepressants. Bupropion is an effective antide-pressant on its own but it is particularly popular as an add-on medication in the cases of incomplete response...

Cytokines And The Hpa Axis In Major Depression And

In 60 major depressed inpatients from the Department of Adult Psychiatry in Poznan, all Caucasians with and without melancholia, the DST test was performed (Sluzewska et al., 1995b). Among those patients with an abnormal DST response, the concentrations of AGP were significantly higher than in the DST suppressors. Pathological results were observed in 33 of the patients and among them 38 suffered fromTRD. In our previous study, a significant correlation between morning plasma Cortisol levels and levels of AGP was found in the depressed patients, which could suggest an effect of glucocorticoides on AGP synthesis (Sluzewska and Rybakowski, 1993). Recent data obtained from 33 TRD patients (Sluzewska et al., 1997c) reveal a significant positive correlation between the morning plasma Cortisol levels and the plasma concentrations of IL-6, sIL-2R, AGP, ACT. Further, Maes et al. (1995c) found positive correlations between IL-6, as well as sIL-2R, and Cortisol in major depressed patients, and...

Choice Of Antidepressant Medication And Dosing

The usual dosages and dose ranges of antidepressant medications are listed in Table 17-1, along with the severity of common side effects. Although they usually are used initially in divided doses, transition to a single daily dose usually is possible due to the relatively long half-lives and wide range of tolerated concentrations of most antidepressants. With the tricyclic antidepressants, dosing is most safely done with single doses up to the equivalent of 150 mg of imipramine. Indications for the MAO inhibitors are limited and must be weighed against their potential toxicity and their complex interactions with other drugs. Thus, the MAO inhibitors generally are considered drugs of late choice for the treatment of severe depression. Nevertheless, MAO inhibitors sometimes are used when vigorous trials of several standard antidepressants have been unsatisfactory and when ECT is refused. In addition, MAO inhibitors may have selective benefits for conditions other than typical major...

Other Antidepressants

Although less extensively studied than the previously mentioned antidepressants, there are some data suggesting the potential utility of bupropion, nefazodone, trazodone, and mir-tazapine for selected pain states (Ansari 2000, Bendtsen and Jensen 2004, Samborski et al. 2004, Saper et al. 2001, Semenchuk and Davis 2000, Ventafridda et al. 1988). Given the limited number of randomized controlled trials and small sample sizes, definitive statements regarding the utility of these agents and the generalizability of results are not possible.

Depressive Disorders in Children

Depressive disorders in children and adolescents include major depressive disorder (MDD), depressive disorder not otherwise specified ( depressive disorder nos) and dysthymic disorder. Discussion in this essay will be limited to major depressive disorder because there are no controlled trials for the treatment of dysthymic disorder or depressive disorder nos. However, in clinical practice, treatment recommendations for MDD are successfully used in the management of dysthymic disorder and depressive disorder nos. MDD in children and adolescents is characterized by one or more major depressive episodes, defined as at least 2 weeks of persistent change in mood manifested by either depressed or irritable mood or loss of interest or pleasure and at least four additional symptoms of depression, including changes in appetite or weight, sleep, psychomo-tor activity, decreased energy, feelings of worthlessness or guilt, difficulty thinking or concentrating, or recurrent thoughts of death or...

Antidepressants and Immune System Activation

The term antidepressant has been depicted, more than once, as a misnomer, given the wide spectrum of activity evinced by these pharmacological agents. Adding to this activity spectrum are findings that antidepressants have clear immunomodulatory effects in animals and humans. In general, antidepressants have been found to decrease immune responsiveness (Kenis and Maes 2002). Because of this, these agents may be of benefit for a wide range of symptoms that arise in the context of immune activation. Of special interest, given the ability of inflammatory cytokines to induce sickness behavior and or major depression, a number of antidepressants have been reported to attenuate proinflammatory cytokine production, not just from peripheral immune cells (Maes 1999) but also from within the CNS, where desipramine has been reported to diminish TNF-k release within the locus coeruleus (Ignatowski and Spengler 1994). Interestingly in this regard, the antidepressant efficacy of desipramine during...

Pharmacologic Antidepressants

Tricyclic antidepressants (TCA) have been shown to be safe and effective in the treatment of neuropathic pain. Commonly used agents include amitriptyline, nortriptyline, imipramine, desipramine. These agents have been studied in double-blind, randomized controlled trials with results suggesting that each of them reduces pain independent of their effect on depression (Portenoy et al. 1984). TCAs are thought to exert their analgesic effect by inhibiting norepinephrine and serotonin reuptake in the central nervous system. Unfortunately, they also effect cholinergic, histaminergic, and adrenergic transmission, resulting in some limiting side effects. These include sedation, orthostasis, cardiac arrhythmia, and urinary retention which may limit their usefulness in certain patient populations, especially the elderly. Since the introduction of tricyclic antidepressants, a number of newer generation of antidepressants have been developed. The selective serotonin and norepinephrine reuptake...

Indications And Efficacy Major Depression

The efficacy of the tricyclic and tetracyclic compounds in major depression is well established. The evidence for their effectiveness has been reviewed previously (Agency for Health Care Policy and Research 1993 Davis and Glassman 1989). Imipramine is the most extensively studied tricyclic antidepressant, in part because for many years it was the standard agent against which other new drugs were compared. In 30 of 44 placebo-controlled studies, imipramine was more effective than placebo. If data from these studies are combined, 65 of 1,334 patients completing treatment with imipramine were substantially improved, whereas 30 of those on placebo improved. Intention-to-treat response rates for placebo-controlled studies of imipramine in outpatients were 51 for imipramine and 30 for placebo (Agency for Health Care Policy and Research 1993). In most comparison studies, the other tricyclic and tetracyclic antidepressants have been found to be comparable to imipramine in efficacy. The...

Immune Effects of Antidepressants in Depressed Patients

Very few investigations have been carried out to assess the effect of antidepressant medication on immune parameters. When comparing various immune parameters, including percentage of T and B lymphocytes and mitogenesis, to psychological markers in two groups of treated and untreated patients, there was no clear relationship between psychological and immune parameters (Udelman & Udelman, 1985). However, some observations in the literature indicate that in patients treated with antidepressants, a normalization of immune parameters occured increased immune parameters were lowered whereas depressed immune parameters were restored (Table 1). Mitogenesis induced by ConA or PHA was reduced in depressed patients treated Table 1. Effects of antidepressants on immune functions in depressed patients Table 1. Effects of antidepressants on immune functions in depressed patients Immune alterations in depressed patients Effects of antidepressants

Possible Mechanisms For Immune Effects Of Antidepressants

In view of all the results presented in this review, it is clear that further research is required to fully elucidate the effect of antidepressant drugs on monocyte function and to specify the role of cytokines in the onset of depression. This line of research would help to extend our understanding of the pathogenesis of depression and may allow the development of new antidepressant drugs. However, different hypotheses can be already suggested with respect to the possible mechanisms underlying the immune effects of antidepressants. Antidepressants may modify immune reactivity by acting on the neural substrate which is involved in neuroimmunomodulation. Lymphocytes and macrophages are innervated by the sympathetic and parasympathetic nervous systems and this innervation modulates immune reactivity. Furthermore, immune cells are known to have receptors for neurotransmitters and antidepressants may modify the activity of immune cells by acting at the level of these receptors....

Do Antidepressants Interfere With Cytokine Production And Action

The hypothesis that cytokines play a key role in the pathophysiology of depression implies that antidepressant treatments should exert their effects by interfering with cytokine production and action. Antidepressants are usually not considered as anti-inflammatory drugs even if some psychopharmacologists have proposed that they behave as central inhibitors of prostaglandins (Leonard, 1987). However, if one goes beyond such general statements to investigate in details the ability of antidepressants to affect cytokine production and action, many surprising effects can be found. The ability of antidepressants to impair the release of Although pharmacologists are prompt to jump from such positive results to pathophysiological interpretations, there is still a long way to go. The preliminary results obtained in animals should encourage more systematic studies on the effects of various classes of antidepressants and non pharmacological treatments of depression (e.g., electroshock) on the...

Immune Alterations In Depressed Patients

Until now, very few investigations have been carried out to assess the effects of antidepressant medications on the immune alterations associated with depression and more specifically to assess whether antidepressants normalize immunity and or abrogate the production and release of proinflammatory cytokines. In order to answer these questions, it is first necessary to depict the immune status that is usually observed during depression. The immune parameters studied in depressed patients usually include mitogen-induced lymphoproliferation, natural killer cell activity, peripheral blood leukocyte counts and cytokine plasma levels. Lymphoproliferation induced by phytohemagglutinin (PHA), concanavalin A (ConA) or pockweed mitogen (PWM) has been usually found to be decreased in depressed patients. For example, Kronfol, Silva, Greden, Dembinski, Gardner, & Carroll (1983) found that this lymphoproliferation was reduced in depressed in-patients compared to healthy out-patient controls,...

Antibodies Against Serotonin And Gangliosides In Major Depression And

Several authors have show the occurrence of antinuclear, antiphospholipid and antiserotonin, antihistone, antibodies in depression (Villemain, 1988 Irwin et al., 1990 Maes et al., 1991 Schott et al., 1992). Some autoimmune disorders have been related to the induction of antihormone and anti-receptor antibodies (Cohen and Cook, 1986). We have recently reported the occurrence of antibodies against serotonin and gangliosides in major depressed patients (Sluzewska et al., 1997d). Antibodies against gangliosides have been shown to be part of the serotonin receptor complex (Fishman, 1988). Patients with major depression showed a significant antibody reactivity of IgG or IgM type to serotonin (55 of the patients) and to gangliosides (50 of the patients). In most patients the antibody against serotonin was associated with the antibody against gangliosides. 73 of the major depressed patients with antibodies against serotonin and 70 major depressed patients with gangliosides antibodies were TRD...

Avoiding Illicit Use by Combining Opioids with Antidepressants Antiepileptics

Antidepressants and antiepileptics are both effective in treating neuropathic pain, but a combination performs best. Nearly 80 of patients who took a combination of antiepileptics and antidepressant medications had a greater than 50 Visual Analogue Scale (VAS) improvement, a statistically significant finding. Whereas clinical trials have shown clear evidence in favor of using antidepressants and antiepileptic medications alone in treating chronic pain, no studies have been designed to focus on the effect of combining antidepressants and antiepileptics for the treatment of neuropathic pain. Over a 2-year period Dr. Robinson and collegues of Beth Israel Deaconess School, Harward Medical at Boston reviewed 6,129 charts with an initial encounter and a diagnosis of neuropathic pain. They also analyzed VAS, medical procedures, and antidepressant and antiepileptic use and dosage at each visit. Patients who had a 50 or greater improvement in their VAS score were considered to have a favorable...

Mechanism Of Action Of Tricyclic Antidepressants

Tricyclic Antidepressants

The termination of action of biogenic amines norepinephrine (NE) and serotonin (5-HT) is determined by reuptake into the presynaptic terminal. Drugs that block reuptake, such as tricyclic antidepressants, increase the efficacy of those transmitters by allowing them to remain in the synaptic cleft and activate the receptors longer (Figure I-51). It should be noted that although the exact mechanism of action of TCAs as analgesics is not known, there appears to be a close relationship between the inhibitory reuptake effects on biogenic amines and analgesic potency. While selective inhibitors of serotonin reuptake are less effective in treating pain, the ability to inhibit norepineprine reuptake is associated more strongly with analgesia. The dose of TCAs is lower than those dosages used to treat depression, suggesting that the analgesic properties are independent of their antidepressant properties. Figure 1-51. Tricyclic antidepressants (TCAs) acting at the descending noradrenergic- and...

The Role of Mixed Action Antidepressants in Therapeutics

Recently marketed non-SSRI antidepressants are considered by most clinicians as second-line therapeutic options for treatment refractory patients or as augmenting agents. Since these antidepressant medications act on different neuronal systems, they are a rational choice in non-responders (182). They are also used as adjunctive agents to augment SSRIs in partial responders. Their overall efficacy as antidepres-sants is comparable to that of the standard antidepressant classes such as SSRIs, TCAs, and MAOIs, and some data indicate superiority compared to SSRI in depression with melancholic or endogenous features. They are second-line agents because the SSRI are easier to dose, are available in generic form, and have few medically serious adverse effects. Trazodone has a limited role, but may be useful in promoting sleep in patients taking energizing antidepressants, or as an augmentation agent. Nefazodone is a very effective antidepressant but its use has declined since reports of...

Major Depression And Activation Of The Inflammatory Response System

Contemporary models of major depression emphasize the role of hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity and of dysfunctions in the turnover of serotonin (5-HT) or catecholamines in the etiopathogenesis of major depression. Contemporary models of major depression do not incorporate the effects of the inflammatory response system (IRS), even though the IRS powerfully influences HPA-axis activity, 5-HT and catecholaminergic turnover and even though activation of the IRS may induce depression-like behavior in animals and humans. There is now evidence that major depression is accompanied by a moderate activation of the IRS (reviews Maes, 1993 1995 1997 Maes, Smith, & Sch rpe, 1995c Holden, Pakula, & Mooney, 1997 Maes & Smith, 1997 Connor & Leonard, 1998 Maier & Watkins, 1998). In this paper we propose a concise IRS model of major depression. Indicators of IRS activation in major depression are confirmed findings of increased numbers of leukocytes, monocytes,...

Total Serum Protein And Electrophoretically Separated Protein Fractions In Major Depression And

Evidence for an apr that accompanies major depression was first reported by Maes et al. (1992a, b). The apr is reflected, too, in lowered levels of total serum protein (TSP) and changes in the major electrophoretically separated serum protein fractions. Several investigators (e.g. Schwartz et al., 1990 Joyce et al., 1992 Song et al., 1994a Maes et al., 1991, 1995b) reported lowered levels of serum albumin (Alb) in major depressed patients suffering major depression compared to normal controls. Interestingly, in the olfactory bulbectomized (OB) rat model of depression, Song and Leonard (1994b) found lower levels of Alb. The different apps migrate electrophoretically between Alb and gamma-globulin fractions. Apps such as AGP, ACT, CRP migrate in the alpha-1 zone, Hp and Cp migrate in the alpha-2 zone, fibrinogen and C3 migrate in the p zone, and immunoglobulines in the gamma-zone (Ritzmann and Daniels, 1976). This may explain why during apr there are alterations in TSP and in...

Effects Of Antidepressants On Depression Induced By Immune Activation

Antidepressants have been used successfully in treating depressive symptoms associated with various medical conditions (Katon & Sullivan, 1990). Both tricyclic antidepressants (TCAs) (Schiffer & Wineman, 1990) and selective serotonin reuptake inhibitors (SSRIs) (Scott, Nussbaum, McConnell, & Brill, 1995) have been used successfully in the treatment of depression associated with multiple sclerosis, stroke (Lauritzen, Bjerg Bendsen, Vilmar, Bjerg Bendsen, Lunde, & Bech, 1994), Alzheimer's disease (Gottfries, 1997 Tueth, 1995), HIV infection (Ayuso, 1994 Rabkin, Wagner, & Rabkin, 1994), and depression induced by IFN administration (e.g., in hepatitis C or multiple sclerosis patients) (Levenson & Fallon, 1993 Mohr, Goodkin, Likosky, Gatto, Baumann, & Rudick, 1997). To further elucidate the relationship between immune activation and depression, and explore the mechanisms underlying the therapeutic action of antidepressants, we employed an experimental animal model....

Topical Tricyclic Antidepressants

Few classes of drugs are more extensively used in the management of chronic pain conditions than the tricyclic antidepressants (TCAs). Substantial and convincing evidence supports their use in a variety of pain conditions including neuropathic pain and the pain associated with fibromyalgia. Their use is so common that it is now normal for them to be initiated by General Practitioners. The pain relief that may be apparent is independent of their antidepressant effects but any mood improvement that may occur is often welcome. In addition to pain reduction and mood improvement, muscle relaxation and normalization of sleep pattern may also occur. All oral TCA used for a pain indication is off label.

Which of the following is true about the use of antidepressants and their analgesic effects

Depressed patients require higher doses for analgesic effect C. Antidepressants do not relieve pain if the patient suffers from depression D. Depressed patients respond faster to analgesic effects of antidepressants C. Analgesics and antidepressants D. Analgesics, axiolytics, and antidepressants 3. The answer is D. Antidepressants relieve pain in patients irrespective of the fact whether they suffer from endogenous depression or not. In both these situation the dose required to produce a reduction in pain is far less than the dose needed to produce the anti depressant effect.

Augmentation Strategies Combinations of Antidepressants

Some clinicians make a distinction between combination and augmentation therapies, with the former referring to the use of antidepressants in combination, and the latter referring to the use of drugs that are not antidepressants to augment-approved antidepressants. In our view, this is an artificial distinction, and prefer the term augmentation to refer to any combination of medications used to enhance antidepressant response. We recognize that a growing segment of clinical pharmacologists are recommending augmentation therapy at the initiation of treatment, with a rationale that the best treatment should be initiated at the start of treatment. This reflects, in part, that primary care providers provide initial pharmacotherapy for depression, and referral to psychiatrists occurs only after monotherapy with antidepressants have failed. The problem with this approach is that there are no augmentation therapies that have superior efficacy. We recommend augmentation approaches only after...

Antidepressants

Tricyclic and related antidepressants Tricyclic and related antidepressants cause dry mouth, coma of varying degree, hypotension, hypothermia, hyperreflex-ia, extensor plantar responses, convulsions, respiratory failure, cardiac conduction defects, and arrhythmias. Dilated pupils and urinary retention also occur. Metabolic acidosis may complicate severe poisoning delirium with confusion, agitation, and visual and auditory hallucinations are common during recovery. Assessment in hospital is strongly advised in case of poisoning by tricyclic and related antidepressants but symptomatic treatment can be given before transfer. Supportive measures to ensure a clear airway and adequate ventilation during transfer are mandatory. Intravenous lorazepam or intravenous diazepam (preferably in emulsion form) may be required to treat convulsions. Activated charcoal given within 1 hour of the overdose reduces absorption of the drug. Although arrhythmias are worrying, some will respond to correction...

Immune Results In Depression

Three general domains of immune measures have been examined in studies of depressed subjects enumerative measures, functional measures, and markers of immune activation. Each domain will be briefly described with a review of the respective immune findings in depressive disorder. cells, and T suppressor cytotoxic cells (Herbert & Cohen, 1993a). A decrease in circulating number of cells that express the NK phenotype has also been reported which in part is moderated by gender a decline of NK cell numbers is found in male but not female depressed subjects as compared to gender matched controls (Evans, Folds, Petitto, Golden Pedersen, Corrigan, Gilmore, Silva, Quade, & Ozer, 1992). However, multiple discrepant findings have also been reported and, in one of the largest study samples of depressed subjects, no difference in the number of peripheral blood lymphocytes or T lymphocyte subsets was found between depressed patients and controls (Schleifer et al., 1989). Indeed, with...

Membrane Transporters In Therapeutic Drug Responses

PHARMACODYNAMICS TRANSPORTERS AS DRUG TARGETS Membrane transporters are the targets of many drugs. For example, neurotransmitter transporters are the targets for drugs used in the treatment of neuropsychiatric disorders. SERT (SLC6A4) is a target for the selective serotonin reuptake inhibitors (SSRIs), a major class of antidepressant drugs. Other neurotrans-mitter reuptake transporters serve as drug targets for the tricyclic antidepressants, amphetamines (including amphetamine-like drugs used in the treatment of attention deficit disorder in children), and anticonvulsants. These transporters also may be involved in the pathogenesis of neuropsychi-atric disorders, including Alzheimer's and Parkinson's diseases. Transporters that are nonneuronal also may be potential drug targets (e.g., cholesterol transporters in cardiovascular disease, nucleo-side transporters in cancers, glucose transporters in metabolic syndromes, and Na+-H+ antiporters in hypertension).

Serotonin Transporters

As is the case for many classical neurotransmitters, termination of the effects of 5-HT in the synaptic cleft is brought about in large part by an active reuptake process mediated by the 5-HT transporter (5-HTT). 5-HT is taken up into the presynaptic terminals, where it is metabolized by the enzyme monoamine oxidase (MAO) or sequestered into secretory vesicles by the vesicle monoamine transporter (see Figure 1-3B). This presumably underlies the mechanism by which MAO inhibitors initiate their therapeutic effects that is, the blockade of monoamine breakdown results in increasing the available pool for release when an action potential invades the nerve terminal. It is now well established that many tricyclic antidepressants and SSRIs exert their initial primary pharmacological effects by binding to the 5-HTT and blocking 5-HT reuptake, thereby increasing the intrasynaptic levels of 5-HT, which initiates a cascade of downstream effects (see Figure 1-3B for details). It has been...

Dopamine Transporters

As with serotonin, the DA signal in the synaptic cleft is terminated primarily by reuptake into the presynaptic terminal. The dopamine transporter (DAT) comprises 12 putative transmembrane domains and is located somatodendritically as well as on DA nerve terminals (see Figure 1-4B). Like other monoamine transporters, the DAT functions as a Na+ K+ pump to clear DA from the synaptic cleft upon its release. However, data suggest that many drugs of abuse are capable of altering the function of these transporters. Thus, the amphetamines are thought to mediate their effects, in part, by reversing the direction of the transporter so that it releases DA. Cocaine is capable of blocking the reuptake of DAT, leading to an increase in DA in the synaptic cleft. Of interest, altered neuronal long-term potentiation in the VTA in response to chronic cocaine exposure has been recently linked to drug-associated memory and likely contributes to the powerful addictive potential of this drug of abuse (Q....

Importance of the individual patient

A classic example demonstrating how different we all are is provided by a trial in which depressed patients were randomized to one of three antidepressants which were, on average, the same 21 . Patients initially randomized to one treatment frequently changed to another. By 9 months only 44 were still taking the treatment to which they had been randomized. Some (about 15 ) were lost to follow-up after baseline or when on any of the randomized treatments. Others either switched to another antidepressant or stopped treatment because of adverse effects or lack of efficacy, again without any difference between the three antidepressants. Each was taken by about the same proportion, on average, just different patients to those initially randomized. Patients and their doctors found the balance of effect and absence of adverse events that was right for them, and almost 70 had a good outcome over the 9 months of the trial.

Pharmacogenetic Phenotypes

PHARMACOKINETICS Germline variability in genes that encode factors that determine the pharmacokinetics of a drug, in particular enzymes and transporters, affect drug concentrations and are therefore major determinants of therapeutic and adverse drug response (Table 4-2). Multiple enzymes and transporters may affect the pharmacokinetics of a given drug. Several polymorphisms in drug metabolizing enzymes are monogenic phenotypic trait variations and thus are referenced using their phenotypic designations (e.g., slow vs. fast acetylation, extensive vs. poor metabolizers of debrisoquine or sparteine) rather than using genotypic designations that reference the gene that is the target of polymorphisms in each case (e.g., NAT2 and CYP2D6, respectively). A large number of medications (-15-25 of all medicines in use) are known substrates for CYP2D6 (Table 4-2). The molecular and phenotypic characterization of multiple racial and ethnic groups has shown that seven variant alleles account for...

Elimination of Proteinaceous and Endogenous Contaminants from Biological Matrices to Minimize Ion Suppression during

In a recent communication, Wille and coworkers110 compared the efficacies of ion exchange sorbents and mixed mode, neutral polymeric and silica-based reverse phase sorbents. The analytes consisted of 13 new generation antidepressants with pKa values ranging from 6.7 to 10.5 and log P values ranging from 0.04 to 7.10. The authors utilized derivatization with hexafluorobutyryl imidazole to facilitate GC MS quantitation of SPE recoveries and to assess the purity of the extracts. They also utilized HPLC for optimizing SPE and for investigating the protein binding of these antidepressant drugs to plasma proteins. Since water absorption and or retention by the sorbents is not compatible with derivatization and GC MS analysis, although Oasis HLB and Focus sorbents retained all the drugs well, they were excluded after initial screening because they are very hydrophilic. The inability to withstand 100 methanol wash for all the drugs tested eliminated silica-based nonpolar sorbents and neutral...

Possible Clinical Implications Of Immune Changes In Depression

The immunologic consequences of major depression and their possible clinical relevance to infectious diseases have not been delineated (Stein et al., 1991). Major To address these issues, we have recently examined the effect of major depression on varicella zoster virus (VZV)-specific cellular immunity (Irwin, Costlow, Williams, Artin, Levin, Hayward, & Oxman, 1998). The frequency of cells in the peripheral blood capable of proliferating in response to VZV antigen (VZV-responder cell frequency, VZV-RCF) was determined in patients with major depression and in age-and gender-matched normal controls. In addition, we evaluated VZV-RCF in a group of older adults to determine whether the decline in VZV-RCF observed in major depression was comparable in magnitude to that typically found in older persons who are known to be at increased risk of developing HZ. Comparison of depressed subjects with age- and gender-matched normal controls demonstrated that the mean age and gender distribution...

Types of clinical trials

Between pragmatic and explanatory clinical trials 14 . Pragmatic clinical trials have the objective of answering practical questions about patient care for example, are tricyclic antidepressants (TCA) useful for relieving pain in patients with phantom limb pain These trials are typically designed to reflect clinical practice to the greatest extent possible, and decisions about various features of the trial are guided by the clinical situation that the results of the trial are intended to inform. The goal of an explanatory clinical trial, however, is to answer a question about the mode of action of a treatment, the etiology of a condition, or both. The methodologic features of an explanatory trial are therefore selected to maximize the likelihood that the trial will answer a specific question about the mechanisms of disease or treatment and without regard to the realities of the clinical situation. In pragmatic trials, the clinical context, tolerability of the treatment, and...

Impact of pain on quality of life

Estimates of the economic burden associated with pain fail to do justice to the extent of suffering and reduced quality of life experienced by patients and warrants pain relief being regarded as a universal human right.18 Chronic pain, along with musculoskeletal disorders, has been shown to be associated with some of the poorest quality-of-life states.60,61,62,63 In patients referred to a Danish multidisciplinary pain center, the severity of impairment was equal to or lower than patients with cardiopulmonary diseases and major depression, and their Psychological General Well-being Scale scores were lower than those with hypertension and gastrointestinal problems, while they also displayed high levels of anxiety and depression, as measured by the Hospital Anxiety and Depression Scale.63 In a study of over 600 patients attending a chronic pain clinic in Sydney, Australia, there were greatly reduced SF-36 domain scores between clinic patients and Australian norm values, as shown in Table...

Transporters as Targets for Drug Discovery

The monoamine transporters are the most established drug targets, and as such there are many excellent reviews covering the launched antidepressant selective serotonin uptake inhibitors (SSRIs), selective serotonin and noradrenaline reuptake inhibitors (SNRIs) and TCAs 37 . In this volume we focus rather on more recent developments in the search for second generation monoamine reuptake inhibitors which address the deficits in current marketed drugs. The SSRIs have a good side effect profile however, as antidepressants they suffer from a slow onset of action and significantly, 30-40 of patients do not respond satisfactorily to them. Conversely, although the TCAs are effective antidepressants they have poor selectivity over muscarinic, his-taminic and adrenergic receptors, resulting in cardiovascular, anticholinergic and sedative side effects. Whitlock et al. describe progress in the discovery of SSRIs, noradrenaline reuptake inhibitors (NRIs), and SNRIs from 2000 to the present day....

Receptor Looking for a Therapeutic

The clinical relevance of 5-HT2C receptor editing has been linked in association studies to suicidality (Niswender et al. 2001), schizophrenia (Sodhi et al. 2001), anxiety (Hackler et al. 2006), depression (Iwamoto et al. 2005), and spatial memory (Du et al. 2007). However, these data need confirmation, as is common in the field. 5-HT2C receptors have been shown to modulate mesolimbic dopaminergic function, where they exert a tonic inhibitory influence over dopamine neurotransmission (Di Giovanni et al. 1999 Bubar and Cunningham 2007) and, therefore, the interest in this receptor as a therapeutic target for treating abuse (Bubar and Cunningham 2006). The 5-HT2C receptor is also believed to mediate, in part, the effects of antidepressants, e.g., mirtazapine or agomela-tine (Cremers et al. 2007), possibly by stimulating neurogenesis, as well as that of atypical antipsychotics (Herrick-Davis et al. 2000). 5-HT2C receptors are expressed in the amygdala, and functional magnetic resonance...

Neurochemicals in Pain Processing

A number of neurotransmitters and chemical substrates are involved in pain transmission several are listed in Table 2-2. For example, in the periphery, tissue injury results in the activation of a number of cellular processes that release chemical compounds that can activate free nerve endings for pain transmission (Snyder 1980), such as acetylcholine, bradykinin, histamine, potassium ion, and serotonin (Levine et al. 1993). Additional agents that are active within the CNS are also listed in Table 2-2. Some of these substances have a pain-promoting role, whereas others have a pain inhibitory role. Many of these substances are the targets of influence when analgesics are employed (e.g., antiinflammatory agents and antidepressants), as is described further in Chapter 5, Pharmacology of Pain, of this book.

Pain Augmenting Mechanisms and the Emergence of Chronic Pain

Ongoing abnormalities in peripheral tissues, with resultant inflammation, can result in activation of nociceptive pathways, rendering pain chronic. In such cases, treatment is best directed at the inflammatory mechanisms (e.g., aspirin or nonsteroidal anti-inflammatory agents). Peripheral nerves may become dysfunctional due to injury or disease (e.g., diabetes, infection, toxin exposure). Damaged neurons may fire spontaneously. Nociceptive fibers firing in this way are perceived in the CNS as signaling pain, yet in the peripheral tissues there may be no current injury. In such cases, antidepressants and anti-convulsants might be the most helpful treatment. Pain can be maintained despite lack of injury or even after effective healing by the actions of the sympathetic nervous system. In such cases, protracted painful conditions can arise, such as reflex sympathetic dystrophy and complex regional pain disorder. Some of these disorders can be alleviated by blockade of sympathetic activity...

Clinical Implications

116-121 and reduce motor complications 121,122 . In L-DOPA treated patients, the atypical antipsychotic clozapine moderately improves motor performance 123-130 and reduces motor fluctuations and dyskinesias 122,130-136 while, in a PD model, it augments AAAD activity and L-DOPA decarboxylation 66 . Finally, the antidepressants mianserin, nefazodone and ritanserin improve parkinsonian symptoms 137-139 and the blockade of 5-HT2A receptors enhances AAAD activity in the striatum of mice 66 . These observations call for further studies to understand the regulation of AAAD and its role in L-DOPA treatment and adjuvant L-DOPA therapies.

Adjuvant Analgesics In Pain Therapy

Adjuvant analgesics are compounds that are not classified as analgesics, but are used clinically for the relief of pain. This class of analgesics contains a wide range of compounds that belong to a variety of chemical families. They are classified according to their use and their mechanisms of action are often not well defined. For example, antidepressants are used to control neuropathic pain, a2-adrenoceptor agonists (e.g. clonidine, dexmedetomidine) potentiate the anti-inflammatory and analgesic effects of COX inhibitors, while corticosteroids block inflammation and may directly modulate the nociceptive action of substance P. Compounds that have been especially beneficial in the treatment of neuropathic and phantom limb pain include local anesthetics (e.g., mexiletine, flecainide), anticonvulsants (gabapentin, carbamazepine, phenytoin, valproate, clonazepam, lamotrigine), GABA agonists, neuroleptics and calcitonin. Other analgesics such as muscle relaxants and benzo-diazepines are...

Central excitatory systems

Several classes of antidepressant including serotonin and noradrenaline reuptake inhibitors (SSRIs, SNRIs), and tricyclic antidepressants, in particular amitriptyline, have proved effective in the treatment of certain types of neuropathic pain 63, 64 . The analgesic mechanism of action of antidepressants is not fully understood but it is thought to be independent of their antidepressant effect. Since these agents increase synaptic levels of noradrenaline and 5HT, their central analgesic action is likely to involve either presynaptic mechanisms reducing nociceptive transmission or postsynaptic mechanisms enhancing the endogenous descending inhibitory pathways. Likely targets include the activation of central inhibitory a2-adrenoreceptors and members of the inhibitory 5HT-1 receptor family as well-known analgesics such as the antihypertensive drug clonidine and the triptan family, used in the treatment of migraine, exert their analgesic effects through these receptors respectively 65,...

Intoxication By Anticholinergic Drugs

In addition to atropine and other muscarinic agents, phenothiazines, antihistamines, and tricyclic antidepressants have central and peripheral anticholinergic activity. The effectiveness of physostigmine in reversing the anticholinergic effects of these agents has been documented. However, other toxic effects of the tricyclic antidepressants and phenothiazines (see Chapters 17 and 18), such as intraventricular conduction deficits and ventricular arrhythmias, are not reversed by physostigmine. In addition, physostigmine may precipitate seizures hence, its usually small potential benefit must be weighed against this risk. The initial intravenous or intramuscular dose of physostigmine is 2 mg, with additional doses given as necessary. Physostigmine, a tertiary amine, crosses the blood-brain barrier, in contrast to the quaternary anti-AChE drugs.

Managing Chronic Pain Using Nonopioid Medications

This section will provide information about using pain medications of various types NSAIDs, opioids, and other coanalgesics, such as antidepressants. The information will be taken from current guidelines developed by the American Pain Society, the American Geriatrics Society, the American Academy of Pain Medicine, and other national organizations (Appendix A). Included will be an order set for pain management based on the World Health Organization Analgesic Ladder and medication charts. The topics of addiction, dependency, and tolerance will be discussed in Section III. Information on integrative therapies that can be combined with medication management will be provided in chapter 6.

Alterations in Physiological Function Circardian Rhythms Sleep Pain Perception and Appetite

Sleep is often disturbed in depression. Imaging studies using 18(F) 2-fluoro-2-deoxy-D-glucose PET have noted changes in oxygen utilization consistent with abnormal arousal in depressed patients associated with increased glucose utilization in ventromedial prefrontal cortex (189) and blunted response in anterior paralimbic regions during REM sleep (190). Hyper-aroused patients demonstrate loss of delta sleep, loss of sleep continuity, and increased core body temperature during sleep. Changes in quantitative perfusion MRI have been noted in treatment responders (191). Since sleep is related to endocrine function and depression, it is interesting that deep sleep has an inhibitory influence on the HPA axis. Activation of the HPA axis or administration of glucocorticoids can lead to arousal and sleeplessness. A 24-h increase of ACTH and cortisol secretion can result in insomnia, consistent with a disorder of CNS hyper-arousal (192). In addition, elevated CRF in depressed patients can...

Pharmacogenetics Moving From Research To The Clinic

With a few exceptions, the current level of knowledge of efficacy pharmacogenetics in psychiatry is still in the exploratory stage, with as yet no robust results for genes predicting efficacy. However, some findings are replicating in independent sample sets and promising leads are developing, for example the serotonin gene promoter gene and SSRI response, dopamine D3 receptor gene and risk of anti-psychotic induced tardive dyskinesia. Many of these are presented within the following chapters of this book. Understanding of the impact of allelic variance on pharmacokinetic parameters can perhaps be considered to represent our current, most advanced state of pharmacogenetic knowledge. An example of this was recently seen in the approval of atomoxetine (Strattera Eli Lilly), approved by the FDA in November 2002 for attention-defeceit hyperreactive disorder. This drug is metabolised by CYP2D6 with the ratio (PM EM) for an area under the curve (AUC) of 10. Lilly conducted a post-facto...

Clinical pain measures

Specific treatments have been designed and tried for different pain conditions, including neuropathic pain. They will be described in detail in other chapters. These treatments, which currently include tricyclic antidepressants, sodium channel blockers (such as carbama-zepine and lamotrigine), gabapentin and pregabalin, opioids, and N-methyl-D-aspartic acid (NMDA) channel blockers have specific targets for their mode of action. It has been suggested that this may help to unravel the mechanisms of neuropathic pain based on the specific action of these drugs. Previous studies have shown that such drugs may have an action not only on pain intensity, but also on specific aspects of pain, such as evoked pain. Studies have shown that in patients with neuropathic pain due to nerve injury and amputation, NMDA receptor antagonists can block both pain and evoked pain produced by touch stimuli, indicating that these phenomena are probably produced by the same mechanism, i.e. a central...

The Acute Phase Response And The Implication Of Alpha1acid Glycoprotein

AGP has been implicated in depression as it is an endogenous inhibitor of platelet serotonin uptake and H3-imipramine binding (Abraham et al., 1987) it is also the important binding protein for many antidepressants (Kremer et al., 1988) and an inhibitor of human platelet aggregation (Costello et al., 1979). Specific alterations in glycosyla-tion of AGP occur in many pathophysiological states (Turner, 1992). These alterations are due to variations in the structure of the oligosaccharides present at a given site and have been referred to as the consequence of microheterogeneity. They accompany changes in the serum concentration of AGP, but are independent of its synthesis rate. The different glycophorms of serum AGP have varied immunoregulatory effects. Con-A-unreactive variants show significant (50-75 ) inhibition of thymocyte proliferation (Pos et al., 1990), and they are also more effective in the induction of release of inter-leukin-1 inhibitor (Durand., 1989). These glycophorms...

The Importance of Monoamine Transporters in the Development of Psychopharmacology

The discovery of norepinephrine uptake in sympathetic nerves by Julius Axelrod and colleagues in the 1960's is an example of how a new scientific discovery can have a profound impact on the development of new therapies. The understanding that antidepressants acted as inhibitors of monoamine reuptake led to the development of many new drugs of this type. The older tricyclic antidepressants suffered from serious toxicology due to secondary pharmacological effects, notably on the heart They were followed by the much safer serotonin selective reuptake inhibitors (SSRIs) (e.g. fluoxetine - Prozac), and subsequently by a new generation of mixed norepinephrine serotonin reuptake inhibitors with improved safety profiles.

Immune Activation In Treatment Resistant Depression

Nearly 30 of depressed patients fail to display an adequate response to psy-chopharmacological treatment and at least 60 fail to achieve complete remission (Fawcett, 1994 Hornig-Rohan and Amsterdam, 1994). Despite advances in psy-chopharmacological treatment the mortality and morbidity of this disorder render depression a major public health hazard in most countries. There are findings that suggest the involvement of HPA axis hyperactivity in the pathogenesis of TRD. Christiansen et al. (1989) found poor response to antidepressant treatment in major depressed patients with high spontaneous Cortisol levels. Others (Mc Leod, 1972 Amsterdam et al., 1983, 1994) observed a poor response to tricyclic antidepressants in patients displaying pathological responses on the dexametha-sone suppression test (DST). Moreover, the findings of Murphy et al. (1991) and of

Drugs as Inhibitors of Monoamine Transporters

The most important CNS drugs that target the norepinephrine and serotonin neurotransmitter transporters (NET and SERT) are the tricyclic antidepressants and their modern counterparts. The discovery that imipramine potently inhibited NET in sympathetic nerves 10 and the finding that this also applied in the brain 11 led to the first understanding of the mechanism of action of the tricyclic antidepressants. Following the discovery of the serotonin uptake system in brain it soon became apparent that the classical tricyclic drugs imipramine and amitriptyline were also potent inhibitors of SERT. This reinforced the monoamine hypothesis of depression as a monoamine deficiency state, and stimulated much further research in the pharmaceutical industry to discover new inhibitors of monoamine uptake. An effort to improve the selectivity of antidepressants was made in the 1970's by scientists at the CIBA-GEIGY Company in Switzerland (now Novartis), who developed the selective norepinephrine...

Some Unanswered Questions

Although the monoamine uptake inhibitors have proved very successful in the treatment of depression and anxiety states many questions remain unanswered. How can drugs that are selective norepinephrine reuptake inhibitors be equally effective as those that selectively target serotonin reuptake In reality none of the antidepressants is completely selective for NET or SERT. In some cases the formation of active metabolites alters the drug selectivity profile. Thus the non-selective compound imipramine and the partially NET-selective compound lofepramine are extensively metabolized to desipramine, a highly potent and selective NE reuptake inhibitor. Similarly whereas amitriptyline has little selectivity for NET or SERT, the metabolite nortriptyline is a selective NET inhibitor. Alternatively some have suggested that the SSRI's act indirectly to modulate noradrenergic function 21,22 . The long term changes in the brain that are triggered by the antidepressants, remain obscure. Although...

Psychological Effects From Patients Seeking Treatment For Chronic Pain

It may come as no surprise that among the most well-documented effects that come with chronic pain is emotional distress or mood disturbance. In their very useful review paper, Banks and Kerns11 reported that depression is disproportionately prevalent in sufferers of chronic pain compared to other chronic medical conditions, that depression is most likely to be a result and not cause of chronic pain, and that 30.0-54.0 percent of patients seeking treatment for chronic pain suffer with a diagnosable depressive disorder. There is also evidence that patients with chronic pain have high prevalence rates of anxiety disorders, including panic disorder and generalized anxiety disorder, and substance use disorders, although the prevalence figures appear varied across studies.12 Rates of current anxiety disorders may range from 16.5 to 28.8 percent and current substance use disorders from 15 to 28 percent.12 In comparison with the clinical data, a recent nationally representative sample of the...

Assessment Methods For Emotional Distress

For assessment of emotional distress in chronic pain, depression is a key target. The Beck Depression Inventory (BDI) has long been a standard and is a very good measure. It is very useful clinically, as its content is comprehensive, and in research where it appears sensitive to psychological differences.31 As each of the 21 items of the BDI potentially includes four statements to read, it may be too long for some applications. The BDI has been well studied in chronic pain samples.50,51 Concerns about the somatic item content of the BDI can be confusing. There is sometimes an assumption that these will contaminate or inflate judgments about the degree of depression present in an individual or sample.50 It seems likely, however, that these can be managed with an examination of endorsed item content in clinical contexts, testing of effects of content in research contexts, and a flexible use of standard cut-off scores. Results from extensive factor analysis of the BDI in patients with...

Nacldependent Transporters

Isolation of Drosophila members of this superfamily of transporters is of interest, in part because, in humans, the transporters for serotonin, dopamine, and norepineph-rine are the sites of action of antidepressants and such psychostimulants as cocaine and amphetamines. Most of the reinforcing properties and abuse potential of psychostimulants are thought to arise from the blockade of the dopamine transporter (Ritz et al., 1987). Indeed, the two Drosophila members of this family isolated by cDNA cloning, discussed below, have been shown to be antidepressant- and cocaine-sensitive. The pharmacological profile of dSERT-mediated transport had some similarity, but was not identical to that of mammalian SERT-mediated transport (Corey et al., 1994 Demchyshyn et al., 1994). Corey et al. (1994) noted that, with respect to a certain group of antidepressants, dSERT had a pharmacological profile with closer similarity to the mammalian catecholamine transporters than to the mammalian 5-HT...

Psychological Assessments

The MMPI's strength is its usefulness in identifying psychological factors that warrant clinical attention (e.g., drawing attention to those characteristics that might present barriers to treatment and that ultimately could require psy-chotherapeutic intervention) (see Table 3-8). The three scales that have the most relevance to patients with pain are Hypochondriasis (Scale 1), Depression (Scale 2), and Hysteria (Scale 3). High scores on Scale 1 suggest that patients, when emotionally distressed, symptomatically channel the distress into somatic complaints. Scale 2 may be an indicator of general distress, but elevated ratings on this scale can suggest a possible depressive disorder. Elevations on Scale 2 may suggest one is unhappy, pessimistic, and self-deprecating. Patients who score high on Scale 3 are characterologically prone to react by developing physical The two most common patterns noted among patients with chronic pain are the conversion V and the neurotic triad (see Figure...

Selective Serotonin Reuptake Inhibitors

Of all three groups of antidepressants, the SSRI group (see Table 5.2) has the poorest profile for pain relief (APS, 2006). When compared with placebo, these medications did not have any significant advantage for pain relief. Given the lack of efficacy for pain relief in these medications and the profile of side effects, sexual dysfunction, anxiety, sleep disorder, and headache, the SSRIs are not medications that should be given unless there is a specific indication for use. The recommended use for this group of medications is for patients who have concurrent depression, anxiety, or insomnia (APS, 2008).

Serotonin Transporter And Antidepressant Anxiolytic Response

Smeraldi and associates (1998) investigated whether the 5HTTLPR genotype is related to the antidepressant response to the SSRI fluvoxamine and or augmentation with the 5HT1A receptor antagonist pindolol in patients with major depression with psychotic features who had been randomly assigned to treatment with a fixed dose of fluvoxamine and either placebo or pindolol for 6 weeks. Both homozygotes for the l variant (l l genotype) of the 5HTTLPR and heterozygotes (l s) showed a better response to fluvoxamine than patients homozygous for the s variant (s s). Interestingly, in the group treated with fluvoxamine plus pindolol all the genotypes acted like l l treated with fluvoxamine alone and the genetic effect could not be detected. Thus, SSRI efficacy in delusional depression seems to be related, in part, to genetic variation of 5HTT function that in the subjects with s s genotype pindolol may have compensated for the altered transcriptional activity of the 5HTT gene. The effect of the...

Hypnotics and anxiolytics

Benzodiazepines Benzodiazepines taken alone cause drowsiness, ataxia, dysarthria, nystagmus, and occasionally respiratory depression, and coma. Activated charcoal can be given within 1 hour of ingesting a significant quantity of benzodiazepine, provided the patient is awake and the airway is protected. Benzodiaz-epines potentiate the effects of other central nervous system depressants taken concomitantly. Use of the benzodiazepine antagonist flumazenil unlicensed indication can be hazardous, particularly in mixed overdoses involving tricyclic antidepressants or in benzodia-zepine-dependent patients. Flumazenil may prevent the need for ventilation, particularly in patients with severe respiratory disorders it should be used on expert advice only and not as a diagnostic test in patients with a reduced level of consciousness.

Translation in Antidepressant Trials Depressing

The outcomes of clinical trials for drugs to treat depression (Blier, 2008 Kirsch, 2009 Kramer, 2005 Leventhal & Martell, 2005) have been a controversial topic with considerable focus on placebo responses. A meta-analysis (Kirsch, Moore, Scoboria, & Nicholls, 2002) of the efficacy data from 47 clinical trials covering the six most widely prescribed antidepressants approved between 1987 and 1999 - fluoxetine, paroxe-tine, sertraline, venlafaxine, nefazodone, and citalopram - determined that approximately 80 of the effect ascribed to drug was also seen in the placebo controls. This led to the oft-repeated claim that four out of six clinical trials for approved antidepressants routinely fail. In a follow-up analysis focusing on fluoxetine, paroxetine, venlafaxine, and nefazodone (Kirsch et al., 2008), it was further established that baseline severity was a critical component for drug-related responses, and that a decreased response to placebo rather than an increased drug response...

Treatment Of Cytokineinduced Mood Disturbance

The recent explosion in the elucidation of the mechanisms of cytokine-induced CNS effects has encouraged innovative trials of pharmacologic interventions, including antidepressants (Goldman, 1994 Levenson & Fallon, 1993), opiate antagonists, (Valentine, Meyers, & Talpaz, 1995), stimulants (Valentine et al., 1998), and corticosteroids (Amato et al., 1995). The synthetic steroid megestrol acetate may be an effective treatment for the anorexia and cachexia caused by cytokine treatment (Plata-Salaman, 1998). In the future it may be possible to specifically inhibit certain induced cytokines responsible for adverse side effects but maintain the therapeutic efficacy of the given cytokine (Taylor & Grossberg, 1998). Finally, non-pharmacologic approaches, including exercise and time management strategies, may be of benefit (Dalakas, Mock, & Hawkins, 1998). From these early experiences it is becoming clear that appropriate interventions will allow patients to continue on effective...

Pharmacological Properties

Response in the endocrine, autonomic, immune, and behavioral systems through the activation of the hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic pathways. The peptide itself is highly conserved between species, and its evolutionary role is to mobilize energy stores and appropriate behavior(s) in response to a stressor. It has since evolved to regulate a variety of responses to stress. CRF was first isolated and characterized by Vale and colleagues in 1981. Due to the similarity in sizes of ACTH and CRF and limits on detection techniques, purification was performed on approximately 490,000 sheep (ovine) hypothalami in order to generate enough samples for isolation. This was part of an ongoing study elucidating a variety of hypotha-lamic peptides. In the majority of studies, the CRF system has consistently been shown to be dysregulated in many patients suffering from a variety of psychiatric illness including post-traumatic stress disorder (PTSD), early life trauma,...

Drug Therapy Of Depression And Anxiety Disorders

Major affective and anxiety disorders represent the most common psychiatric illnesses and are those encountered most often by primary-care clinicians. Major depression may represent a spectrum of disorders, varying in severity from mild and self-limited conditions to extraordinarily severe, psychotic, incapacitating, and deadly diseases. The antipsychotic, antianxiety, antimanic, and antidepressant drugs affect cortical, limbic, hypothalamic, and brainstem mechanisms that are of fundamental importance in the regulation of arousal, consciousness, affect, and autonomic functions. Physiological and pharmacological modifications of these brain regions may have important behavioral consequences and useful clinical effects regardless of the underlying cause of any mental disorder. The lack of diagnostic or even syndromal specificity of most psychotropic drugs tends to reduce the chances of finding a discrete mechanistic correlate for a specific disease based simply on the actions of...

Characterization Of Depressive And Anxiety Disorders

The primary clinical manifestations of major depression are significant depression of mood and impairment of function. Some features of depressive disorders overlap those of the anxiety disorders, including panic-agoraphobia syndrome, severe phobias, generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Extremes of mood also may be associated with psychosis, as manifested by disordered or delusional thinking and perceptions that often are congruent with the predominant mood. Conversely, secondary changes in mood may be associated with psychotic disorders. This overlap of disorders can lead to errors in diagnosis and suboptimal treatment. Mood and anxiety disorders are the most common mental illnesses, each affecting up to 10 of the general population at some time in their lives. Clinical depression must be distinguished from normal grief, sadness, disappointment, and the dysphoria or demoralization often associated...

The Burden of Reductionistic Thinking

Another factor that has significantly influenced research patterns has been the quest to identify, with increasing specificity, cures for mental disorders. This search represents something of a conundrum, which can be outlined in broad strokes as follows Psychological distress is a heterogeneous and nonspecific concept, and its experience is unique to each sufferer. One can define, albeit in rather nebulous terms, some of the features that separate one form of psychological distress from another, but it remains true that most people with schizophrenia, or most depressed patients, share in common only the most obvious features of their diagnoses. Nevertheless, the aim of much of mental health research in the past 50 years has been to search for increasingly specific remedies. We are therefore placed in the awkward position of positing molecular cures for molar concepts that are heterogeneous, nonspecific, and experienced in an absolutely unique...

Experimental Pain Studies And Depression

Consistent with epidemiologic studies which have identified a direct association between chronic pain and depression, experimental studies have demonstrated that patients with depression have altered pain thresholds and tolerances.6 In a recent study, 30 patients diagnosed with major depressive disorder, using DSM-IV criteria, were matched with 30 nondepressed control subjects.7 Pain thresholds and tolerances were assessed bilaterally in

Substance Abuse and Dependence

Although chronic pain patients may be vulnerable to developing new substance use disorders in the course of treatment (Dersh et al. 2002, Brown et al. 1996, Dunbar and Katz 1996), investigations assessing the presence of opioid dependence in chronic pain patients have reported contradictory conclusions. Some contend that this is an extraordinarily rare event (Zenz et al. 1992) whereas other investigators have found high rates of opioid dependence in chronic pain populations (Ives et al. 2006, Wu et al. 2006). Risk factors for opioid dependence include a prior history of substance abuse prior physical sexual abuse major depression, anxiety disorders, and personality disorders (Dersh et al. 2002, Ives et al., Fishbain et al. 1998). Opioids have been a predominant focus however, several other agents used in pain treatment are likewise prone to abuse and dependence including the muscle relaxant carisoprodol ketamine ergot alkaloids and barbiturates employed in migraine treatment and...

Functional Imaging Pain And Depression

Activation of brain structures by acute pain stimuli is different among individuals with chronic pain. In general, the primary and secondary somatosensory, anterior cin-gulate, insula, and thalamus are activated significantly less compared to normal subjects. In the aforementioned meta-analysis, the average incidence of activation of these brain regions in normal controls was 82 percent compared to 42 percent for individuals with chronic pain.14 Alternatively, among adults with chronic pain, the incidence of prefrontal cortex activation was 81 percent compared to 55 percent in normal subjects.14 The observation that activity in brain structures associated with the affective-motivational dimension of pain are accentuated in patients with chronic pain is consistent with clinical observations that these patients experience more pain-related emotions and affective distress. This postulate is also consistent with neuroimaging findings from patients with comorbid depression and chronic...

Hints Of Phenotypes For Variant Sert Alleles From Genetic Studies In Mouse And

Although functional coding variants have yet to be identified in hSERTs, functional variants in promoter and intronic regions have been investigated for their relationship to clinical syndromes. As noted above, the s alleles of the 5HTTLPR have been found to associate with reduced transcriptional activity of the SERT promoter and with neuroticism and anxiety traits (Lesch et al., 1996). However, the degree to which the 5-HTTLPR influences SERT expression is at present controversial, with both supportive (Little et al., 1998 Heinz et al., 2000) and contradictory (Willeit et al., 2001) evidence. Recently, Du and co-workers (Du et al., 2000) were able to replicate the finding of Lesch of an association between 5-HTTLPR s alleles and neuroticism, but only in a male population, the gender of the original Lesch studies. These findings suggest that gender-specific expression of phenotypes may need to be considered in evaluation of SERT variants and that neuroti-cism and anxiety continue to...

Pharmacotherapy Of Anxiety

Currently, the benzodiazepines and the SSRIs are the most commonly employed pharma-cotherapies for common clinical anxiety disorders (see Chapter 16). Benzodiazepines sometimes are given to patients presenting with anxiety mixed with symptoms of depression, although their efficacy in altering the core features of severe major depression has not been demonstrated. OTHER THERAPEUTIC USES OF THESE DRUGS The various antidepressant agents have found broad utility in other disorders that may not be related psychobiologically to the mood disorders. Current applications include rapid but temporary suppression of enuresis with low (e.g., 25 mg) pre-bedtime doses of tricyclic antidepressants, including imipramine and nor-triptyline, by uncertain mechanisms in children and in geriatric patients, as well as a beneficial effect of duloxetine on urinary stress incontinence. Antidepressants have a growing role in attention-deficit hyperactivity disorder in children and adults, for which imipramine,...

Generalized painful symptoms of depression

Several randomized controlled trials of duloxetine for depression reported significant improvements in a variety of pain symptoms, including back pain, shoulder pain, and headache.96,97,98 II The findings from these and other similar trials have been summarized and subjected to further pooled analyses.99,100,101 I Painful physical symptoms among patients with depression was the primary outcome measure for a randomized placebo-controlled trial of duloxetine.102 In this particular study, subjects who received duloxetine 60 mg daily experienced significant improvements in pain and activity-related pain interference. These clinical improvements occurred independent of changes in depressive symptoms.

Causes and Treatment of Behavioral Changes

Summary This article describes Alzheimer's disease as an increasingly common management concern for primary care physicians. Although little can be done for the primary symptoms of the dementing process, the secondary behavioral complications of this illness may be amenable to behavioral or pharmacologic manipulation. Agitation may be responsive to environmental or psychosocial intervention. Treatment with low doses of antidepressants can improve depressive symptoms. Mild anxiety is best treated with emotional support from the family and caregiver. Benzodiazepines can be used with caution. Insomnia can be reduced by encouraging a routine that prevents daytime napping and keeping the patient busy during the day. Pharmacotherapy for disturbed sleep often causes more harm than good and should be avoided if possible. 3 references. (AA-M).

Treatment Of Mania

Evidence for the safety and the efficacy of lithium salts in the treatment of mania and the prevention of recurrent attacks of bipolar manic-depressive illness is both abundant and convincing. However, the limitations and adverse effects of lithium salts have become increasingly well appreciated, and efforts to find alternative antimanic or mood-stabilizing agents have intensified. The most successful alternatives or adjuncts to lithium to date are the anticonvulsants carbamazepine, lamotrigine, and valproic acid.

Burning Mouth Syndrome

Summary This article discusses burning mouth syndrome (BMS), a condition that is characterized by a burning sensation in the tongue or other oral sites, usually in the absence of clinical and laboratory findings. Affected patients often present with multiple oral complaints, including burning, dryness, and taste alterations. Burning mouth complaints are reported more often in women, especially after menopause. Typically, patients awaken without pain but note increasing symptoms through the day and into the evening. Conditions that have been reported in association with BMS include chronic anxiety or depression, various nutritional deficiencies, type 2 diabetes, and changes in salivary function. However, these conditions have not been consistently linked with the syndrome, and their treatment has had little impact on BMS symptoms. Recent studies have pointed to dysfunction of several cranial nerves associated with taste sensation as a possible cause of BMS. Given in low dosages,...

Burden And Outcome Of Bipolar Disorder

The lifetime prevalence of BPAD, based on the DSM-IV criteria, is ranging from 1,3 to 1,6 with a sex-ratio around 1 (Weissman et al., 1996). The peak age of onset seems to fall around 20 yo in Hungary (Szadoczky et al., 1998), from 18 to 23.8 yo in Germany (Wittchen et al., 2003) and 25 yo in Australia (Morgan et al., 2005). The age of onset of manic episodes is usually 6 to 8 years before depressive episodes. There is often a 5 to 10 years interval before correct diagnosis is obtained. After a first episode of mania, most of the patients show a low functional recovery. Although the overt symptoms are relatively well controlled, continued impairments in the overall quality remain. This fact concerns both BPAD I and BPAD II. BPAD II has been considered for a long time as a minor expression of the classic BPAD I. Recently, important studies have focused on the natural history of BPAD II. Judd et al. (2003) have followed a cohort of BPAD II patients during a mean of 13.4 years of...

Pharmacological Interventions

Sibutramine affects the reuptake of norepinephrine, serotonin and dopamine, and was originally thought to be a potential antidepressant compound, but was ultimately commercialized as a weight loss agent. Sibutramine was tested in a 12-week doubleblind, randomized, placebo-controlled study in 37 overweight and obese subjects taking olanzapine for schizophrenia or schizoaffective disorder 70 . For the first 8 weeks all subjects participated in weekly group sessions focused on nutrition and behavioral modification. Although the sibutramine group exhibited a mean increase in systolic blood pressure of 2.1 mm Hg, and presented with a higher rate of anticholinergic side effects and sleep disturbances, greater weight loss was observed at week 12 versus placebo (-3.8 vs. -0.8 kg). A similarly designed study with clozapine conducted among 21 patients by the same research group failed to demonstrate a therapeutic advantage for adjunctive sibutramine 71 . Because sibutramine affects serotonin...

Pharmacologic Treatments for Temporomandibular Disorders

Summary This article on pharmacologic treatments for temporomandibular disorders is from a special supplement issue on the NIH Technology Assessment Conference on the management of temporomandibular disorders (TMDs), held in April 1996. The author notes that drugs are widely used in the management of acute and chronic orofacial pain. Whereas the use of analgesics for acute orofacial pain is well documented, the use of a broad spectrum of drugs for chronic pain is based on few studies. In the absence of data supporting a therapeutic benefit for a drug used chronically for pain, toxicity associated with the drug can still occur. It is critical, therefore, to assess the balance between therapeutic benefit and safety. The author reviews current evidence supporting the use of several drug classes for TMD and identifies therapeutic controversies in need of further research. Drug classes discussed include nonopioid analgesics, opioids, corticosteroids, antidepressants, benzodiazepines, and...

Genetic Manipulations

Major depression is a heritable disorder that likely involves multiple genes, each with small effects (Wong and Licinio 2001). Targeted gene deletions and gene transfers in animal models are beginning to elucidate the functional significance of potentially relevant genes (Insel 2007). Consider, for example, dysregulation of the HPA axis evinced in depression by an increase in cortisol levels (see Chapter 45, Neurobiology of Mood Disorders). Receptors for cortisol are densely expressed in the prefrontal cortex (Webster et al. 2002), where they function as transcription factors that regulate gene expression (Chrousos and Kino 2005). Hundreds of genes in prefrontal cortex appear to be differentially expressed in humans with a history of major depression based on postmortem analysis of whole-genome microarray data (Choudary et al. 2005 Evans et al. 2004 Iwamoto et al. 2004 Sequeira et al. 2006). Genetic manipulations of receptors for Cortisol are not yet feasible in human patients but...

The Adult With Chronic Pain

Stress model the diathesis, or vulnerability to depression, consists of previous depression or pre-pain experiences which may heighten the risk of becoming depressed and the stress consists of pain and its negative impact on the individual's life.10 There is an urgent need for better understanding of the significance of previous depression, and the process of acceptance and adaptation.15,16,17 There may also be depressive content and cognitive processing specific to chronic pain which warrants more careful identification and targeted treatment. As in depression without chronic pain, it may be that the efficacy of antidepressants has been overestimated and cognitive-behavior treatment is appropriate for depression or depressed mood in the context of chronic pain. Severe depression in the context of chronic pain needs immediate attention because of the risk of suicide and because pain treatment cannot proceed until the patient is able to foresee some worthwhile future.18,19 I

Psychoneuroendocrinology Introduction

Major depression is considered to be a maladaptive, exaggerated response to stress, and although it is accompanied by abnormalities in multiple endocrine systems, it is the hypothalamic-pituitary-adrenal (HPA) axis that is the main component of the physiological stress response that plays the key role. Stressful life events, particularly those related to loss, have a strong causal relationship with depressive episodes. However, not all people who experience such events develop depression, and an individual's vulnerability to depression depends on the interaction of genetic, developmental, and environmental factors. In addition to the role of the HPA axis in depression, there is growing evidence of HPA axis abnormalities in anxiety disorders and posttraumatic stress disorder (PTSD).

Pharmacologic Management of Myofascial Pain and Dysfunction

Summary This article on the pharmacologic management of myofascial pain and dysfunction is from an issue of Oral and Maxillofacial Clinics on the medical management of temporomandibular disorders (TMD). The authors discuss the most frequently used classes of drugs, providing information about their mechanism of action, indications and contraindications, methods of use, and possible adverse side effects. Specific drugs discussed include anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs, and corticosteroids muscle relaxants (other than benzodiazepines) antianxiety medications antidepressant medication opiate narcotic analgesics and local anesthetics. A final section covers the placebo effect. The author emphasizes the importance of understanding the patient in terms of compliance and tolerance of side effects in order to achieve successful management with pharmacologic therapy. 2 figures. 6 tables. 25 references. (AA-M).

Posttraumatic Stress Disorder

Given the stress-related etiology of PTSD, it was expected that PTSD patients would show HPA axis abnormalities similar to those seen in depressed patients or chronically stressed animals, but this has not always been the case. An initial study (Mason et al. 1986) found that urinary free cortisol (UFC) excretion was lower in PTSD than in major depression. However, another study (Pitman and Orr 1990) found increased UFC excretion in outpatient PTSD veterans compared with combat-exposed control subjects without PTSD. Since then, there have been various findings, but the most comprehensive studies of PTSD, those by Yehuda and colleagues (for a review, see Yehuda 2002), continue to show low cortisol and enhanced cortisol suppression in response to dexamethasone in combat veterans with PTSD. Interestingly, the presence of comorbid major depression does not change the neuroendocrine picture. The main criticism of this body of work is that the sample comprised only male combat veterans and...

Depression And Reproductive Hormone Changes

In women with a previous episode of depression, times of rapidly changing gonadal steroid concentrations, such as those occurring premenstrually or postpartum, mark particularly vulnerable times for the occurrence of depressive symptoms. Several studies have shown that in women, a history of depression increases the risk of both postpartum blues and postpartum major depression (O'Hara 1986 O'Hara et al. 1991 Reich and Winokur 1970) and that hormonal changes occurring premenstrually may affect mood (Halbreich et al. 1984, 1986). When they were euthymic, 62 of women with a history of major depressive episodes reported the occurrence of premenstrual mood changes and biological symptoms typical of major depressive disorder. Other studies found a relationship between the rise in estrogen and testosterone levels and the rising incidence of depression in girls during adolescence (Angold et al. 1999). More recently in two epidemiological cohorts (Cohen et al. 2006 Freeman et al. 2006), there...

Reproductive Abnormalities in Depression

In depression, response to GnRH has been assessed by several groups. Some studies have reported a normal LH and FSH response to GnRH in pre- and postmenopausal women (Unden et al. 1988 Winokur et al. 1982). However, given the major differences in LH pulse amplitude and mean LH levels between follicular and luteal phases, it would be extremely difficult to observe a difference in basal LH secretion between major depression and control women without strict control of menstrual cycle phase. However, Brambilla et al. (1990) noted a decreased LH response to GnRH in both premenopausal and postmenopausal women, with lower baseline LH concentrations in postmenopausal depressed women. It may be that the increased secretion of LH following removal of the negative feedback of gonadal steroids in postmenopausal women unmasks a decrease in LH secretion that is not as easily observed in women with intact estrogen and progesterone feedback. Other studies examining depressed patients of both sexes,...

Estrogen and Depression

Because of increased incidence of depression at critical hormonal transition phases such as postpartum and perimenopause, much speculation has taken place about estrogen's role as a precipitant. Recent studies have found increased incidence of depressive symptoms and major depression during the menopause transition (Cohen et al. 2006 Freeman et al. 2006). The initial findings of Freeman et al. (2004) in regard to estrogen were that both high and low estrogen levels were associated with depression. More recently, the data suggest that variability in estrogen levels may drive depression. A model of differential sensitivity to estrogen has been proposed for premenstrual dysphoric disorder (PMDD) and also by Cohen et al. (2006) to explain the findings of increased depression during the menopause transition. Increased FSH, suggesting ovarian aging, and overall low or variable estrogen were also found to be strongly associated with depression (Freeman et al. 2006). And in the Freeman et al....

Growth Hormone And The Hypothalamicpituitarysomatotrophic Axis

Regulation make it difficult to extrapolate to humans from animal studies. It is well established, however, that the final common pathways for control of GH release from the pituitary are hypothalamic growth hormone-releasing hormone (GHRH) (stimulation) and somatostatin (inhibition). The wide variety of metabolic, endocrine, and neural influences that alter GH secretion do so primarily through effects on GHRH and or somatostatin. Neural influences may be mediated by noradrenergic, cholinergic, dopaminergic, 7 aminobutyric acid (GABA)-ergic, and serotonergic neurotransmission. Clear physiological regulatory roles, however, have only been well documented in humans for noradrenergic and cholinergic inputs. Dopamine, serotonin, and GABAergic drugs can alter GH release but do so in contradictory ways, depending on the experimental paradigm, leaving their roles as GH regulatory agents uncertain at present (Devesa et al. 1992 Muller 1987). In humans, GH is released by acute stress, but is...

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Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. Mirtazapine (Remeron) is a...

Box 111 Evidence of treatments for adult fibromyalgia syndrome

For an association of antidepressants with improved health-related quality of life (HRQOL) (SMD -0.31, 95 CI -0.42 to -0.20). Effect sizes for pain reduction were large for tricyclic antidepressants (TCA) (SMD -1.64, 95 CI -2.57 to -0.71), medium for MAOI (SMD -0.54, 95 CI -1.02 to -0.07) and small for SSRIs (SMD -0.39, 95 CI -0.77 to -0.01) and SNRIs (SMD -0.36, 95 CI -0.46 to -0.25) 74 . Multicomponent treatment (MT) programs There is no internationally accepted definition of mul-ticomponent therapy. The existing systematic reviews on MT agree that MT should include at least one educational or other psychologic therapy and at least one exercise therapy 67, 78 . The German FMS guideline group meta-analyzed 9 14 RCT, with 1119 subjects with a median treatment time of 24 hours included in the meta-analysis. There is strong evidence that MT reduces pain (SMD -0.37, 95 CI -0.62 to -0.13), fatigue (WMD -0.85, 95 CI -1.50 to -0.20), depressive symptoms (SMD -0.67, 95 CI -1.08 to -0.26) and...

Central Nervous System Stimulants

This chapter discusses a broad range of agents that stimulate the central nervous system (CNS). The analeptics classically are a group of agents with a limited range of use because of the general nature of their effects. The methyl-xanthines have potent stimulatory properties, mainly cortical at low doses but with more general effects as the dose is increased. The central sympathomimetic agents amphetamine and close relatives have alerting and antidepressant properties but are medically used more often as anorexi-ants. The antidepressant drugs are used most frequently in depressive disorders and can be broadly grouped into the monoamine oxidase inhibitors (MAOIs), the monoamine reuptake inhibitors, and agents acting on autoreceptors. A small group of miscellaneously acting drugs, which includes several hallucinogens, cocaine, and cannabinoids, concludes the chapter.

Intravenous Lidocaine

Conventional pharmacological treatment revolves around the use of acetaminophen, opioids and non-steroidal anti-inflammatories, with the use of antidepressants, anti-epileptics, membrane stabilizers and N-methyl-D-aspartate (NMDA) antagonists in particular circumstances, and requires the patients to either ingest or apply transdermally medication on a regular day-in, day-out basis. Where longer dosing intervals are appropriate, this is because extended release preparations are used. The aim is to achieve a steady state plasma concentration of the drug so that pain relief may be obtained. Unfortunately this may also expose the patient to day-in, day-out side effects with these side effects ranging from the trivial to the severe end of the spectrum and may be immediately obvious or more insidious.

Systemic Sodium Channel Blockers

Although this group of drugs comprises the local anesthetics and related membrane-stabilizing cardiac anti-arrhythmics, it should be appreciated that sodium channel inhibition is a property of many other groups of drugs, including many anticonvulsants, antidepressants, and mainstream analgesics such as pethidine (meperidine), and it is possible that at least some of the therapeutic effects of these drugs are mediated through sodium channel inhibition.

Drug InteractionsP450 Metabolism

SSRIs are predominantly metabolized by the hepatic cytochrome P450 system and may inhibit their own metabolism or that of other drugs (Table 6). Among SSRIs, sertraline, citalopram, and escitalopram possess minimal interactions within the P450 system this quality makes them the antidepressants of choice in medically ill patients requiring coadministration of other medications. Since SSRIs are also substrates for the hepatic cytochrome system, medications such as carbamazepine, rifampin, dexamethasone, which induce CYP 450 isoenzymes, accelerate SSRI metabolism if coadministered. Medications such as quini-dine, cimetidine, and diltiazem inhibit CYP 450 they will delay SSRI clearance and may produce toxic levels of SSRI (34, 63, 64). Comprehensive lists of drug interactions with SSRI antidepressants can be accessed at The Medical Letter Adverse Drug Interactions Program, or other computer databases (35, 63-67).

MMethylDAspartate Antagonists

Widely available as an over-the-counter medication, dextromethorphan is notable for its cough-suppressing effects. It is a low-affinity NMDA receptor antagonist that, when combined with opiate analgesics, may enhance opiate analgesia and reduce opiate tolerance (Elliott et al. 1994). Analgesic effects require dosing at rates substantially higher than those for antitussive effects. Dextromethorphan augments 5-HT in the CNS. Consequently, combination with serotonergic antidepressants (e.g., SSRIs) may predispose a patient to serotonin syndrome.

Burning Mouth Syndrome An Update

Summary This article provides an overview of burning mouth syndrome (BMS), a chronic oral-facial pain condition that affects many U.S. adults. The authors provide an update on what is known about the epidemiology, etiology, and treatment of BMS. Specific topics include the clinical presentation of BMS statistics on the incidence and prevalence of BMS oral disorders that can result in BMS, such as denture allergy, salivary dysfunction, or taste disturbances systemic conditions that can result in BMS, such as hematological disorders, nutritional disorders, anemias, central nervous system disorders, psychological disorders, diabetes mellitus, or Sjogren's syndrome and treatment options, including the use of antidepressants and benzodiazepines. The authors conclude that the dental profession should formulate standardized symptom and diagnostic criteria so that multidisciplinary investigations can identify effective and reliable treatment strategies. 2 figures. 2 tables. 65 references....

Interventions supported by evidence

There are two systematic reviews 13, 14 on the use of antidepressants which used data from three RCT to suggest that they may be effective in atypical facial pain 14-17 . There is also a systematic review that looks at all types of pharmacologic treatments for this condition 18 . Only the larger studies will be included here.

HT2CDopamine Interactions in Psychiatric Disorders 1171 Depression

Although dopamine has received little attention in biological research on depression, as compared with other monoamines such as serotonin and noradrenaline, current research on the dopaminergic system is about to change this situation. It is now well established that disturbances of mesolimbic and nigrostriatal DA function are involved in the pathophysiology of depression (Fibiger 1995 Brown and Gershon 1993). Moreover, stress promotes profound and complex alterations involving DA release, metabolism, and receptor densities in the mesolimbic system (Puglisi-Allegra et al. 1991 Cabib and Puglisi-Allegra 1996). It seems that exposure to unavoidable uncontrollable aversive experiences leads to inhibition of DA release in the mesoaccumbens DA system as well as impaired responding to rewarding and aversive stimuli. These alterations could elicit stress-induced expression and exacerbation of some depressive symptoms in humans (Cabib and Puglisi-Allegra 1996). Thus, in view of the hypothesis...

Discussion of evidence

All the studies are small and may contain a very heterogeneous group of patients. Given the prevalence of orofacial pain, it is surprising that there are so few high-quality studies. Although there is some evidence for the success of antidepressants, some patients do not have a good response and this could be due to certain patient characteristics nonanxious somatiz-ers, dysfunctional health beliefs, history of unsuccessful surgery, no life event before pain onset. Treatment needs to be continued for a long time and relapses are

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