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The roles of either the continuous outcome measures cyklokapron 500mg with amex, including the HAM-D 500 mg cyklokapron fast delivery, SAMe or St purchase cyklokapron 500 mg without a prescription. The very low rate of response both to active may be a useful focus of study. Acupuncture Thus, although the randomized clinical studies using pla- cebo suggest that hypericum has some antidepressant effect As reviewed in Ernst and colleagues (171), several case series in humans (and has effects in animal models for depression), and open clinical trials suggest possible efficacy of acupunc- the data are simply inadequate to say how well St. The NIMH and National Institutes of Health Office ture to amitriptyline. One study (172) compared 5 weeks on Alternative Medicine is currently funding a study of of amitriptyline (average daily dose 142 mg) to electro-acu- hypericum perforatum versus SSRI or placebo, which may puncture in a total of 47 subjects and found no significant further elucidate the efficacy of this compound. A larger replication found no significant difference in outcome between amitriptyline and electro-acupuncture in a 6-week RCT in a total of 241 S-adenosyl-L-methionine depressed inpatient subjects (173). As is well understood, lack of statistically significant difference of a putative treat- S-adenosyl-L-methionine (SAMe) has been tested as a po- ment from a 'known effective' treatment is not strong evi- tential antidepressant over the past 25 years. It is the primary dence for the efficacy of a treatment. In addition, the dura- methyl donor in the CNS for methyl acceptor molecules tion of treatment was relatively short, which would including catecholamines and phospholipids. A 1994 underestimate the maximal amitriptyline effect in these metaanalysis (167) examined the literature through 1992, studies. Although those authors be specific to the treatment of depression), placebo acu- found the aggregate data to show statistically significant puncture (acupuncture at nonspecific locations) or no acu- superiority of SAMe to placebo and equivalence of SAMe puncture. Both the specific and control acupuncture treat- to TCAs, all but two of the comparisons with placebo and ments showed statistical superiority to the no acupuncture two of the comparisons with TCAs were 21 days or less in group on several of the measures, although the differences duration. Equivalence to TCA for such a short interval (be- were not large. There was no difference on any measure fore most of the TCAs effects have been realized) is uncon- between the specific and control acupuncture treatments in vincing. Of the two placebo comparisons of longer duration, this study. Thus, the results of this study are compatible one trial of 30 days was positive and one of 42 days was with a nonspecific effect of the additional attention and negative. A large open investigation (169) efficacy in the treatment of major depression. However, suggested, as did earlier studies, efficacy and very rapid onset results of a recently published small, but randomized, con- of antidepressant effect of parenteral SAMe in humans. One trolled, and double-masked study of women with major study found imipramine-like 'antidepressant' effects of depression (n 38) suggest that acupuncture can provide 1090 Neuropsychopharmacology: The Fifth Generation of Progress significant symptom relief from depression, at rates compa- or managing the illness. Research to find clinically obtain- rable to those of psychotherapy and pharmacotherapy able measures of the disease process would remarkably im- (175). FUTURE RESEARCH ACKNOWLEDGMENTS The aim of treatment is remission, not simply response, Supported in part by the Betty Jo Hay Distinguished Chair given the better prognosis and better function associated in Mental Health, the Rosewood Corporation Chair in with remission. Clinical issues raised by this recognition Biomedical Science, and the Sara M. Seay include: (a) Do medications truly differ in their ability to Center for Basic and Applied Research in Psychiatry. Altshuler, Stanton Sharp combinations of more selective monotherapies) are used Distinguished Chair and Professor, Department of Psychia- compared to more neurotransmitter-selective agents? How much time and effort should be expended to attain Dr. Rush has received research support from: Abbott remission? Wood Johnson Foundation, Meadows Foundation, Na- The importance of functional recovery, in addition to tional Institute of Mental Health, Novartis, Organon, Inc. Some prelimi- Stanley Foundation, Wyeth-Ayerst, and Zeneca. This contention deserves more thorough and Cyberonics, Inc. More research to develop evidence to establish valid pathways and to test their impact compared A. John Rush has received $5,000 per year or more in the to treatment as usual is needed. Mental Health, Stanley Foundation, Robert Wood Johnson Does a particular treatment history (or family history of Foundation, Cyberonics, Inc. Additionally, earlier intervention with less complex treat- Neal Ryan has received $5,000 per year or more in the ments, perhaps in the prodromal stages of the disorder, de- form of honoraria and/or research grant support for the last serves further evaluation—especially with the potential 3 years from the following entities: National Institute of availability of CRF antagonists. If these agents modify the Mental Health, National Library of Medicine, Forest Labo- stress response, could they be given quickly, close in time ratories, Pfizer, Pharmacia & Upjohn, Solvay, SmithKline to the stress, before a full depressive episode appears in those Beecham, and Wyeth-Ayerst. Finally, we still are hampered by having to rely on symp- REFERENCES toms and signs to gauge the adequacy of our treatments. American Psychiatric Press Most of medicine can rely in part on laboratory measures textbook of psychopharmacology, second ed. Washington, DC: to also inform clinicians about modifying the treatment plan American Psychiatric Press, 1998. Chapter 75: Current and Emerging Therapeutics for Depression 1091 2. WPA series in evidence and residual depression by cognitive therapy. Affective disorders: course over the life- depression with cognitive therapy: preliminary findings. Six-year outcome for cott Williams & Wilkins, this volume. Arch Gen Psychiatry 1995;52: ing myocardial infarction. Part 3: Psychosocial functioning before and month prognosis after myocardial infarction. Circulation 1995; after treatment with sertraline or imipramine. The treatment patients with long-standing type I diabetes mellitus. Part 2: A double-blind, randomized trial Psychiatry 1988;45:64–68. Platelet monoamine oxidase and the dexametha- respond to nefazodone and when? Clinical practice guideline, num- dysthymia, biochemical correlates of the therapeutic response to ber 5. Urinary metabolites of serotonin, norepinephrine, Rockville, MD: US Dept. Am J Psychiatry 1993;150(Suppl study of fluoxetine in dysthymia. Pharmacotherapy of dysthymic and chronic depres- treatment of patients with major depressive disorder (revision). A prospective 12-year therapy for chronic depression: A controlled trial of desipra- study of subsyndromal and syndromal depressive symptoms in mine. Major depressive disorder: tion treatment of major depression. Hum Psychopharmacol a prospective study of residual subthreshold depressive symp- 1995;10:393–405. Remission and residual symptomatology in major Disord 2001;65:27–36. Three-year outcomes for 1092 Neuropsychopharmacology: The Fifth Generation of Progress maintenance therapies in recurrent depression. Five-year outcome for drome/premenstrual dysphoric disorder: a randomized con- maintenance therapies in recurrent depression. Nortiptyline and faxine extended-release capsules in nondepressed outpatients interpersonal psychotherapy as maintenance therapies of recur- with generalized anxiety disorder: a 6-month randomized con- rent major depression: a randomized, controlled trial in patients trolled trial. Columbia atypical release venlafaxine in nondepressed outpatients with generalized depression. A subgroup of depressives with better response to anxiety disorder.

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Sedative-hypnotic drugs: interaction with calcium benzodiazepine receptors in type II alcoholics measured with channels discount 500mg cyklokapron mastercard. Chapter 100: Ethanol Abuse generic cyklokapron 500 mg overnight delivery, Dependence discount 500mg cyklokapron free shipping, and Withdrawal 1439 107. Inhibition of dihydropyri- human 5-HT1D receptor-mediated functional responses in sta- dine-sensitive Ca2 channels by ethanol in undifferentiated bly transfected rat C6-glial cell lines: further evidence differ- and nerve growth factor-treated PC12 cells: interaction with entiating human 5-HT1D and 5-HT1B receptors. Ritanserin, a 5-HT2A/2C in up-regulation of dihydropyridine-sensitive calcium channels antagonist, reverses direct dopamine agonist-induced inhibition by ethanol. Genetic regulation of dihydro- expressed in HEK293 cells. Neuropharmacology 1997;36: pyridine-sensitive calcium channels in brain may determine sus- 713–720. Calcium currents and meta-chlorophenylpiperazine in healthy human subjects. Psy- peptide release from neurohypophyseal terminals are inhibited chiatry Res 1991;38:227–236. Ethanol effects on two treatment of alcohol dependence—a multi-center clinical trial. Serotonin transporter pro- mediates up-regulation of N-type calcium channels by ethanol. Dose-related ethanol- populations and in alcohol-dependent subjects. Hum Genet like effects of the NMDA antagonist, ketamine, in recently de- 1997;101:243–246. Arch Gen Psychiatry 1996;53: alcohol withdrawal state. Dopamine D1, D2 and ethanol-like discriminative stimulus effects of 5-HT receptor D3 receptor genes in alcohol dependence. Psychiatr Genet 1995; agonists as a function of ethanol training dose. Specificity of ethanollike 5-hydroxyindoleacetic acid concentration associated with a tryp- effects elicited by serotonergic and noradrenergic mechanisms. Arch Gen Psychiatry 1994; Arch Gen Psychiatry 1994;51:898–911. Ethanol intake and psychological, and alcohol craving changes after m-chlorophe- 3H-serotonin uptake. II: A study in alcoholic patients using nylpiperazine administration in alcoholics. Alcohol Clin Exp Res platelets 3H-paroxetine binding. Behavioral and take in men with family histories of alcoholism. Neuropsycho- neuroendocrine responses to m-chlorophenylpiperazine in sub- pharmacology 1991;4:83–86. Eur J Nucl Med 1997;24: chlorophenylpiperazine challenge test in cocaine addicts: hor- 1253–1260. Fluoxetine treatment drenergic dysregulation in alcoholism: m-chlorophenylpipera- seems to reduce the beneficial effects of cognitive-behavioral zine and yohimbine effects in recently detoxified alcoholics and therapy in type B alcoholics. Alcohol Clin Exp Res 1996;20: healthy comparison subjects. Fluoxetine atten- nylpiperazine on regional brain glucose utilization: a positron uates alcohol intake and desire to drink. Int Clin Psychopharma- emission tomographic comparison of alcoholic and control sub- col 1994;9:163–172. Blockade of the discriminative stimulus Sci 1992;50:599–605. Ondansetron for 1440 Neuropsychopharmacology: The Fifth Generation of Progress reduction of drinking among biologically predisposed alcoholic receptors but not in dopamine transporters in alcoholics. Cellular and molecular mechanisms of drug adrenoceptor function in abstinent alcoholics. Clinical conditions and of nigral dopaminergic neurons in unanesthetized rats. Brain concentrations of MOPEG in the cerebrospinal fluid and urine Res 1984;292:63–69. Alcoholism and alleles genetic and motivational determinants. J Pharmacol Exp Ther of the human D2 dopamine receptor locus. No structural mutation medial prefrontal cortex influence ethanol and sucrose-rein- in the dopamine D2 receptor gene in alcoholism or schizophre- forced responding. Analysis using denaturing gradient gel electrophoresis. Suppression of ethanol-reinforced behav- JAMA 1994;271:204–208. The A1 allele at the D2 induced increase in dialysate dopamine levels in the nucleus dopamine receptor gene and alcoholism. Bromocriptine in intake in the rat: effects of nicotinic acetylcholine receptor the treatment of alcoholics with the D2 dopamine receptor A1 blockade or subchronic nicotine treatment. Ethanol self-administra- ment for antisocial personality disorder alcoholics: a preliminary tion restores withdrawal-associated deficiencies in accumbal do- study. Effects of nimodipine on Am J MedGenet 1997;74:483–487. Association be- tween alcoholism and the dopamine D4 receptor gene. Low doses of ethanol disrupt alcoholics and controls. Basal firing of rat locus coeruleus neurons ese populations: six polymorphisms tested separately and as hap- affects sensitivity to ethanol. Lack of association and their receptors and enzymes. Antagonism by alpha between the dopamine D4 receptor (D4DR) 16 amino acid methyltyrosine of the ethanol-induced stimulation and euphoria repeat polymorphism and novelty seeking. No association between sponse to acute ethanol administration in healthy subjects: com- polymorphisms in the human dopamine D3 and D4 receptors parison with intravenous yohimbine. Reversal of ethanol between novelty seeking and the type 4 dopamine receptor gene intoxications in humans: an assessment of the efficacy of pro- (DRD4) in two New Zealand samples. Acute and chronic ethanol intoxication in humans: an assessment of the efficacy of L-dopa, treatment changes endorphin levels in brain and pituitary. Changes in dopamine in vitro on the b-endorphin system in the rat. Life Sci 1987; receptor sensitivity in humans after heavy alcohol intake. Decreases in dopamine regulation of opioid peptides. Chapter 100: Ethanol Abuse, Dependence, and Withdrawal 1441 186. Ethanol exposure decreases age, or does alcohol damage the brain? J Neuropathol Exp Neurol pituitary corticotropin-releasing factor binding, adenylate cy- 1998;57:101–110. Do alcoholics drink their neurons sin mRNA levels are differentially affected by chronic ethanol away? Alcohol interactions with brain opiate tions in rat CA1 hippocampal cell dendrites resulting from receptors. The contribution of alcohol, thiamine deficiency and of striatal opiate receptors. Ethanol alters kinetic char- Metab Brain Dis 1995;10:9–16.

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