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Influence of antidepressant drugs on macrophage cytotoxic activity in rats.

Belowski D, Kowalski J, Madej A, Herman ZS.

Department of Clinical Pharmacology, Silesian University School of Medicine, Medykow 18, PL 40-752 Katowice, Poland.

The aim of the study was to evaluate the in vivo and in vitro effects of antidepressant drugs on cytotoxic activity of rat spleen macrophages. In the in vivo experiment, rats were injected subcutaneously with two different doses (2 or 10 mg/kg) of desipramine, fluvoxamine and fluoxetine. The drugs were given once, for 2, 4 or 8 weeks. In the in vitro experiment, spleen macrophages were cultured with three different concentrations of desipramine (3.75, 0.75, or 0.075 mM), fluvoxamine (3.14, 0.62, or 0.062 mM), and fluoxetine (3.23, 0.64, or 0.064 mM) for 72 h. The cytotoxic activity of macrophages was evaluated by measuring the lysis of ((51)Cr) chromate-labelled P-815 target cells. In the in vivo experiment, a single dose of fluvoxamine (2 and 10 mg/kg) and fluoxetine (10 mg/kg) significantly decreased macrophage cytotoxic activity. Fluvoxamine (2 and 10 mg/kg), fluoxetine (10 mg/kg) and desipramine (10 mg/kg) administrated for 14 days also decreased macrophage cytotoxic activity. Twenty-eight day treatment with desipramine (2 and 10 mg/kg) decreased macrophage cytotoxic activity. Desipramine, fluvoxamine and fluoxetine given for 56 days did not affect macrophage cytotoxic activity. In the in vitro experiment, antidepressant drugs did not affect the cytotoxic activity of macrophages. The results of the study indicate that the effects of antidepressant drugs on macrophage cytotoxic activity depend on the drug type, dose and duration of the treatment.

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COMORBID CONDITIONS.

[No authors listed]

Staud R, Price DD, Robinson ME, Mauderli AP, Vierck CJ. Maintenance of windup of second pain requires less frequent stimulation in fibromyalgia patients compared to normal controls. Pain. 2004;110:689-696. Many chronic pain syndromes, including fibromyalgia (FM), show evidence of central nervous system hyperexcitability related to central sensitization. Windup (WU) of second pain reflects increased excitability of spinal cord neurons that is related to central sensitization. Psychophysical testing can help characterize this important central nervous system phenomenon because of the parallels between electrophysiological WU and WU of second pain. Animal experiments have shown that once WU has been established, only low frequency tonic nociceptive input is required to maintain the sensitized state of dorsal horn neurons (WU-maintenance or WU-M). The stimulus frequency necessary to maintain the hyperexcitability of spinal cord neurons can provide a measure of central sensitization. Because central sensitization plays an important role in many chronic pain syndromes including FM, we compared WU-M in 72 normal controls (NC) and 104 FM subjects. WU of second pain was produced by a train of 0.7-second duration thermal pulses applied to the glabrous surface of the hands at a frequency of 0.3 Hz. Enhanced second pain associated with WU could, thereafter, be maintained in FM but not NC subjects for up to 120 seconds by stimuli delivered at 0.16 and 0.08 Hz (WU-M stimuli). These two frequencies of stimulation do not produce WU when delivered alone. Thus, unlike NC subjects, FM subjects showed enhanced second pain during WU-M stimuli at very low stimulus frequencies, indicating central sensitization. Increased WU sensitivity, enhanced WU-M, and increased WU-related aftersensations help account for persistent pain conditions in FM subjects. In addition to WU, WU-M appears to be a useful tool to study mechanisms of pain in patients with characteristics of central sensitization. Comment: Interesting study as we become more and more concerned with central senitization in primary headache patients.-Stewart J. Tepper, MD Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004;292:338-343. Background: The relation between the use of antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), and suicidal ideation and behaviors has received considerable public attention recently. The use of such drugs among teenagers has been of particular concern. Objective: To estimate the relative risks (RRs) of nonfatal suicidal behavior in patients starting treatment with one of three antidepressant drugs compared with patients starting treatment with dothiepin. Design and Setting: Matched case-control study of patients treated in UK general practices using the UK General Practice Research Database for 1993-1999.Participants: The base population included 159,810 users of the four antidepressant drugs. Participants could have used only one of these antidepressants and had to have received at least one prescription for the study antidepressant within 90 days before their index date (the date of suicidal behavior or ideation for cases and the same date for matched controls). Main Outcome Measures: Frequency of first-time exposure to amitriptyline, fluoxetine, paroxetine, and dothiepin of patients with a recorded diagnosis of first-time nonfatal suicidal behavior or suicide compared with comparable patients who did not exhibit suicidal behavior. Results: After controlling for age, sex, calendar time, and time from first antidepressant prescription to the onset of suicidal behavior, the relative risks for newly diagnosed nonfatal suicidal behavior in 555 cases and 2062 controls were 0.83 (95% confidence interval, [CI] 0.61-1.13) for amitriptyline, 1.16 (95% CI, 0.90-1.50) for fluoxetine, and 1.29 (95% CI, 0.97-1.70) for paroxetine compared with those using dothiepin. The RR for suicidal behavior among patients first prescribed an antidepressant within 1 to 9 days before their index date was 4.07 (95% CI, 2.89-5.74) compared with patients who were first prescribed an antidepressant 90 days or more before their index date. Time since first antidepressant prescription was not, however, a confounder of the relation between specific antidepressants and suicidal behavior since its relation to suicidal behavior was not materially different among users of the four study drugs. Similarly for fatal suicide, the RR among patients who were first prescribed an antidepressant within 1 to 9 days before their index date was 38 (95% CI, 6.2-231) compared with those who were first prescribed an antidepressant 90 days or more before their index date. There were no significant associations between the use of a particular study antidepressant and the risk of suicide. Conclusions: The risk of suicidal behavior after starting antidepressant treatment is similar among users of amitriptyline, fluoxetine, and paroxetine compared with the risk among users of dothiepin. The risk of suicidal behavior is increased in the first month after starting antidepressants, especially during the first 1 to 9 days. A possible small increase in risk (bordering statistical significance) among those starting the newest antidepressant, paroxetine, is of a magnitude that could readily be due to uncontrolled confounding by severity of depression. Based on limited information, we also conclude that there is no substantial difference in effect of the four drugs on people aged 10 to 19 years. Comment: This is an interesting study by the Boston collaborative group trying to unravel whether any of the antidepressants used in young people to treat a first attack of depressive illness were more likely to be linked to suicidal behavior. This was carried out using the UK General Practice Database which allows record linkage between diagnosis, treatment, and outcomes. As a primary care practitioner who contributes data to the GPRD, I am concerned that this study does not have the statistical power to exclude the possibility of an association. The authors rightly acknowledge the limited data upon which their conclusion is based. Moreover, the GPRD data base does not allow for the severity of depression to be categorized, hence the statement that "the possible small increase in risk (bordering statistical significance) among those starting the newest antidepressant, paroxetine, is of a magnitude that could readily be due to uncontrolled confounding by severity of depression" cannot be excluded using the GPRD.-David S. Millson, MD March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J, Treatment for Adolescents With Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA. 2004;292:807-820. Background: Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI). However, little is known about their relative or combined effectiveness. Objective: To evaluate the effectiveness of four treatments among adolescents with major depressive disorder. Design, Setting, and Participants: Randomized controlled trial of a volunteer sample of 439 patients between the ages of 12 and 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003. Interventions: Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered double-blind; CBT alone and CBT with fluoxetine were administered unblinded. Main Outcome Measures: Children's Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score. Results: Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P= 0.001) on the Children's Depression Rating Scale-Revised. Compared with fluoxetine alone (P= .02) and CBT alone (P= .01), treatment of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment to CBT alone (P= .01). Rates of response for fluoxetine with CBT were 71.0% (95% confidence interval [CI], 62%-80%); fluoxetine alone, 60.6% (95% CI, 51%-70%); CBT alone, 43.2% (95% CI, 34%-52%); and placebo, 34.8% (95% CI, 26%-44%). On the Clinical Global Impressions improvement responder analysis, the two fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all four treatment groups. Fluoxetine with CBT showed the greatest reduction (P= .02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides. Conclusion: The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder. Comment: The evidence is accumulating that the suicide risk may be up slightly due to the activating effects of the SSRIs when initially treating severe depression, especially in adolescents, though apparently less so with fluoxetine. The risk is reduced by having the patient simultaneously undergo Cognitive Behavioral Therapy (CBT). In headache management, we rarely have such severely depressed patients when we initiate therapy, but depression is co-morbid with migraine, and discussion of depression and mood is important before initiation of SSRI therapy.-Stewart J. Tepper, MD Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, Gould TD, Manji HK, Chen G. Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci. 2004;24:6590-6599. Manic-depressive illness has been conceptualized as a neurochemical illness. However, brain imaging and postmortem studies reveal gray-matter reductions, as well as neuronal and glial atrophy and loss in discrete brain regions of manic-depressive patients. The roles of such cerebral morphological deficits in the neuropathophysiology and therapeutic mechanisms of manic-depressive illness are unknown. Valproate (2-propylpentanoate) is a commonly used mood stabilizer. The ERK (extracellular signal-regulated kinase) pathway is used by neurotrophic factors to regulate neurogenesis, neurite outgrowth, and neuronal survival. We found that chronic treatment of rats with valproate increased levels of activated phospho-ERK44/42 in neurons of the anterior cingulate, a region in which we found valproate-induced increases in expression of an ERK pathway-regulated gene, bcl-2. Valproate time and concentration dependently increased activated phospho-ERK44/42 and phospho-RSK1 (ribosomal S6 kinase 1) levels in cultured cortical cells. These increases were attenuated by Raf and MEK (mitogen-activated protein kinase/ERK kinase) inhibitors. Although valproate affects the functions of GSK-3 (glycogen synthase kinase-3) and histone deacetylase (HDAC), its effects on the ERK pathway were not fully mimicked by selective inhibitors of GSK-3 or HDAC. Similar to neurotrophic factors, valproate enhanced ERK pathway-dependent cortical neuronal growth. Valproate also promoted neural stem cell proliferation-maturation (neurogenesis), demonstrated by bromodeoxyuridine (BrdU) incorporation and double staining of BrdU with nestin, Tuj1, or the neuronal nuclei marker NeuN (neuronal-specific nuclear protein). Chronic treatment with valproate enhanced neurogenesis in the dentate gyrus of the hippocampus. Together, these data demonstrate that valproate activates the ERK pathway and induces ERK pathway-mediated neurotrophic actions. This cascade of events provides a potential mechanism whereby mood stabilizers alleviate cerebral morphometric deficits associated with manic-depressive illness. Comment: Valproate has important structural effects on the brain in patients with bipolar illness, where underlying structural differences ("morphometic deficits") exist. Morphometic differences are also present in epilepsy patients, and it may not be a stretch to assume them in primary headache patients. So, the chronic effects of valproate are biochemical, electrical, and structural, and we are just beginning to understand them.-Stewart J. Tepper, MD.

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Behavioural analysis of the anorectic effects of fluoxetine and fenfluramine.

Willner P, McGuirk J, Phillips G, Muscat R.

Psychology Department, City of London Polytechnic, UK.

Two sets of experiments were carried out to compare the effects of fenfluramine and fluoxetine on consummatory and operant behaviour. In food-deprived rats allowed access to a 35% sucrose solution, an initial period of sucrose consumption was followed by a short period of grooming and exploratory behaviour, later superceded by resting. This "behavioural satiety sequence" was advanced by fluoxetine, but disrupted by dl-fenfluramine, which suppressed post-prandial resting, even at sub-anorectic doses. Fluoxetine also elicited resting behaviour following water drinking. However, this did not appear to be a non-specific sedative effect, since fluoxetine increased post-prandial grooming. In rats performing on random interval schedules of food reinforcement, fluoxetine caused proportionally greater decreases in responding on a reinforcement-lean schedule (RI-300s), as compared to a reinforcement-rich schedule (RI-7.5s); this effect is similar to that of a reduction in level of food deprivation. By contrast, fenfluramine reduced responding equally on both schedules. In both paradigms, the effects of fluoxetine were compatible with an increase in postprandial satiety, but the effects of fenfluramine were not.

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Fluoxetine treatment of children and adolescents with Tourette's and obsessive compulsive disorders: preliminary clinical experience.

Riddle MA, Hardin MT, King R, Scahill L, Woolston JL.

Child Study Center, Yale University School of Medicine, New Haven, CT.

Fluoxetine hydrochloride is the first selective serotonin uptake inhibitor introduced commercially in the United States. This report describes preliminary clinical experience with fluoxetine in 10 children and adolescents, aged 8 to 15 years, with primary obsessive compulsive disorder (OCD) or Tourette's syndrome (TS) plus OCD. In general, fluoxetine, which was administered from 4 to 20 weeks at a dosage of 10 or 40 mg per day, was well tolerated. Adverse effects included behavioral agitation/activation in four patients and mild gastrointestinal symptoms in two patients. No abnormalities were noted in the seven children who had follow-up EKGs. Five of the 10 patients (50%) were considered responders; their obsessive-compulsive symptoms decreased substantially during treatment with fluoxetine. Responder rates were similar in the primary OCD (two of four, 50%) and TS + OCD (three of six, 50%) groups. In conclusion, short-term fluoxetine administration appears to be safe in children and adolescents. Placebo-controlled trials are needed to further assess the efficacy of fluoxetine.

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Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study.

Suvanto-Luukkonen E, Koivunen R, Sundstrom H, Bloigu R, Karjalainen E, Haiva-Mallinen L, Tapanainen JS.

Department of Obstetrics and Gynecology, Oulu University Hospital, PL 24, 90029 OYS, Oulu, Finland. Eila.Suvanto-Luukkonen oulu.fi

OBJECTIVE: Nonhormonal treatment of postmenopausal symptoms is a subject of great interest today. The results of studies on selective serotonin reuptake inhibitors (SSRIs) are promising, but long-term results do not exist. The objective of this study was to evaluate the efficacy of citalopram and fluoxetine in the treatment of physical and psychological menopausal symptoms and their effects on psychosocial and sexual well being in symptomatic postmenopausal women. DESIGN: One hundred fifty healthy women suffering from menopausal symptoms were recruited to this placebo-controlled double-blind study with a follow-up period of 9 months. They were randomized into three groups receiving placebo, fluoxetine, or citalopram. The initial dose was 10 mg of both fluoxetine and citalopram, and it was increased to 20 mg at 1 month and to 30 mg at the 6-month visit. The main outcome measures were hot flushes and Kupperman index. The RAND-36 Quality of Life questionnaire, Beck's Depression Scale, and the McCoy Female Sexuality Questionnaire were used at every control visit. RESULTS: There were no statistically significant differences between the groups in respect to number of hot flushes, Kupperman index, or Beck's Depression Scale, although there was a tendency in all these parameters in favor of SSRIs versus placebo. Insomnia improved significantly in the citalopram group versus placebo. Discontinuation rates at nine months were 40% in the placebo group, 34% in the fluoxetine group and 34% in the citalopram group. CONCLUSIONS: Compared with placebo, citalopram and fluoxetine have little effect on hot flushes and cannot therefore be recommended for the treatment of menopausal symptoms, if vasomotor symptoms are the main complaint. Whether the improvement of insomnia by means of citalopram affects the quality of sleep needs further investigation.

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Fluoxetine reduces intravenous cocaine self-administration in rats.

Carroll ME, Lac ST, Asencio M, Kragh R.

Psychiatry Department, University of Minnesota Medical School, Minneapolis 55455.

Rats self-administered intravenously delivered cocaine (0.2 mg/kg) under a fixed-ratio (FR) 4 schedule during 24-hr sessions. Water was freely available from both a drinkometer and a standard water bottle. After behavior had stabilized, the rats were injected with fluoxetine HCl at 10:00 a.m. and 4:00 p.m. for 5 consecutive days. Three groups of 5 rats each received a different dose of fluoxetine (2.5, 5 or 10 mg/kg) via the IV cannula. In three other groups of rats a glucose and saccharin solution (G + S) was substituted for water in the automatic drinking device and saline was substituted for cocaine. These three groups of rats received the same fluoxetine doses as the cocaine self-injecting groups. In two additional groups of 5 rats each, the cocaine dose was changed to 0.1 or 0.4 mg/kg, and 5 mg/kg fluoxetine injections were given. The two higher doses of fluoxetine (5 and 10 mg/kg) reduced cocaine infusions (0.2 mg/kg) by at least 50 percent on all 5 days of treatment, and cocaine infusions returned to baseline levels within 48 hr after fluoxetine treatments were terminated. Behavior maintained by the G + S solution was also reduced by the two higher fluoxetine doses; however, this reduction did not reliably occur until the last two days of fluoxetine administration. The G + S intakes returned to baseline levels within 24 hr after fluoxetine treatment. Fluoxetine also reduced cocaine infusions in the group of rats that received the lower unit dose of cocaine (0.1 mg/kg); however, it had almost no effect on behavior maintained by a higher cocaine dose (0.4 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

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Fluoxetine reduces food intake by a cholecystokinin-independent mechanism.

Cooper SJ, Dourish CT, Barber DJ.

School of Psychology, University of Birmingham, U.K.

The selective serotonin uptake inhibitor, fluoxetine (3.0-10 mg/kg), produced a significant dose-related suppression of palatable food consumption in nondeprived rats. The anorectic effect of fluoxetine (10 mg/kg) was not reversed by the potent and highly selective cholecystokinin receptor antagonist MK-329 [1-methyl-3-(2-indolyl) amino-5-phenyl-3H-1,4-benzodiazepin-2-one], administered in doses of 10-100 micrograms/kg. Fluoxetine (10 mg/kg) also significantly reduced the consumption of powdered laboratory chow in a 6-hr nocturnal free-feeding test. The anorectic effect in this paradigm was also not antagonized by MK-329. In contrast to previous data for d-fenfluramine (which enhances serotonin release), these results indicate that fluoxetine may suppress food intake by a mechanism which is independent of endogenous cholecystokinin.

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Modafinil enhances the increase of extracellular serotonin levels induced by the antidepressant drugs fluoxetine and imipramine: A dual probe microdialysis study in awake rat.

Ferraro L, Fuxe K, Agnati L, Tanganelli S, Tomasini MC, Antonelli T.

Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Ferrara, Italy.

In view of a postulated role of the vigilance-promoting drug modafinil in depression, the interaction of modafinil and two classical antidepressant drugs, fluoxetine and imipramine, were studied in 5-HT levels in the dorsal raphe-cortical system using dual-probe microdialysis. Fluoxetine (1-10 mg/kg) dose-dependently increased dorsal raphe-cortical 5-HT levels. Modafinil at a very low dose (3 mg/kg), by itself ineffective, enhanced the fluoxetine (5 mg/kg)-induced increases of 5-HT levels in both brain areas. A synergistic interaction was observed in the prefrontal cortex with fluoxetine (1 mg/kg) in terms of 5-HT release, but not in the dorsal raphe. Imipramine (1.3 mg/kg) increased 5-HT levels in the dorsal raphe, but not in the prefrontal cortex, while the higher doses (10.9-21.8 mg/kg) caused substantial increases in both brain areas. Modafinil (3 mg/kg), injected before imipramine (1.3 mg/kg), which by itself was ineffective on cortical 5-HT levels, increased cortical 5-HT levels. On other hand, modafinil failed to affect the high-dose imipramine (10.9 mg/kg)-induced increase of 5-HT levels in the prefrontal cortex and the imipramine (1.3; 10.9 mg/kg)-induced increase of 5-HT levels in the dorsal raphe nucleus. These results demonstrate that modafinil in low doses enhances the acute effects of fluoxetine and imipramine on 5-HT levels in the dorsal raphe nucleus (fluoxetine only) and especially in the prefrontal cortex of the awake rat. These findings suggest a therapeutic potential of low doses of modafinil in the treatment of depression when combined with low doses of classical antidepressants, especially by increasing 5-HT transmission in cortical regions. Synapse 55:230-241, 2005. (c) 2005 Wiley-Liss, Inc.

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