Prozac
Fluoxetine treatment of bipolar II depression.

Simpson SG, DePaulo JR.

Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland.

We have previously reported on the familial aggregation of bipolar II affective disorder and have speculated that new treatment approaches might be required for this difficult disorder. Based on Reimherr's report that fluoxetine responders were more likely to have poor prior responses to tricyclics and to have chronic depressions with "atypical" clinical features, we used fluoxetine to treat the chronic atypical depression in selected bipolar II outpatients. The 16 bipolar II patients in our series had been depressed for an average of 5.3 years prior to starting fluoxetine and had had poor responses to tricyclics, MAOIs, and lithium. All but one have had some response to fluoxetine. Ten of the 13 patients who have been taking fluoxetine for 10 or more months have had a good to very good response and the other 3 have had a fair response. Only one patient discontinued fluoxetine because of side effects. These findings should encourage further treatment research using fluoxetine and other serotonin reuptake blockers as well as research into the pathophysiologic identity of bipolar II as a possible distinct form of affective disorder.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2040716&dopt=Abstract fluoxetine Prozac



Prozac
Randomized, double-blind, placebo-controlled trial of fluoxetine treatment for elderly patients with dysthymic disorder.

Devanand DP, Nobler MS, Cheng J, Turret N, Pelton GH, Roose SP, Sackeim HA.

Late-Life Depression Clinic, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 126, New York, NY 10032, USA. dpd3 columbia.edu

OBJECTIVE: The authors compared the efficacy and side effects of fluoxetine and placebo in elderly outpatients with dysthymic disorder. METHODS: Patients were randomly assigned to fluoxetine (20 mg-60 mg/day) or placebo for 12 weeks in a double-blind trial. RESULTS: Of 90 randomized patients, 71 completed the trial. In the intent-to-treat sample, random regression analyses of the Hamilton Rating Scale for Depression (Ham-D; 24-item) and Cornell Dysthymia Rating Scale (CDRS) scores at each visit produced significant time x treatment group interactions favoring the fluoxetine group. Analysis of percentage change in Ham-D scores yielded no effect for treatment group, but a similar analysis of percentage change in CDRS scores yielded a main effect for treatment group, favoring fluoxetine over placebo. In the intent-to-treat sample, response rates were 27.3% for fluoxetine and 19.6% for placebo. In the completer sample, response rates were 37.5% for fluoxetine and 23.1% for placebo. CONCLUSION: Fluoxetine had limited efficacy in elderly dysthymic patients. The clinical features of elderly dysthymic patients are typically distinct from those of dysthymic disorder in young adults, and the findings suggest that treatments effective for young adult dysthymic patients may not be as useful in elderly dysthymic patients. Further research is needed to identify efficacious treatments for elderly patients with dysthymic disorder, and investigative tools such as electronic/computerized brain scans and neuropsychological testing may help identify the factors that moderate antidepressant treatment response and resistance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15653941&dopt=Abstract fluoxetine Prozac



Prozac
Solid-phase extraction of fluoxetine and norfluoxetine from serum with gas chromatography-electron-capture detection.

Dixit V, Nguyen H, Dixit VM.

Varian Sample Preparation Products, Harbor City, CA 90710.

A rapid, selective, and sensitive method is described for the purification and analysis of fluoxetine and norfluoxetine using a solid-phase extraction column and gas chromatography-electron-capture detection. Linear quantitative response curves for fluoxetine and norfluoxetine are generated over a concentration range of 20-200 ng/ml. Overall extraction efficiency of the extraction procedure is found to be greater than 90% and greater than 75% with correlation coefficients of 0.997 and 0.993 for fluoxetine and norfluoxetine, respectively.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2056002&dopt=Abstract fluoxetine Prozac



Prozac
5HT, fluoxetine, imipramine and dopamine target distinct 5HT receptor signaling to modulate Caenorhabditis elegans egg-laying behavior.

Dempsey CM, Mackenzie SM, Gargus A, Blanco G, Sze JY.

University of California Irvine.

Drugs that target the serotonergic system are the most commonly prescribed therapeutic agents and are used for the treatment of a wide range of behavioral and neurological disorders. However, the mechanisms of the drug action remain a conjecture. Here, we dissect genetic targets of serotonin (5HT), the selective 5HT reuptake inhibitor (SSRI) fluoxetine (Prozac), the tricyclic antidepressant imipramine, and dopamine. Using the well-established serotonergic response of stimulated egg laying in C elegans as a paradigm, we show that action of fluoxetine and imipramine at the 5HT reuptake transporter (SERT) and at 5HT receptors are separable mechanisms. Even mutants completely lacking 5HT or SERT can partially respond to fluoxetine and imipramine. Furthermore, distinct mechanisms for each drug can be recognized to mediate these responses. Deletion of SER-1, a 5HT1 receptor, abolishes the response to 5HT but has only a minor effect on the response to imipramine and no effect to fluoxetine. In contrast, deletion of SER-4, a 5HT2 receptor, confers significant resistance to imipramine while leaving the responses to 5HT or fluoxetine intact. Further, fluoxetine can stimulate egg laying via the Gq protein EGL-30, independent of SER-1, SER-4 or 5HT. We also show that dopamine antagonizes the 5HT action via the 5HT-gated ion channel MOD-1 signaling, suggesting that this channel activity couples 5HT and dopamine signaling. These results suggest that the actions of these drugs at specific receptor subtypes could determine their therapeutic efficacy. SSRIs and tricyclic antidepressants may regulate 5HT outputs independent of synaptic level of 5HT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15654117&dopt=Abstract fluoxetine Prozac



Prozac
Brain region and dose effects of an olanzapine/fluoxetine combination on extracellular monoamine concentrations in the rat.

Koch S, Perry KW, Bymaster FP.

Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA.

Clinical studies of patients with treatment-resistant depression have shown that combined treatment with fluoxetine and olanzapine rapidly and significantly improved depressive symptoms. The present study used in vivo microdialysis to investigate the brain regional and dose effects of these drugs on extracellular monoamine concentrations in the rat prefrontal cortex, hypothalamus, nucleus accumbens and striatum. In the prefrontal cortex, the olanzapine/fluoxetine combination (3/10 mg/kg, respectively) increased catecholamine concentrations to a significantly greater extent than either drug alone (dopamine mean+/-S.E.M. percent of baseline: olanzapine (120 +/- 12.4), fluoxetine (123 +/- 6.2), combination (185 +/- 8.8); norepinephrine: olanzapine (124 +/- 7.2), fluoxetine (126 +/- 5.0), combination (215 +/- 15.8)). The combination also increased serotonin concentrations to 156 +/- 11.0% of baseline, but to a lesser extent than fluoxetine alone (210 +/- 14.5%). Similar synergistic effects of the combination were observed in the hypothalamus, but not in the other regions studied. The dose response effects of the drugs alone and in combination were complex, but larger doses of the combinations produced greater monoamine concentration increases than smaller dose combinations.The effects of the olanzapine/fluoxetine combination are meaningful in prefrontal cortex and hypothalamus due to their hypothesized role in the etiology and pharmacotherapy of depression. The wide-ranging neurochemical effects of this drug combination may make it particularly useful as a treatment for complex, resistant depressions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14680761&dopt=Abstract fluoxetine Prozac



Prozac
Ineffectiveness of parenteral fluoxetine or RU-486 to alter long-term food intake, body weight or body composition of genetically obese mice.

Dubuc PU, Peterson CM.

Sansum Medical Research Foundation, Santa Barbara, California.

The effects of 3 weeks of daily subcutaneous injections of a serotonin agonist (fluoxetine, 20 mg/kg) or agent having antiglucocorticoid properties (RU-486, 20 mg/kg) on food intake and body growth were examined in C57BL/6 ob/ob and lean mice. Fluoxetine injections during ad libitum feeding led to depressed food intake and body weight in both obese and lean mice over the initial 10 days of treatment with full recovery of both intake and weight by the end of the study. Fluoxetine treatment of mice restricted to 3.2 g of laboratory diet per day caused small but persistent depressions of body weight in both phenotypes. RU-486 did not affect food intake weight or weight gain in either phenotype or feeding condition and neither drug affected carcass composition. Insulin levels were also unaffected by treatment but final corticosterone concentrations were consistently higher in fluoxetine-treated mice and lower in RU-486-treated mice. Although transient benefits on feeding and weight gain were observed with fluoxetine administration, the present results show that neither fluoxetine nor RU-486 administered parenterally provides significant long-term improvement in the metabolic, growth or behavioral disturbances that characterize ob/ob mice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2124625&dopt=Abstract fluoxetine Prozac



Prozac
How stress and fluoxetine modulate serotonin 2C receptor pre-mRNA editing.

Englander MT, Dulawa SC, Bhansali P, Schmauss C.

Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, 10032, USA.

In two inbred strains of mice, C57BL/6 and 129Sv, the majority of forebrain neocortical pre-mRNA encoding the serotonin 2C (5-HT2C) receptor is altered by adenosine-to-inosine editing. As a result, >60% of all mRNAs encode receptors with reduced constitutive and agonist-stimulated activity. However, in the BALB/c strain, a genetically distinct inbred strain with lower forebrain serotonin levels, spontaneously elevated anxiety, and increased stress reactivity, the majority of 5-HT2C mRNA is nonedited and encodes receptors with the highest constitutive activity and the highest agonist affinity and potency. Neither acute stress (the forced swim test) nor chronic treatment with the serotonin-selective reuptake inhibitor fluoxetine elicit significant changes in 5-HT2C pre-mRNA editing in C57BL/6 mice. In contrast, exposure of BALB/c mice to acute stress and chronic treatment of nonstressed BALB/c mice with fluoxetine elicit significant, site-specific increases in 5-HT2C pre-mRNA editing that increase the pool of mRNA encoding receptors with reduced function. These changes in 5-HT2C pre-mRNA editing resemble those detected previously in the prefrontal cortex of subjects with major depression. However, when chronic fluoxetine treatment is combined with stress exposure of BALB/c mice, these changes in 5-HT2C pre-mRNA editing are no longer detected. These findings illustrate that 5-HT2C pre-mRNA editing responses to stress and chronic fluoxetine are modulated by the genetic background, as well as the behavioral state of the animal. They suggest further that the changes in 5-HT2C pre-mRNA editing found in major depression reflect a previously unrecognized molecular response to stress that can be prevented by chronic antidepressant treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15659601&dopt=Abstract fluoxetine Prozac



Prozac
Interaction of fluoxetine with the human placental serotonin transporter.

Cool DR, Liebach FH, Ganapathy V.

Department of Cell and Molecular Biology, Medical College of Georgia, Augusta 30912-2100.

The interaction of fluoxetine, a non-tricyclic antidepressant, with the human placental serotonin transporter was investigated by studying its influence on [3H]paroxetine binding to the transporter and on [3H]serotonin uptake via the transporter. These studies were done using brush-border membrane vesicles purified from normal term human placentas. Fluoxetine inhibited binding of paroxetine to the membrane vesicles in a concentration-dependent manner, with a Ki value of 3 nM. Kinetic analysis revealed that the inhibition was competitive because the presence of 10 nM fluoxetine increased the Kd for paroxetine from 72 to 461 pM, but had no effect on the Bmax. Fluoxetine also caused a time-dependent dissociation of paroxetine already bound to the transporter. The dissociation followed first-order kinetics. Uptake of serotonin in these membrane vesicles was also inhibited by fluoxetine. The inhibition was concentration dependent with a Ki value of 66 nM at pH 7.5 and 80 nM at pH 6.5. The effect of fluoxetine on the uptake kinetics was to increase the apparent dissociation constant (Kt) for serotonin without influencing the maximal transport capacity (Vmax). The results demonstrate that fluoxetine is a high-affinity ligand and a potent inhibitor of the serotonin transporter found in the human placental brush-border membrane.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2146964&dopt=Abstract fluoxetine Prozac