Combination Of Fluoxetine Research Articles

Combination of fluoxetine and extinction treatments forms a unique synaptic protein profile that correlates with long-term fear reduction in adult mice

The antidepressant fluoxetine induces synaptic plasticity in the visual and fear networks and promotes the structural remodeling of neuronal circuits, which is critical for experience-dependent plasticity in response to an environmental stimulus. We recently demonstrated that chronic fluoxetine administration together with extinction training in adult mice reduced fear in a context-independent manner. Fear conditioning and extinction alter excitatory and inhibitory transmissions within the fear circuitry. In this study, we investigated whether fluoxetine, extinction or their combination produced distinct long-lasting changes in the synaptic protein profile in the amygdala, hippocampus and prefrontal cortex of conditioned mice. We determined that extinction induced synaptophysin expression and down-regulated the GluA1:GluA2 ratio throughout the fear network in water- and fluoxetine-treated mice, suggesting a common fluoxetine-independent mechanism for increased synaptic transmission and re-arrangement of AMPA-receptors by extinction training. In contrast to common changes, the presynaptic vesicular neurotransmitter transporters VGAT and Vglut1 were upregulated after extinction in water- and fluoxetine-treated mice, respectively. The cortical levels of the GABA transporter Gat1 were reduced in high-freezing water-drinking mice, suggesting a maladaptive increase of GABA spillover at cortical inhibitory synapses. Fear conditioning decreased, and extinction induced the expression of GABA-receptor alpha1 and alpha2 subunits in water- and fluoxetine-treated mice, respectively. Only a combination of fluoxetine with extinction enhanced GluN2A expression in the amygdala and hippocampus, emphasizing the role of this NMDA-receptor subunit in the successful erasure of fear memories. Our finding provides novel data that may become helpful in developing beneficial pharmacological fear-reducing treatment strategies.

Transient serotonin toxicity evoked by combination of electroconvulsive therapy and fluoxetine.

The serotonin syndrome has been described only in rare instances for electroconvulsive therapy combined with an antidepressant medication. We describe a case of serotonin toxicity induced by electroconvulsive therapy in combination with fluoxetine.

Effect of Saraswatarishta in animal models of behavior despair.

Background:Saraswatarishta (SA) is a herbo-mineral formulation consisting of 18 plants some of which are Medhyarasayanas. It has been claimed to be useful in treating central nervous system disorders.Objective:To evaluate antidepressant effect of ‘Saraswatarishta’(SA) alone and in combination with imipramine and fluoxetine in animal models of depression.Materials and Methods:After obtaining IAEC permission, 144 rats (n = 36/part) were randomized into 6 groups- Group 1: Distilled water (1 mL), Group 2: Imipramine (30 mg/kg), Group 3: Fluoxetine (10 mg/kg), Group 4: SA (1.8 mL/kg), Group 5: Imipramine + SA, Group 6: Fluoxetine + SA. Effects of study drugs were evaluated in forced swim test (FST) with single exposure to FST (Part 1) and repeated exposure for 14 days (Part 2). In Part 3, reserpine was used with FST and effects of study drugs were evaluated against single exposure to FST. Same model was used with repeated exposures to FST (Part 4). In each part, rats were subjected to open field test (OFT) for 5 min prior to final FST. The variables measured: Immobility time in FST; line crossing, rearing and defecation in the OFT.Results:In all four parts, individual drugs and combinations thereof produced significant decrease in immobility time as compared to control, and extent of decrease was comparable amongst these groups. However, values for combination of fluoxetine with SA group were found to be lesser than that for individual agents in Parts 2 and 3. Combination of SA with imipramine did not enhance its anti-depressant effect in any of the parts. OFT findings did not vary significantly amongst the study groups.Conclusion:Decreased immobility in FST and absence of generalized stimulation or depression of motor activity in OFT point towards potential antidepressant effect of Saraswatarishta. Its co-administration with fluoxetine showed more promising effects.

Relative Contributions of Norepinephrine and Serotonin Transporters to Antinociceptive Synergy between Monoamine Reuptake Inhibitors and Morphine in the Rat Formalin Model

Multimodal analgesia is designed to optimize pain relief by coadministering drugs with distinct mechanisms of action or by combining multiple pharmacologies within a single molecule. In clinical settings, combinations of monoamine reuptake inhibitors and opioid receptor agonists have been explored and one currently available analgesic, tapentadol, functions as both a µ-opioid receptor agonist and a norepinephrine transporter inhibitor. However, it is unclear whether the combination of selective norepinephrine reuptake inhibition and µ-receptor agonism achieves an optimal antinociceptive synergy. In this study, we assessed the pharmacodynamic interactions between morphine and monoamine reuptake inhibitors that possess different affinities and selectivities for norepinephrine and serotonin transporters. Using the rat formalin model, in conjunction with measurements of ex vivo transporter occupancy, we show that neither the norepinephrine-selective inhibitor, esreboxetine, nor the serotonin-selective reuptake inhibitor, fluoxetine, produce antinociceptive synergy with morphine. Atomoxetine, a monoamine reuptake inhibitor that achieves higher levels of norepinephrine than serotonin transporter occupancy, exhibited robust antinociceptive synergy with morphine. Similarly, a fixed-dose combination of esreboxetine and fluoxetine which achieves comparable levels of transporter occupancy potentiated the antinociceptive response to morphine. By contrast, duloxetine, a monoamine reuptake inhibitor that achieves higher serotonin than norepinephrine transporter occupancy, failed to potentiate the antinociceptive response to morphine. However, when duloxetine was coadministered with the 5-HT3 receptor antagonist, ondansetron, potentiation of the antinociceptive response to morphine was revealed. These results support the notion that inhibition of both serotonin and norepinephrine transporters is required for monoamine reuptake inhibitor and opioid-mediated antinociceptive synergy; yet, excess serotonin, acting via 5-HT3 receptors, may reduce the potential for synergistic interactions. Thus, in the rat formalin model, the balance between norepinephrine and serotonin transporter inhibition influences the degree of antinociceptive synergy observed between monoamine reuptake inhibitors and morphine.

Effect of risperidone on the fluoxetine-induced changes in extracellular dopamine, serotonin and noradrenaline in the rat frontal cortex

BackgroundSeveral clinical reports have documented a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants, in particular selective serotonin reuptake inhibitors, in the treatment of drug resistant depression. The aim of our study was to understand the mechanism of the clinical efficacy of a combination of fluoxetine (FLU) and risperidone (RIS) in drug-resistant depression.We studied the effect of FLU and RIS, given separately or jointly on the extracellular levels of dopamine (DA), serotonin (5-HT) and noradrenaline (NA) in the rat frontal cortex. MethodsAnimals were given single intraperitoneal injections of RIS at a doses of 0.1 or 1mg/kg and FLU at a dose of 10mg/kg. The release of DA, 5-HT and NAin the rat frontal cortex was investigated using microdialysis in freely moving animals. The extracellular level of DA, 5-HT and NA was assayed by HPLC with coulochemical detection. ResultsRIS (0.1 and 1mg/kg) and FLU (10mg/kg) increased the extracellular level of cortical DA, 5-HT and NA. Co-treatment of both drugs was more effective in increasing DA release than administration of each of the drugs alone at doses of RIS 1mg/kg and FLU 10mg/kg. Co-treatment of FLU and RIS 0.1mg/kg was more potent than FLU alone, while the effect of joint injection of FLU and RIS 1mg/kg was stronger than RIS 1mg/kg alone on 5-HT release. The combination of FLU with both doses of RIS was not effective in increasing NA release as compared to drugs given alone. ConclusionsOur data indicate that the effect of the combined administration of RIS and FLU on DA and 5-HT release in the rat frontal cortex may be of crucial importance to the pharmacotherapy of drug resistant depression.

Use of antipsychotics in the treatment of depressive disorders.

SummaryThere is a long history of using antipsychotic medications in the treatment of depressive disorders. Atypical antipsychotics, which have fewer side effects than traditional antipsychotics, have been used as monotherapy or adjunctively with antidepressants to treat depressive disorders with or without psychotic symptoms. The antidepressant effect of atypical antipsychotics involves regulation of monoamine, glutamate, gamma-aminobutyric acid (GABA), cortisol, and neurotrophic factors. To date, the United States Food and Drug Administration (USFDA) has approved aripiprazole and quetiapine slow-release tablets as adjunctive treatment for depressive disorders, and the combination of olanzapine and fluoxetine for the treatment of treatment-resistant depression. When using atypical antipsychotics in the treatment of depressed patients, clinicians need to monitor patients for the emergence of adverse effects including extrapyramidal symptoms (EPS), weight gain, and hyperglycemia.

Drug therapy for obstructive sleep apnoea in adults

The treatment of choice for moderate to severe obstructive sleep apnoea (OSA) is continuous positive airways pressure (CPAP) applied via a mask during sleep. However, this is not tolerated by all individuals and its role in mild OSA is not proven. Drug therapy has been proposed as an alternative to CPAP in some patients with mild to moderate sleep apnoea and could be of value in patients intolerant of CPAP. A number of mechanisms have been proposed by which drugs could reduce the severity of OSA. These include an increase in tone in the upper airway dilator muscles, an increase in ventilatory drive, a reduction in the proportion of rapid eye movement (REM) sleep, an increase in cholinergic tone during sleep, an increase in arousal threshold, a reduction in airway resistance and a reduction in surface tension in the upper airway. To determine the efficacy of drug therapies in the specific treatment of sleep apnoea. We searched the Cochrane Airways Group Specialised Register of trials. Searches were current as of July 2012. Randomised, placebo controlled trials involving adult patients with confirmed OSA. We excluded trials if continuous positive airways pressure, mandibular devices or oxygen therapy were used. We excluded studies investigating treatment of associated conditions such as excessive sleepiness, hypertension, gastro-oesophageal reflux disease and obesity. We used standard methodological procedures recommended by The Cochrane Collaboration. Thirty trials of 25 drugs, involving 516 participants, contributed data to the review. Drugs had several different proposed modes of action and the results were grouped accordingly in the review. Each of the studies stated that the participants had OSA but diagnostic criteria were not always explicit and it was possible that some patients with central apnoeas may have been recruited.Acetazolamide, eszopiclone, naltrexone, nasal lubricant (phosphocholinamine) and physiostigmine were administered for one to two nights only. Donepezil in patients with and without Alzheimer's disease, fluticasone in patients with allergic rhinitis, combinations of ondansetrone and fluoxetine and paroxetine were trials of one to three months duration, however most of the studies were small and had methodological limitations. The overall quality of the available evidence was low.The primary outcomes for the systematic review were the apnoea hypopnoea index (AHI) and the level of sleepiness associated with OSA, estimated by the Epworth Sleepiness Scale (ESS). AHI was reported in 25 studies and of these 10 showed statistically significant reductions in AHI.Fluticasone in patients with allergic rhinitis was well tolerated and reduced the severity of sleep apnoea compared with placebo (AHI 23.3 versus 30.3; P < 0.05) and improved subjective daytime alertness. Excessive sleepiness was reported to be altered in four studies, however the only clinically and statistically significant change in ESS of -2.9 (SD 2.9; P = 0.04) along with a small but statistically significant reduction in AHI of -9.4 (SD 17.2; P = 0.03) was seen in patients without Alzheimer's disease receiving donepezil for one month. In 23 patients with mild to moderate Alzheimer's disease donepezil led to a significant reduction in AHI (donepezil 20 (SD 15) to 9.9 (SD 11.5) versus placebo 23.2 (SD 26.4) to 22.9 (SD 28.8); P = 0.035) after three months of treatment but no reduction in sleepiness was reported. High dose combined treatment with ondansetron 24 mg and fluoxetine 10 mg showed a 40.5% decrease in AHI from the baseline at treatment day 28. Paroxetine was shown to reduce AHI compared to placebo (-6.10 events/hour; 95% CI -11.00 to -1.20) but failed to improve daytime symptoms.Promising results from the preliminary mirtazapine study failed to be reproduced in the two more recent multicentre trials and, moreover, the use of mirtazapine was associated with significant weight gain and sleepiness. Few data were presented on the long-term tolerability of any of the compounds used. There is insufficient evidence to recommend the use of drug therapy in the treatment of OSA. Small studies have reported positive effects of certain agents on short-term outcomes. Certain agents have been shown to reduce the AHI in largely unselected populations with OSA by between 24% and 45%. For donepezil and fluticasone, studies of longer duration with a larger population and better matching of groups are required to establish whether the change in AHI and impact on daytime symptoms are reproducible. Individual patients had more complete responses to particular drugs. It is possible that better matching of drugs to patients according to the dominant mechanism of their OSA will lead to better results and this also needs further study.

Effects of antidepressant and treadmill gait training on recovery from spinal cord injury in rats

Experimental, controlled, animal study. To evaluate the influences of antidepressant treatment, treadmill gait training and a combination of these therapies in rats with experimental, acute spinal cord injury (SCI). Brazil. 48 Wistar rats were given standardized SCI; rats were then randomly assigned to four treatment groups: (1) motor rehabilitation therapy for 1 hour daily (gait training); (2) daily treatment with the antidepressant, fluoxetine (0.3 ml per 100 g intraperitoneally), beginning 24 h after the trauma; (3) combined fluoxetine treatment and gait training, or (4) untreated (controls). Neurological recovery was tested with the Basso, Beattie and Bresnahan (BBB) scale at 2, 7, 14, 21, 28 ,35 and 42 days after injury. Moreover, on day 42, all rats underwent a motor-evoked potential test (MEP); then, after euthanasia, histopathological evaluation was conducted in the area of SCI. Based on the BBB scale, the combined treatment group showed significantly greater improvement compared with the other three groups, from the 14th to the 42nd day of observation. The MEP revealed that all treated groups showed significant improvement compared with the control group (P<0.02 for latency and P<0.01 for amplitude). Our results indicated that a combination of antidepressant and treadmill gait training was superior to either treatment alone for improving functional deficits in rats with experimental, acute SCI.

Abstract WP105: An Effective Delayed Treatment for Ischemic Stroke Uses Fluoxetine and Simvastatin

For more than 90% of ischemic stroke patients there exists no standardized drug treatment other than giving aspirin or beginning statin treatment for the prevention of future strokes. The purpose of this study was to develop a delayed pharmacological treatment for ischemic stroke, utilizing a combination of drugs that would enhance adult neurogenesis and brain-derived neurotrophic factor. An endothelin-induced stroke was produced in 10-12 month old rats, which have previously been trained on Montoya Staircase and Forelimb Asymmetry tests. Combination drug treatments were tested against vehicle controls, beginning 20-26 hours after stroke induction and continuing for 31 days. Functional tests were performed at various times post-stroke. Daily treatments of 5 mg/kg fluoxetine in combination with 0.5 mg/kg simvastatin and 20 mg/kg ascorbic acid produced a 19-fold increase in neurogenesis (P=0.001 compared to vehicle control), while fluoxetine alone produced a 10-fold increase in neurogenesis (P=0.007 compared to vehicle control). This combination drug treatment results in almost complete functional recovery as measured by Montoya Staircase (mean recovery to 85% of pre-stroke function, P=0.023) and Forelimb Asymmetry tests (mean recovery to 90% of pre-stroke function, P=0.041 and P= 0.05) in 10-12 month old stroked female Long Evans rats. Additional testing of 5 mg/kg fluoxetine and 20 mg/kg ascorbic acid drug combination as a delayed post-stroke treatment has only given half of the functional recovery seen when all three drugs are included, indicating that the statin is essential for full recovery. Fluoxetine is likely to be the other essential component of this combination treatment as it alone resulted in a significant increase in adult neurogenesis.

Adjuvant Use of Melatonin with Fluoxetine for Management of Fibromyalgia

Fibromyalgia (FMS) is a chronic musculoskeletal disorder characterized by generalized muscular pain and tenderness at specific anatomical sites. Although melatonin was effective in treating the pain associated with this syndrome, no defined clinical evidence supports this claim. The present study was designed to evaluate the clinical significance of using melatonin, alone or in combination with fluoxetine in FMS. A double-blind clinical study was conducted on 45 patients with FMS randomized into 4 groups; group A, treated with fluoxetine 20mg/day alone; group B, treated with melatonin 5mg alone; group C, treated with combination of fluoxetine 20 mg+3 mg melatonin; group D treated with combination of fluoxetine 20 mg+5 mg melatonin. Both fluoxetine and melatonin were given once daily in the morning and night time respectively for 8 weeks. Each patient clinically evaluated using Fibromyalgia Impact Questionnaire (FIQ). Serum levels of serotonin, malondialehyde and nitric oxide were also evaluated. Using melatonin (3 and 5mg/day) in combination with 20mg/day fluoxetine significantly decreased total FIQ score values; the combination therapy significantly decreased serum serotonin level associated with reduction in the oxidative stress parameters (MDA and NO). In conclusion, adjuvant use of melatonin with fluoxetine improves the biochemical and clinical parameters of FMS patients.

Slow channel congenital myasthenic syndrome responsive to a combination of fluoxetine and salbutamol

Slow channel congenital myasthenic syndrome is a dominant disorder characterized by prolonged acetylcholine receptor ion-channel activation. Molecular genetic techniques, electrophysiology, and binding studies in human embryonic kidney (HEK) 293 cells determined mutant function and expression levels. Patient response to treatment was measured by quantitative myasthenic gravis and Medical Research Council grade strength scores. We report an unusual case due to heteroallelic mutations in CHRNE. The slow channel mutation, p.εS278del, is accompanied by a severe low-expression mutation, p.εR217L, on the second allele. Expression studies and cosegregation of p.εS278del with the disorder in the patient's offspring demonstrate robust expression of the p.εS278del mutation. The patient showed modest benefits from standard treatment with fluoxetine, but there was dramatic improvement when salbutamol was combined with fluoxetine. This case suggests that salbutamol, which is beneficial in some other congenital myasthenic syndromes, might also be considered in addition to fluoxetine in slow channel syndrome.

Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder

To compare the therapeutic effects of vitamin D3 plus fluoxetine and fluoxetine alone in patients with major depressive disorder. In the present double-blind, randomized, placebo-controlled trial, 42 patients with a diagnosis of major depressive disorder based on DSM-IV criteria were randomly assigned into two groups to receive daily either 1500 IU vitamin D3 plus 20 mg fluoxetine or fluoxetine alone for 8 weeks. Depression severity was assessed at 2-week intervals using the 24-item Hamilton Depression Rating Scale (HDRS) as a primary outcome measure and the 21-item Beck Depression Inventory (BDI) as a secondary outcome measure. Serum 25(OH) vitamin D was measured at baseline and after intervention. Forty patients completed the trial. A two-way repeated-measures analysis of variance showed that depression severity based on HDRS and BDI decreased significantly after intervention, with a significant difference between the two groups. The vitamin D + fluoxetine combination was significantly better than fluoxetine alone from the fourth week of treatment. In the present 8-week trial, the vitamin D + fluoxetine combination was superior to fluoxetine alone in controlling depressive symptoms.

Fluoxetine potentiation of methylphenidate‐induced neuropeptide expression in the striatum occurs selectively in direct pathway (striatonigral) neurons

Concomitant therapies combining psychostimulants such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs) are used to treat several mental disorders, including attention-deficit hyperactivity disorder/depression comorbidity. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone induces gene regulation that mimics partly effects of cocaine, consistent with some addiction liability. We previously showed that the SSRI fluoxetine potentiates methylphenidate-induced gene regulation in the striatum. The present study investigated which striatal output pathways are affected by the methylphenidate + fluoxetine combination, by assessing effects on pathway-specific neuropeptide markers. Results demonstrate that fluoxetine (5 mg/kg) potentiates methylphenidate (5 mg/kg)-induced expression of substance P and dynorphin, markers for direct pathway neurons. In contrast, no drug effects on the indirect pathway marker enkephalin were found. Because methylphenidate alone has minimal effects on dynorphin, the potentiation of dynorphin induction represents a more cocaine-like effect for the drug combination. On the other hand, the lack of an effect on enkephalin suggests a greater selectivity for the direct pathway compared with psychostimulants such as cocaine. Overall, the fluoxetine potentiation of gene regulation by methylphenidate occurs preferentially in sensorimotor striatal circuits, similar to other addictive psychostimulants. These results suggest that SSRIs may enhance the addiction liability of methylphenidate.

Glycogen synthase kinase-3β regulates anti-inflammatory property of fluoxetine

A selective serotonin reuptake inhibitor fluoxetine not only is widely used in the treatment of depression but also has an anti-inflammatory property. Glycogen synthase kinase-3beta (GSK-3β) is a vital factor in the inflammation process. How fluoxetine interferes with inflammation via a GSK-3β-dependent pathway remains unclear. The aim of this study is to investigate the effects of fluoxetine on lipopolysaccharide (LPS)-induced inflammation. Results showed that fluoxetine decreased mortality rate of the mice. It also inhibited LPS-induced release of nitric oxide (NO) and prostaglandin E2 (PGE2) in serum and RAW264.7 murine macrophages and expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Upon LPS stimulation, fluoxetine caused a delay but increased in the phosphorylated levels of GSK-3β (ser9), whereas it did not affect LPS-induced activation of mitogen-activated protein kinase (MAPK) and generation of reactive oxygen species (ROS). Fluoxetine in combination with phosphatidylinositol 3-kinases/Akt inhibitors (LY294002 and Wortmannin) did not have a synergistic inhibition on LPS-induced NO release and PGE2 production. In addition, peroxisome proliferator-activated receptor γ (PPARγ) antagonist GW9622 showed no reverse effects of this inhibition of fluoxetine. GSK-3β knockdown blocked the inhibitory effects of fluoxetine on LPS-induced iNOS/NO release and COX-2/PGE2 production. These results indicated that GSK-3β regulated anti-inflammatory property of fluoxetine. However, Akt activation, ROS generation, and altered PPARγ activity were not involved in this inhibition of fluoxetine.

Synergistic effect of estradiol and fluoxetine in young adult and middle-aged female rats in two models of experimental depression

The antidepressant effect of estrogens combined with antidepressants is controversial: some preclinical data showed that estrogens facilitate the effect of antidepressants in the forced swimming test (FST) in young adult rats, while others failed to find such effect in middle-aged rats in the chronic mild stress (CMS) model. In clinics similar differences were reported and may be due to the compounds, the depression model or type of depression, the experimental design, and the age of the subjects or the women's menopause stage. The objective of this study was to analyze the antidepressant-like effect of the combination of 17β-estradiol (E2) and fluoxetine (FLX) in young adults (2–4 months) and middle-aged (12–14 months) ovariectomized (OVX) rats in two experimental models: FST and CMS. E2 (5 and 10μg/rat) and FLX (2.5 and 10mg/kg) per se dose-dependently reduced immobility in both age groups and, in young adults both compounds increased swimming, whereas in middle-aged rats they increased swimming and climbing. Analysis of the antidepressant-like effect of the combination of suboptimal doses of FLX (1.25mg/kg) and E2 (2.5μg/rat) showed a decrease in immobility and an increase in swimming in both age groups. In the CMS, chronic E2 (2.5μg/rat) with FLX (1.25mg/kg) augmented relative sucrose intake, but middle-aged rats responded 2 weeks earlier than young adults. These results show that the antidepressant-like effect of the combination of E2 and FLX in young adult and middle-aged female rats is evidenced in the two animal models of depression: FST and CMS.

The administration of olanzapine and fluoxetine has synergistic effects on intracellular survival pathways in the rat brain

Recently, several studies have emerged suggesting a role of the intracellular survival pathways in the treatment of mood disorders. In addition, the beneficial effects of using a combination of antipsychotics and antidepressants have been shown. With this in mind, we evaluated the effects of the acute administration of fluoxetine (FLX), olanzapine (OLZ) and the combination of fluoxetine/olanzapine on the brain-derived-neurotrophic factor (BDNF), cAMP response element-binding (CREB), Protein Kinase B (PKB, Akt), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated death promoter (BAD) in the rat brain. Adult Wistar rats received an acute injection of OLZ (3 or 6 mg/kg) and/or FLX (12.5 or 25 mg/kg), and were evaluated for Akt, BDNF, CREB, Bcl-2 and BAD protein levels in the prefrontal cortex, hippocampus and striatum. Our results showed that treatment with FLX and OLZ alone or in combination increased the Akt, CREB, BDNF, Bcl-2 and BAD levels in the prefrontal cortex, hippocampus and striatum. However, the combination of FLX and OLZ at high doses was associated with a greater increase in the levels of Akt in the prefrontal cortex, and did not have an effect on the levels of BAD in any of the brain areas that we evaluated. Finally, these findings further support the hypothesis that treatment with FLX and OLZ alone or in combination exert neuroprotective effects, and that intracellular survival pathways could be involved in the therapeutic effects of combining antipsychotic and antidepressant drugs in mood disorders.

Polymorphic Ventricular Tachycardia (PMVT) secondary to a combination of azithromycin and fluoxetine in a case of acute pancreatitis

Polymorphic ventricular tachycardia (PMVT) is characterized by QRS complexes of changing amplitude that appear to twist around the isoelectric line. Torsades de Pointes (Tdp) is a variant of PMVT in which there is prolongation of QTc interval (generally exceeding 500 milliseconds). A number of medications have been noted to prolong the QTc interval. We describe a clinical case in which the culprits are Azithromycin and Fluoxetine. Azithromycin has been regarded as a “safer” macrolide when it comes to proarrhythmia as compared to erythromycin or clarithromycin. However, in certain clinical circumstances like combination drug usage, unique clinical features like underlying pancreatitis in this particular patient, some of the medications that are deemed low risk can certainly be more proarrhythmic. It is therefore important to review the clinical and pharmaceutical profiles of every patient before choosing which medications to prescribe.

Ferulic acid exerts antidepressant-like effect in the tail suspension test in mice: Evidence for the involvement of the serotonergic system

Ferulic acid (4-hydroxy-3-methoxycinnamic acid) is a phenolic compound present in several plants with claimed beneficial effects in prevention and treatment of disorders linked to oxidative stress and inflammation. In this study, we aimed to verify the possible antidepressant-like effect of acute oral administration of ferulic acid in the forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the mechanisms involved in the antidepressant-like action and the effects of the association of ferulic acid with the antidepressants fluoxetine, paroxetine, and sertraline in the TST were investigated. Ferulic acid produced an antidepressant-like effect in the FST and TST (0.01–10mg/kg, p.o.), without accompanying changes in ambulation. The pretreatment of mice with WAY100635 (0.1mg/kg, s.c., a selective 5-HT1A receptor antagonist) or ketanserin (5mg/kg, i.p., a 5-HT2A receptor antagonist) was able to reverse the anti-immobility effect of ferulic acid (0.01mg/kg, p.o.) in the TST. The combination of fluoxetine (5mg/kg, p.o.), paroxetine (0.1mg/kg, p.o.) or sertraline (1mg/kg, p.o.) with a sub-effective dose of ferulic acid (0.001mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST, without causing hyperlocomotion in the open-field test. Taken together, these results demonstrate that ferulic acid exerts antidepressant-like effect in the FST and TST in mice through modulation of the serotonergic system.

Olanzapine–fluoxetine combination for the treatment of bipolar depression

Introduction: Olanzapine–fluoxetine combination is one of only two products currently approved by the US FDA for the acute treatment of depressive episodes associated with bipolar disorder.Areas covered: This treatment evaluation reviews double-blind randomized controlled trials of olanzapine–fluoxetine combination for bipolar depression. A total of three primary study reports are found in the peer-reviewed literature. Additional data regarding the trials are obtained from study synopses disclosed on the internet by the manufacturer and from product labeling.Expert opinion: Number needed to treat for antidepressant response for olanzapine–fluoxetine combination versus placebo in the 8-week trials was 4 (95% CI 3 – 8), and that for remission was 5 (95% CI 3 – 8). Single-digit numbers needed to harm (NNH) values were observed for the treatment-emergent adverse events of weight gain (NNH 7, 95% CI 5 – 16) and diarrhea (NNH 9, 95% CI 5 – 30). NNH versus placebo for weight gain ≥ 7% from baseline was 6 (95% CI 4 – 10). When contrasted with lamotrigine, olanzapine–fluoxetine combination demonstrates statistically significantly greater improvement in depressive and manic symptoms but there is a higher incidence of treatment-emergent adverse events, weight gain and elevation in metabolic factors. Studies that directly compare quetiapine monotherapy with olanzapine–fluoxetine combination, the only two approved products for the treatment of bipolar depression, are not available. Nonetheless, indirect comparisons indicate similar efficacy outcomes but different tolerability profiles, with quetiapine principally being associated with sedation. Additional approved treatment options would be welcome.

The continuum of unipolar depression - bipolar II depression - bipolar I depression: different treatments indicated?

Strakowski et al indicate that bipolar depression may need to be treated differently from unipolar depression because in bipolar depression antidepressants may be ineffective and may precipitate the risk of a switch to (hypo)mania (and induction of rapid cycling). While this could be a major argument to discriminate bipolar depression form unipolar depression, a critical appraisal of the available literature is indicated. First, are antidepressants ineffective in bipolar depression? Compared to around 1,500 randomized controlled trials (RCTs) with antidepressants in unipolar depression, there are around 15 RCTs in bipolar depression and only four of them exceeded 50 patients per treatment arm. Therefore, the main conclusion is that, compared to unipolar depression, bipolar depression is heavily understudied 1. Nevertheless, in a meta-analysis, antidepressants as a group appeared to be effective 1. Of the four larger studies, two reported positive results. The first study found that the combination of fluoxetine and olanzapine was more effective than placebo plus olanzapine 2. The second study reported response rates of 50-60% when sertraline, bupropion or venlafaxine was added to an ongoing treatment with mood stabilizers 3. The limitation of this study was the lack of a placebo arm. On the other hand, in a third study, paroxetine was not more effective than placebo, while two doses of quetiapine (300 and 600 mg/day) did separate from placebo 4. Finally, in the STEP-BD study, sertraline or bupropion as add-on to ongoing treatment with (among other medications) lithium or valproate was not found more effective than the addition of placebo 5. Although this is the largest study which investigated the efficacy of antidepressants in bipolar depression, it has major methodological limitations (e.g., patients were allowed to continue with another antidepressant during the first two weeks of the study; they could also use other drugs with an antidepressant effect, such as quetiapine, olanzapine and lamotrigine; 69% of the patients participated at the same time in a study comparing three different forms of psychotherapy with treatment as usual). It is clear that the conclusion that antidepressants are not effective cannot be drawn on the basis of this study. My overall conclusion is that, due to a lack of well designed RCTs, we can only state that it has not (yet) been proven that antidepressants are effective in bipolar depression. Second, do antidepressants cause a switch into (hypo)mania and rapid cycling? In our meta-analysis 1, we did not find that in the acute treatment of bipolar depression antidepressants were more often associated with a switch into (hypo)mania than placebo. However, in all studies comparing different antidepressants, the treatment arms with a tricyclic (TCA) were associated with a greater risk of switch into (hypo)mania than the treatment arms with other antidepressants, suggesting that TCAs have a greater risk of switch. Concerning the risk associated with long-term antidepressant treatment, we argued that there is a scarcity of randomized studies, and that the available studies all suffer from various forms of bias 6. Nevertheless, we concluded that antidepressants, when combined with a mood stabilizer, seemingly do not induce a switch into hypomania or mania. Ghaemi et al 7 presented a meta-analysis of seven RCTs in which antidepressants were used for at least 6 months. Three of these RCTs (total n=50) compared the effects of antidepressants monotherapy with placebo; five (total n=246) compared antidepressants plus a mood stabilizer versus a mood stabilizer alone (or in combination with placebo); and three (total n=108) compared antidepressants alone with a mood stabilizer alone. In most of the studies the antidepressant was a TCA. When combining all RCTs, the antidepressants yielded a significant 27% lower risk of a depressive recurrence versus control treatment without an antidepressant, but also a significant 72% greater risk for a manic recurrence. However, in RCTs with an antidepressant alone versus placebo, the only significant result was fewer depressive recurrences with the antidepressant, while in RCTs with an antidepressant alone versus a mood stabilizer alone (lithium), the only significant result was fewer manic recurrences with lithium. Therefore, my conclusion is that antidepressants do protect against depressive recurrences, while lithium does protect against manic recurrences. Whether antidepressants may accelerate episode frequency and/or cause other forms of destabilization in patients with bipolar disorder remains to be properly studied. In conclusion, there is not enough evidence to conclude that bipolar depression needs to be treated differently from unipolar depression. Especially in bipolar II depression, antidepressants still have a role even in monotherapy, as also suggested by recent guidelines 8,9. Therefore, bipolar I depression and unipolar depression should be seen as the ends of a continuum, with arbitrary demarcations and bipolar II depression in between.