Effects Of Antidepressant Drugs Research Articles

The Changing Face of U.S. Mental Health Care

The Changing Face of U.S. Mental Health Care

Meta-Regression Analysis of Paroxetine Clinical Trial Data

It is unknown to which degree the effect of antidepressant drugs are related to baseline degree of depression, dose level, patient's age, or type of questionnaire used. We explored this for paroxetine. We used placebo-controlled published and unpublished randomized, double-blind, clinical trials of paroxetine that included moderate to severely depressed patients in an outpatient setting. We specified random-effect models for the Hamilton 17-item and Hamilton 21-item studies separately and jointly. Among 35 studies retrieved, we considered 26 appropriate for a pooled analysis. Paroxetine (placebo) was given to 2958 (2123) patients. We found that the effects of paroxetine, the differences between score reduction in drug versus placebo group, are smaller in Hamilton 17 (3.8%) than in Hamilton 21 studies (7.0%). The mean difference is 3.2% (95% confidence interval, 0.94%-5.42%), statistically significant by meta-regression analysis. Treatment effects did not change with mean age of patients, early or late studies, baseline score value, or maximal daily dose. We forward 2 hypotheses for explanation. The Hamilton 21 studies had better selection of patients, thereby smaller effect of regression to the mean than the Hamilton 17 studies, meaning the Hamilton 21 studies reveal true somewhat higher treatment effects. Alternatively, the study groups contained some patients with psychotic symptoms tested for with the Hamilton 21-item questionnaire and thereby becoming decisive for the outcome. If so, paroxetine would have an antipsychotic effect. This is in accordance with some experimental and clinical observations.

Concomitant use of carbamazepine and olanzapine and the effect on some behavioral functions in rats

As shown in clinical studies, combinations of first generation normothymics (carbamazepine – CBZ) with atypical neuroleptics (olanzapine – OLA) lead to improvements in approximately half of patients treated for relapses of bipolar affective disease. Our previous studies have shown OLA to have an antidepressant effect when administered at a dose of 0.5mg/kg only upon single administration; the effect did not last throughout chronic administration, whereas CBZ administered at a dose of 30mg/kg showed an antidepressant effect only after 7 days of administration. As shown in our previous studies, both OLA and CBZ improve memory in rats but only after chronic administration. The improved antidepressant effect of many drugs, including OLA and CBZ used in combined therapy – as observed in our clinic – as well as confirmed evidence of OLA’s and CBZ’s positive effects on cognitive functions in humans and animals substantiated commencement of research on defining the effect of combined administration of OLA and CBZ on sedation (tested in a locomotor activity test), antidepressant effect (Porsolt test) and spatial memory (Morris test) in animals. The tests were performed on male Wistar rats. It was found that in combined administration of CBZ and OLA for 7 and 14 days, OLA would completely prevent the CBZ’s sedative effect. With combined administration of CBZ and OLA, both as a single dose and after prolonged treatment for 7 days, a significant reduction in immobility time was observed. Combined administration of CBZ and OLA did not improve memory in rats that received these drugs in a single dose, whereas statistically significant differences were observed in the chronic experiments. It can be assumed that the observed effects of combined administration of CBZ and OLA may be due to the pharmacokinetic interactions, but further studies are necessary to confirm these assumptions.

Effects of Citalopram on Cognitive Performance in Passive Avoidance, Elevated Plus-Maze and Three-Panel Runway Tasks in Naïve Rats

Recent studies have shown that learning and memory capacity is disturbed in depressive patients, and it is important to reveal the effects of antidepressant drugs on cognitive function in depressive patients with memory problems. Citalopram, a selective serotonin reuptake inhibitor (SSRI), is one of the most widely used drugs for the treatment of disorders related to serotonergic dysfunction like depression and anxiety. Contradictory findings exist regarding the effects of SSRIs on memory. The aim of this study is to investigate whether citalopram affects memory in various models of learning and memory tasks in rats. Citalopram (at 20 and 50 mg/kg) significantly shortened the retention latency in the passive avoidance test and prolonged the transfer latency on the second day at 10 and 50 mg/kg doses in the elevated plus-maze test. Citalopram also significantly increased the number of errors (at the 10 mg/kg dose) and prolonged the latency values compared to the control group in both reference and working memory trials in the three-panel runway test. Citalopram also impaired reference memory trials of animals at the 20 mg/kg dose. In conclusion, citalopram impaired cognitive performance in passive avoidance, elevated plus-maze and three-panel runway tasks in naive rats. These effects might be related to serotonergic and nitrergic mechanisms, which need to be investigated in further studies.

5-HT and depression: is the glass half-full?

Mood disorders such as major depression are common illnesses with considerable morbidity and significant mortality. A long-standing theory is that a breakdown in brain serotonin (5-hydroxytryptamine; 5-HT) signalling is critically involved in the symptoms and drug treatment of clinical depression. However, the nature of this 5-HT defect has proved to be frustratingly elusive, and it remains unclear how the 5-HT signalling effects of antidepressant drugs might alter neuropsychological mechanisms to bring about relief of depressed mood. This article highlights recent discoveries that advance our understanding of how 5-HT-evoked changes at molecular, cellular and neuropsychological levels might interact to alleviate the symptoms of clinical depression.

Brain ischemia changes the long term response to antidepressant drugs in mice

Depression is a frequent but often unrecognized and under treated complication of stroke that has scarcely been investigated in animal models particularly regarding treatment issues. Using the Forced Swim Test (FST) and testing spontaneous motor activity, we studied whether a transient focal cerebral ischemia modifies mice behaviours and antidepressant drug effects. We first evaluated whether FST realized 2 days or 1 week after brain reperfusion may be routinely used in male Swiss mice previously submitted to a 15, 30 or 60-min transient occlusion of the right middle cerebral artery. We then evaluated behavioural changes up to 5 weeks in mice previously submitted to a 15-min ischemia. Behaviours according to the administration of imipramine or fluvoxamine at 1 and 5 weeks after a 15-min ischemia were finally evaluated. Transient ischemia was associated with a decrease in immobility in the FST performed 2 days after reperfusion while no changes were observed in 1 and 5 weeks post-ischemia groups. Changes were related neither to brain ischemia duration nor to infarct volume. At both 1 and 5 weeks after brain ischemia, a dramatic decrease in the antidepressant response to imipramine related to a decrease in climbing behaviour was observed while the effects of fluvoxamine were improved through an increase in both climbing and swimming. Behaviours in the FST were unrelated to any spontaneous motor activity changes. Responses to anti-depressant drugs are strongly modified in mice previously submitted to brain ischemia. Present results underline that not all antidepressant drugs are appropriate after ischemic stroke.

Sleep Interventions for the Treatment of Depression

Sleep disturbances are common in depressed patients. Insomnia may predate the onset of major depression, increases the likelihood of a depressive relapse, and is associated with an impaired response to treatment. Benzodiazepine drugs may have inherent antidepressant effects; thus, these and other sedative-hypnotic drugs can be beneficial for treating insomnia in depressed patients and may enhance the overall effectiveness of antidepressant drugs. Sedating antidepressant drugs are used for treating primary insomnia, but their sleep-promoting effects have been demonstrated primarily in depressed patients. Several second-generation antipsychotic drugs are used in low doses to promote sleep, but they also have inherent antidepressant effects. Cognitive-behavioral therapy targeting insomnia can effectively enhance the response to antidepressant medication. Sleep deprivation, which is also associated with a transient antidepressant effect, is difficult to use in routine clinical practice but might be an appropriate strategy for treatment-resistant forms of depression.

HERG K+ channel-associated cardiac effects of the antidepressant drug desipramine

Cardiac side effects of antidepressant drugs are well recognized. Adverse effects precipitated by the tricyclic drug desipramine include prolonged QT intervals, torsade de pointes tachycardia, heart failure, and sudden cardiac death. QT prolongation has been primarily attributed to acute blockade of hERG/I(Kr) currents. This study was designed to provide a more complete picture of cellular effects associated with desipramine. hERG channels were expressed in Xenopus laevis oocytes and human embryonic kidney (HEK 293) cells, and potassium currents were recorded using patch clamp and two-electrode voltage clamp electrophysiology. Ventricular action potentials were recorded from guinea pig cardiomyocytes. Protein trafficking and cell viability were evaluated in HEK 293 cells and in HL-1 mouse cardiomyocytes by immunocytochemistry, Western blot analysis, or colorimetric MTT assay, respectively. We found that desipramine reduced hERG currents by binding to a receptor site inside the channel pore. hERG protein surface expression was reduced after short-term treatment, revealing a previously unrecognized mechanism. When long-term effects were studied, forward trafficking was impaired and hERG currents were decreased. Action potential duration was prolonged upon acute and chronic desipramine exposure. Finally, desipramine triggered apoptosis in cells expressing hERG channels. Desipramine exerts at least four different cellular effects: (1) direct hERG channel block, (2) acute reduction of hERG surface expression, (3) chronic disruption of hERG trafficking, and (4) induction of apoptosis. These data highlight the complexity of hERG-associated drug effects.

The Effects of Antidepressants on Mitochondrial Function in a Model Cell System and Isolated Mitochondria

The in vitro effects of antidepressant drugs on mitochondrial function were investigated in a CHOβ(2)SPAP cell line used previously to determine the effects of antidepressants on gene transcription (Abdel-Razaq et al., Biochem Pharmacol 73:1995-2003, 2007) and in rat heart isolated mitochondria. Apoptotic effects of clomipramine (CLOM), desipramine (DMI) and of norfluoxetine (NORF, the active metabolite of fluoxetine), on cellular viability were indicated by morphological changes and concentration-dependent increases in caspase-3 activity in CHO cells after 18 h exposure to CLOM, DMI and NORF. However, tianeptine (TIAN) was without effect. CLOM and NORF both reduced integrated mitochondrial function as shown by marked reductions in membrane potential (MMP) in mitochondria isolated from rat hearts. DMI also showed a similar but smaller effect, whereas, TIAN did not elicit any significant change in MMP. Moreover, micromolar concentrations of CLOM, DMI and NORF caused significant inhibitions of the activities of mitochondrial complexes (I, II/III and IV). The inhibitory effects on complex IV activity were most marked. TIAN inhibited only complex I activity at concentrations in excess of 20 μM. The observed inhibitory effects of antidepressants on the mitochondrial complexes were accompanied by a significant decrease in the mitochondrial state-3 respiration at concentrations above 10 μM. The results demonstrate that the apoptotic cell death observed in antidepressant-treated cells could be due to disruption of mitochondrial function resulting from multiple inhibition of mitochondrial enzyme complexes. The possibility that antimitochondrial actions of antidepressants could provide a potentially protective pre-conditioning effect is discussed.

Influence of antidepressant drugs on chlorpromazine metabolism in human liver -an in vitro study

The aim of the present study was to investigate the possible effects of antidepressant drugs (fluvoxamine, imipramine) on the metabolism of the aliphatictype phenothiazine neuroleptic chlorpromazine in the human liver. The experiment was performed in vitro using human liver microsomes. The kinetic analysis of chlorpromazine metabolism carried out in the absence or presence of antidepressants showed that fluvoxamine potently inhibited chlorpromazine 5-sulfoxidation (Ki=2.8μΜ), mono-N-demethylation (Ki=1.4μΜ) and di-N-demethylation (Ki=1.1μΜ) via a competitive mechanism at therapeutic antidepressant concentrations. Imipramine moderately diminished the rate of chlorpromazine 5-sulfoxidation (Ki =8.7μΜ, competitive inhibition), mono-N-demethylation (Ki=16.0μΜ, non-competitive inhibition) and di-N-demethylation (Ki =13.5μΜ, mixed inhibition). Considering the serious side-effects of chlorpromazine and some of its metabolites, metabolic interactions between this neuroleptic and antidepressant drugs (especially the chlorpromazine-fluvoxamine interaction) may be of pharmacological and clinical importance.

Psychotropic Drugs on In Vitro Brain-Derived Neurotrophic Factor Production in Whole Blood Cell Cultures From Healthy Subjects

The aim of this study was to evaluate the effects of certain antidepressant and antipsychotic drugs on the in vitro production of brain-derived neurotrophic factor (BDNF) in whole blood cell culture from healthy volunteers. Whole blood cells from 41 healthy volunteers were stimulated with or without phytohemagglutinin and lipopolysaccharides with treatments of amitriptyline, paroxetine, mirtazapine, and venlafaxine, which are antidepressant drugs, and haloperidol and clozapine, which are antipsychotic drugs. Brain-derived neurotrophic factor levels were measured in supernatants of unstimulated and stimulated whole blood cell cultures. When the effects of each antidepressant agent at the therapeutic concentration were compared with the effects in control subjects using the Wilcoxon test, the in vitro BDNF production was significantly enhanced in the stimulated cultures treated with amitriptyline (P = 0.021). When analyzing the change in the BDNF productions by each of the drugs using the Friedman test, amitriptyline significantly increased the BDNF production in stimulated cultures (P = 0.002), whereas paroxetine, mirtazapine, and venlafaxine did not stimulate the BDNF production (P > 0.05). However, BDNF production by amitriptyline was only increased by 12% to 17%. Haloperidol and clozapine at therapeutic concentrations did not significantly alter the BDNF production in unstimulated and stimulated whole blood cells (P > 0.05). Our study suggests that some antidepressant and antipsychotic agents do not have a direct effect on increasing the BDNF production in whole blood cells during immediate treatment. Thus, the level of BDNF production in human blood cells may not influence the plasma or serum BDNF levels of subjects in clinical studies.

PATHOPHYSIOLOGY OF DEPRESSION: DO WE HAVE ANY SOLID EVIDENCE OF INTEREST TO CLINICIANS?

Due to the clinical and etiological heterogeneity of major depressive disorder, it has been difficult to elucidate its pathophysiology. Current neurobiological theories with the most valid empirical foundation and the highest clinical relevance are reviewed with respect to their strengths and weaknesses. The selected theories are based on studies investigating psychosocial stress and stress hormones, neurotransmitters such as serotonin, norepinephrine, dopamine, glutamate and gamma-aminobutyric acid (GABA), neurocircuitry, neurotrophic factors, and circadian rhythms. Because all theories of depression apply to only some types of depressed patients but not others, and because depressive pathophysiology may vary considerably across the course of illness, the current extant knowledge argues against a unified hypothesis of depression. As a consequence, antidepressant treatments, including psychological and biological approaches, should be tailored for individual patients and disease states. Individual depression hypotheses based on neurobiological knowledge are discussed in terms of their interest to both clinicians in daily practice and clinical researchers developing novel therapies.

Attentional bias in untreated panic disorder

The role of attentional biases in panic disorder has been well characterised. However, recent studies suggest an important effect of antidepressant and anxiolytic drugs on cognitive bias and most studies have included medicated patients in their sample. This study therefore examined cognitive bias in an untreated sample of participants with panic disorder (PD). A sample of 23 untreated participants with panic disorder with or without agoraphobia (PPD) and 22 healthy controls (HC) were tested with a Facial Expression Recognition task featuring different emotional intensities, a Faces Dot Probe task, a Self Beliefs task and an Emotional Stroop task. PPD showed exaggerated attentional biases to negative face and word stimuli in two different paradigms and endorsed more panic-related and negative self-attributions. They also showed enhanced perception of facial expressions of sadness. These tasks are sensitive to cognitive bias in a community-based sample of untreated PD participants. Attentional biases in panic disorder cannot be explained by the use of medication in this group and may therefore play a critical role in the underlying pathogenesis of the disorder.

Differential effects of antipsychotic and antidepressant drugs on neurogenic regions in rats

Increased neurogenesis in the hippocampus and subventricular zone (SVZ) of the brain of animals has been demonstrated following administration of several psychotropic medications. Such changes are thought to regenerate tissues and contribute to the beneficial effects of the medications. This study sought to determine if another neurogenic tissue, the peripheral olfactory epithelium (OE), might also exhibit changes after treatment with psychotropic medications. Young adult male rats were treated with risperidone and paliperidone, atypical antipsychotic medications; fluoxetine, a selective serotonin reuptake inhibitor (SSRI) antidepressant; and diluent control for 28 days via drinking water. Bromodeoxyuridine (BrdU) was injected to label dividing cells and positive cells were quantified in the OE, cortical SVZ, and dentate gyrus (DG) of the hippocampus. In the first of two studies, paliperidone and risperidone treatment (at 1 mg/kg/day) resulted in increased numbers over controls of BrdU positive cells in the OE. In the second study, examining OE, SVZ and DG in the same animal, paliperidone, but not risperidone or fluoxetine (0.6 mg/kg/day) resulted in increased cells in the OE and posterior SVZ. However, fluoxetine, but not paliperidone or risperidone treatment increased BrdU positive cells in the DG. These results show that psychotropic drug-induced cell proliferation occurs in the OE and parallels changes in the SVZ but not DG. Thus, the peripheral OE can serve as a proxy for certain psychotropic drug-induced actions on SVZ brain cell proliferation. This olfactory model can be employed in human research as a method to explore the neurogenesis effects of various pharmacologic treatments of neuropsychiatric disorders.

P.2.b.002 Risperidone, an atypical antipsychotic, enhances the effect of antidepressant drugs in animal models of depression

We examined the effects of 11 antidepressants on the activities of three rat GABA transporters (GAT1, GAT2 and GAT3) expressed in COS-7 cells. Desipramine and maprotiline inhibited all subtypes of GABA transporter, while doxepin, mianserin, trimipramine, nortriptyline and amitriptyline inhibited certain types of GABA transporters. Amitriptyline inhibited the GAT1 and GAT3 at the reasonable dosage for clinical administration. These results suggest that the inhibition of GABA uptake might have some role in the prescribed antidepressive and sedative nature of this drug.

Effectiveness of antiepileptic or antidepressant drugs when added to opioids for cancer pain: systematic review

Neuropathic pain mechanisms are present in up to 40% of patients with cancer pain. In these situations, additional or adjuvant analgesic drugs (such as antidepressants or antiepileptics) are often required to optimize pain control alongside standard opioid therapy. This systematic review aimed to determine the effectiveness of antidepressants and antiepileptics when added to opioids, compared to opioids alone, for the management of pain caused directly by cancer. Prospective clinical studies, published in English that used a before-after design or randomized or non-randomized group comparisons were identified. Data were extracted on pain intensity, pain relief and adverse events. Eight studies were eligible (five randomized controlled trials) that recruited 465 patients in total, of whom 370 (79.5%) completed the study period. A narrative analysis was performed because clinical and methodological heterogeneity prevented meta-analysis. Included studies suggested that adjuvants improve pain control within 4–8 days when added to opioids for cancer pain; the strongest evidence supports gabapentin. However, a reduction in pain intensity of greater than 1 point on a 0–10 numerical rating scale is unlikely, but an increase in adverse events is likely. For all adjuvants, the effect size was much less than that seen in patients with non-cancer neuropathic pain. Dosing strategies that can be examined in future clinical trials are suggested.

Caution Urged in Interpreting Antidepressant Efficacy Data

Caution Urged in Interpreting Antidepressant Efficacy Data

Dopamine is involved in the antidepressant-like effect of allopregnanolone in the forced swimming test in female rats

Evidence from both animal and human studies suggests a role for dopamine in the therapeutic effect of antidepressant drugs. Consistently, dopamine receptor antagonists antagonize the effect of antidepressant drugs in different experimental models of depression. Neurosteroids, and in particular allopregnanolone, seem to be involved both in the pathophysiology of depression and in the mechanism of action of antidepressant drugs, and their role seems to be particularly important in the understanding of mood disturbances related to the different phases of the reproductive life in women. The aim of this study was to investigate the possible role of dopamine on the antidepressant-like effect of allopregnanolone in a model of depression. Thus, we examined (i) the behaviour of female Sprague-Dawley rats in the forced swimming test during estrus and diestrus and their response to allopregnanolone treatment (0.5, 1 and 2 mg/kg), and (ii) the effect of the dopamine D1-like and D2-like receptor antagonists SCH 23390 (0.01 and 0.025 mg/kg) and raclopride (0.05 and 0.2 mg/kg) on the antidepressant-like effect of allopregnanolone (2 mg/kg) in the same experimental model. We failed to observe differences in depressive-like behaviour between estrous phases, and allopregnanolone administration in both estrus and diestrus resulted in an antidepressant-like effect consisting in an increase of swimming behaviour. The allopregnanolone effect was unaffected by a dose of the dopamine D1-like receptor antagonist SCH 23390 displaying a marked inhibitory effect on basal activity, while it was turned into a potentiation of the depressive-like behaviour of the forced swimming condition by treatment with the higher dose of raclopride. The present results indicate an involvement of dopamine transmission in the allopregnanolone antidepressant-like effect in the forced swimming model of depression, and suggest that this effect depends mainly on stimulation of dopamine D2-like receptors.

Antidepressant drug effects and depression severity: a patient-level meta-analysis.

Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with less severe depression. To estimate the relative benefit of medication vs placebo across a wide range of initial symptom severity in patients diagnosed with depression. PubMed, PsycINFO, and the Cochrane Library databases were searched from January 1980 through March 2009, along with references from meta-analyses and reviews. Randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder were selected. Studies were included if their authors provided the requisite original data, they comprised adult outpatients, they included a medication vs placebo comparison for at least 6 weeks, they did not exclude patients on the basis of a placebo washout period, and they used the Hamilton Depression Rating Scale (HDRS). Data from 6 studies (718 patients) were included. Individual patient-level data were obtained from study authors. Medication vs placebo differences varied substantially as a function of baseline severity. Among patients with HDRS scores below 23, Cohen d effect sizes for the difference between medication and placebo were estimated to be less than 0.20 (a standard definition of a small effect). Estimates of the magnitude of the superiority of medication over placebo increased with increases in baseline depression severity and crossed the threshold defined by the National Institute for Clinical Excellence for a clinically significant difference at a baseline HDRS score of 25. The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

S33-03 - Involvement of cytoskeletal microtubules in the action of antidepressant drugs

Growing evidence suggests that alterations in cytoskeletal microtubules dynamics may be involved in the effects of antidepressant drugs on brain structural neuronal plasticity phenomena such as remodelling of axons and dendrites. The speaker will review the most recent data in the field obtained in either naïve animals or in animal models of stress/depression. These results were gathered using a multidisciplinary approach, ranging from behavioural tests to neurochemistry and molecular analyses of specific markers of microtubule dynamics and synaptic remodelling. Several classes of antidepressant drugs have been shown to differentially modulate the expression of microtubular proteins and synaptic markers in specific rat brain regions depending from the dose and length of administration. Importantly, such antidepressant-induced effects on microtubular and synaptic proteins showed a very different pattern of changes in environmental (social isolation from weaning) or genetic (Flinders Sensitive Line) rat models of depression, which were not always accompanied by recover of the “depressive-like” behavioural phenotypes. Therefore, antidepressant drugs can modulate brain cytoskeletal and synaptic remodelling, but the pattern of these phenomena seems related to a complex gene-environment interaction. These data may be considered of translational human relevance when put in the context of partial- or non responders to antidepressant therapy. Finally, MAPREG developed new molecules specifically targeting neuronal microtubules and promoting structural neuronal plasticity, which may represent novel tools for the therapy of depressive disorders. Novel data on the antidepressant efficacy of one of these promising molecules in rat models of depression will be presented.