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PubMed2000

Antidepressant drugs appear to enhance cocaine-induced toxicity.

It has been shown that cocaine-induced convulsions and lethality appear to be mediated by serotonin and dopamine neurotransmission, respectively. However, many antidepressants considered for treatment of cocaine addiction target these monoamine systems and may thus amplify these toxic effects during relapse. In this study, the authors assessed whether pretreatment with antidepressants influences cocaine-induced toxicity in mice as well as the potency of these medications at cocaine-binding sites previously shown to be associated with cocaine toxicity. Overall, selective serotonin reuptake inhibitors (SSRIs) facilitated cocaine-induced convulsions but not lethality. Dopamine uptake inhibition facilitated cocaine-induced lethality, but not convulsion. The SSRI sertraline enhanced neither convulsions nor lethality and may be unique due to its high affinity for sigma receptors. These results have important implications for safe and effective addiction treatments.

Animals↗
PubMed1996

Effects of long-term treatment with antidepressant drugs on proopiomelanocortin and neuropeptide Y mRNA expression in the hypothalamic arcuate nucleus of rats.

Antidepressant drugs have in common a delayed onset of clinical efficacy. In rats, long-term, daily administration of four different types of clinically effective antidepressant drugs results in decreased corticotropin releasing hormone (CRH) mRNA expression levels in the hypothalamic paraventricular nucleus (PVN). Because a subpopulation of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (Arc) projects to the PVN, we measured NPY and POMC mRNA expression in the Arc using in situ hybridization histochemistry at several time points following daily administration of four different antidepressant drugs. After 14 and 56 days of imipramine treatment, Arc NPY mRNA levels are decreased to 85% and 75% of control levels, but are unchanged compared to control after one or five days of treatment. Arc POMC mRNA levels are unchanged compared to controls at 1, 5, 14, or 56 days following imipramine treatment. Unlike after imipramine, Arc NPY and POMC mRNA levels are increased significantly to 134-172% of control following 56-day treatment with the antidepressant drugs fluoxetine, phenelzine, or idazoxan. The divergent effects of imipramine vs the other 3 antidepressant drugs on Arc NPY mRNA expression are similar to the pattern of changes in tyrosine hydroxylase (TH) mRNA expression levels in the locus coeruleus (LC) using the same experimental paradigm, but are different from the unidirectional depressive effects of all four drugs on CRH mRNA expression in the PVN. Thus, the Arc NPY and LC noradrenergic systems may act coordinately in mediating antidepressant effects. The present data are consistent with the delayed onset of clinical efficacy for antidepressant drugs, and suggest that Arc NPY and POMC neurotransmitter systems play a role in the pathophysiology of depression.

Adrenergic alpha-Antagonists↗
PubMed1999

Are the newer antidepressant drugs as effective as established physical treatments? Results from an Australasian clinical panel review.

OBJECTIVE: The aim of this study was to determine, in a clinical panel sample, the extent to which patients with depression (and melancholic and non-melancholic subtypes) judged the effectiveness of previously received antidepressant treatments, particularly the comparative effectiveness of the older and newer antidepressant drugs. METHOD: Twenty-seven Australasian psychiatrists assessed 341 non-psychotic depressed patients and rated the extent to which previous antidepressant treatments had been effective. Patients were assigned to 'melancholic' and residual 'non-melancholic' categories by two processes (DSM-IV decision rules, and a cluster analysis-derived allocation) and treatment effectiveness examined within each category. RESULTS: Electroconvulsive therapy (both bilateral and unilateral) was judged as highly effective by both melancholic and non-melancholic patients. Antipsychotic medication similarly rated highly (but was judged as more effective by the non-melancholic than melancholic patients). The tricyclics and irreversible monoamine oxidase inhibitors (MAOIs) were rated as more effective by the whole sample than several newer antidepressant classes (including the selective serotonin re-uptake inhibitors [SSRIs], venlafaxine, mianserin and moclobemide), whether effectiveness was examined dimensionally or categorically. Comparison of the overall tricyclic and SSRI classes indicated that any superior tricyclic effectiveness was specific to the melancholic subjects. CONCLUSIONS: Despite methodological limitations intrinsic to such clinical panel data, the judged greater effectiveness of the older antidepressants (tricyclics and irreversible MAOIs) for melancholic depression is of importance. If valid, such data are of intrinsic clinical relevance but also have the potential to inform us about the neurobiological determinants of 'melancholia' and pharmacological actions which contribute to its effective treatment.

Antidepressive Agents↗
PubMedDate not supplied

Retrospective analysis of the health-care costs of bupropion sustained release in comparison with other antidepressants.

OBJECTIVE: The objective of this study was to evaluate the health care costs associated with the treatment of a new episode of depression with bupropion sustained release (SR) rather than with other antidepressants (selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs], and serotonin norepinephrine reuptake inhibitors [SNRIs]). METHODS: This was a retrospective cohort study based on the private-pay, fee-for-service 1997 and 1998 MEDSTAT MarketScan databases. Individuals were included if they were 18 years of age or older, had an initial prescription for an antidepressant under study with an index prescription date between July 1997 and June 1998, and had a claim for a diagnosis of depression diagnosis within 30 days of the index date. All patients' claims from six months before and after receiving their index antidepressant prescription were examined. Total, outpatient, and pharmacy costs were compared among antidepressant groups using an intent-to-treat analysis with exponential regression models and bootstrapped 95% confidence intervals. RESULTS: A total of 1771 patients were included in the study cohort. The mean age was 41.6 years, and 69.5% of subjects were female. Most patients (75%) continued with the index antidepressant during the 6-month follow-up period. Although the drug acquisition cost was lowest for TCAs, total costs were significantly higher for patients treated with TCAs than for those treated with bupropion SR (p < .05). In comparison with bupropion SR, patients initiating therapy with sertraline had significantly higher mental health payments (p < .05). CONCLUSIONS: Initiating treatment of depression with bupropion SR was associated with lower total mental health care costs compared with TCAs and with sertraline. This study reaffirms that formulary and medical decision-makers should consider the overall impact of antidepressant treatment, including but not limited to drug acquisition costs, other health care costs, and drug efficacy and safety.

Adolescent↗
PubMed2001

Effects of Hypericum perforatum (St. John's wort) on passive avoidance in the rat: evaluation of potential neurochemical mechanisms underlying its antidepressant activity.

Along with traditional pharmacotherapies, extracts of Hypericum perforatum L. (St. John's wort) are used in the treatment of mild to moderately severe depression. Hypericum is a nonspecific inhibitor of the neuronal uptake of monoamines (serotonin, 5-HT; noradrenaline, NA; dopamine, DA) as well as GABA and glutamate. Hypericum extracts have been shown to be active in several different "animal models for antidepressant drugs". As one of a large number of chemical constituents, the phoroglucinol derivative hyperforin might be an important "antidepressant component" of hypericum. However, the exact role of neurochemical mechanisms underlying in vivo actions of hypericum and hyperforin are not well defined. In the present study, we compared the effects of hypericum, hyperforin and hyperforin-free hypericum and the three conventional antidepressants paroxetine, imipramine and desipramine using the passive avoidance (PA) task in the rat. The 5-HT-releasing compound p-chloroamphetamine (PCA), which operates through the 5-HT neuronal transporter, was used to reveal the potential in vivo effects on 5-HT uptake mechanisms. To examine the ability of the test-compounds to enhance noradrenaline (NA) transmission in vivo, subeffective doses of scopolamine were used. Taken together, our results suggest that (1) hypericum given at high doses can probably affect the neuronal 5-HT uptake mechanisms in a manner more reminiscent of TCAs than SSRIs; (2) similar to TCAs and SSRIs, hypericum and hyperforin are active in the scopolamine test. Hyperforin appears to play a major role in the action of hypericum in this model. Both 5-HT and NA might concomitantly contribute to the effects of different antidepressants in the "low-dose scopolamine" model; (3) hypericum might enhance both 5-HT and NA transmission in forebrain limbic brain circuits important for mood control, which could underly its antidepressant effects. However, the relative contribution of different constituents and exact mechanisms of action require further evaluation.

Animals↗
PubMed2001

A study of the antidepressant activity of Hypericum perforatum on animal models.

The treatment of non-selected depressed patients with a hydro-alcoholic extract of Hypericum perforatum has been reported to have an efficacy similar to that of classical antidepressants. The effects of H. perforatum on three animal depression models have been studied: (a) an acute form of escape deficit (ED) induced by unavoidable stress; (b) a chronic model of ED, which can be maintained by the administration of mild stressors on alternate days; (c) a model of anhedonia based on the finding that repeated stressors prevent the development of appetitive behavior induced by vanilla sugar in satiated rats fed ad libitum. H. perforatum: (i) acutely protects animals from the sequelae of unavoidable stress; (ii) reverts the chronic escape deficit state maintained by repeated stressors and (iii) preserves the animal's capacity to acquire motivated appetitive behavior. Exposure to chronic stress not only induces escape deficit, but also decreases extraneuronal levels of dopamine in the nucleus accumbens shell; both behavioral and neurochemical effects are reverted by long-term treatment with antidepressants. Three-week treatment with H. perforatum reverted the chronic stress effect on extraneuronal dopamine in the nucleus accumbens. A consistent body of data in the literature suggests that, among the components of H. perforatum extract, hyperforin is the compound (or one of the compounds) responsible for the antidepressant activity. We compared the efficacy of the total extract with the efficacy of hyperforin after p.o. administration. In the acute-escape deficit model, hyperforin showed a potency of about ten times that of the total extract in protecting rats from the sequelae of unavoidable stress. Thus, hyperforin appears to be the most likely active component responsible for the antidepressant activity of H. perforatum.

Animals↗
PubMed1996

Low plasma thyroid indices of depressed patients are attenuated by antidepressant drugs and influence treatment outcome.

Decreased turnover of thyroid indices and blunting of TSH release after TRH administration has been associated with depressive disorder. A further decrease in plasma thyroid hormone; during antidepressant treatment has been reported. However, the putative association between the plasma thyroid indices' concentration and response has not been addressed. In the present study 21 depressed inpatients underwent a four-week double blind antidepressant with amitriptyline and mianserin; their plasma thyroid hormone indices (total thyroxine [TT4], free thyroxine [FT4], total triiodothyronine [TT3], free triiodothyronine [FT3], thyrotropin [TSH], and thyroglobulin [TBG]) were quantified to elucidate their involvement in depression and during antidepressant drug treatment. Depressed patients' plasma TSH, when corrected for age, was significantly lower than that of healthy subjects. During antidepressant treatment the entire patient cohort showed a significant decrease in plasma TT4 and FT4 concentrations. Responders showed a significant drop in TT4 FT4, FT3, and T4/TBG, but nonresponders only a decrease in FT4. During mianserin treatment, a decrease was observed in TT4, FT4, FT3, and T4/TBG. FT4 and FT3 baseline levels correlated positively with the improvement in the Hamilton Depression Rating Score (HDRS). These findings show that depressed inpatients' serum TSH levels are within the reference range, but significantly lower than those of healthy subjects, and those patients who turn out to be nonresponders have potentially lower availability of thyroid hormones than responders. Therefore, we hypothesize that in order to assure clinical improvement in depression, an adequate capacity of the thyroid hormone pool is necessary to compensate for the additional antidepressant-provoked decrease in serum thyroid hormone availability.

Adult↗
PubMed2006

Chronic antidepressants potentiate via sigma-1 receptors the brain-derived neurotrophic factor-induced signaling for glutamate release.

Up-regulation of BDNF (brain-derived neurotrophic factor) has been suggested to contribute to the action of antidepressants. However, it is unclear whether chronic treatment with antidepressants may influence acute BDNF signaling in central nervous system neurons. Because BDNF has been shown by us to reinforce excitatory glutamatergic transmission in cultured cortical neurons via the phospholipase-gamma (PLC-gamma)/inositol 1,4,5-trisphosphate (IP3)/Ca2+ pathway (Numakawa, T., Yamagishi, S., Adachi, N., Matsumoto, T., Yokomaku, D., Yamada, M., and Hatanaka, H. (2002) J. Biol. Chem. 277, 6520-6529), we examined in this study the possible effects of pretreatment with antidepressants on the BDNF signaling through the PLC-gamma)/IP3/Ca2+ pathway. Furthermore, because the PLC-gamma/IP3/Ca2+ pathway is regulated by sigma-1 receptors (Hayashi, T., and Su, T. P. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 491-496), we examined whether the BDNF signaling is modulated by sigma-1 receptors (Sig-1R). We found that the BDNF-stimulated PLC-gamma activation and the ensued increase in intracellular Ca2+ ([Ca2+]i) were potentiated by pretreatment with imipramine or fluvoxamine, so was the BDNF-induced glutamate release. Furthermore, enhancement of the interaction between PLC-gamma and TrkB (receptor for BDNF) after imipramine pretreatment was observed. Interestingly, BD1047, a potent Sig-1R antagonist, blocked the imipramine-dependent potentiation on the BDNF-induced PLC-gamma activation and glutamate release. In contrast, overexpression of Sig-1R per se, without antidepressant pretreatment, enhances BDNF-induced PLC-gamma activation and glutamate release. These results suggest that antidepressant pretreatment selectively enhance the BDNF signaling on the PLC-gamma/IP3/Ca2+ pathway via Sig-1R, and that Sig-1R plays an important role in BDNF signaling leading to glutamate release.

Animals↗
PubMed2003

Effects of antidepressants on function and viability of human neutrophils.

BACKGROUND: Antidepressants are frequently used in chronic pain therapy and are under investigation as long-acting local anesthetics. Because of the structural similarities between antidepressants and local anesthetics, the authors hypothesized that these compounds act similarly, and they investigated the effects of nortriptyline, amitriptyline, imipramine, and fluoxetine on priming and activation of human polymorphonuclear neutrophils (hPMNs). METHODS: Effects of 30-, 120-, and 240-min preincubation with nortriptyline (10(-7)-10(-4) M), amitriptyline (10(-6)-10(-3) M), imipramine (10(-6)-10(-3) M), or fluoxetine (10(-7)-10(-4) M) on O(2)- generation of platelet activating factor-primed (10-6 M) and/or formyl-methionyl-leucyl-phenylalanine-activated (10(-6) M) isolated hPMNs were determined. All data are reported as mean +/- SD (statistics: t test, P < 0.05). RESULTS: Brief incubation in low concentrations of nortriptyline, amitriptyline, or fluoxetine (all at 10(-5) M) did inhibit priming but not activation of hPMNs. Imipramine (10(-5) M) affected neither priming nor activation. Prolonged incubation in lower concentrations of all antidepressants influenced neither priming nor activation. However, at higher concentrations, all four compounds exerted cytotoxic effects: virtually all hPMNs were killed by amitriptyline and imipramine (both at 10(-3) M) or nortriptyline and fluoxetine (both at 10(-4) M). CONCLUSION: Antidepressants, in low concentrations, inhibited priming but not activation of hPMNs. However, at concentrations similar to those attained after local injection, and in marked contrast to local anesthetics, antidepressants are profoundly toxic to hPMNs.

Antidepressive Agents↗
PubMed2003

Diffusion of new generation antidepressant treatment among elderly diagnosed with depression.

RESEARCH OBJECTIVE: This study analyzes the prevalence of new generation antidepressant treatment including selective serotonin reuptake inhibitor (SSRI) use from 1992 to 1997 among the elderly diagnosed with depression, using a large, nationally representative survey of Medicare beneficiaries. Relationships between use of new generation antidepressant treatment and socioeconomic characteristics, physical comorbidity, insurance coverage, and care sector (mental health specialty vs. general health services) are explored. RESEARCH DESIGN: Merged survey data, Medicare claims, and detailed self-reports from the Medicare Current Beneficiary Survey were used to explore use of new generation antidepressant treatment.SUBJECTS Medicare beneficiaries aged 65 and older living in the community, enrolled in fee-for-service Medicare throughout the year and diagnosed with depression. RESULTS: In 1997, among an estimated 1.1 million community dwelling older adults with diagnosis of depression in health care claims, nearly two thirds received antidepressant treatments. Among those diagnosed with depression and treated with antidepressants, the use of new generation antidepressants increased from 35% in 1992 to 77% in 1997. The rates of use increased among all subgroups examined. In the early years after the introduction of these new antidepressant medications (1992-1994), there were socioeconomic disparities in use of these medications, with less use by less educated and poor patients. However, these differences abated over time. CONCLUSIONS: An increasing proportion of elderly treated for depression with antidepressants received the new generation antidepressants. The diffusion of these new medications lagged for those with low socioeconomic status defined by education and income. This diffusion process conforms to a general model of diffusion in which during the initial years following introduction of a new treatment, especially one which is costly, early adopters of the treatment are likely to disproportionately represent those of higher socioeconomic status.

Age Factors↗
PubMed2004

Use of antidepressant medications: are there differences in psychiatric visits among patient treatments in the Veterans Administration?

BACKGROUND: Information on the effectiveness of newer antidepressants like serotonin-norepinephrine reuptake inhibitors in terms of healthcare utilization is limited. Treatment guidelines affect evaluation. Second-line medications are usually prescribed to patients with higher utilization. OBJECTIVES: The objective of this study was to compare antidepressants within the Veterans Affairs (VA) healthcare system on the basis of the number of outpatient psychiatric visits for each class of antidepressants. RESEARCH DESIGN AND SUBJECTS: We conducted a retrospective cohort design using precollected information from VA national databases from 1999 and 2000. The study identified 92,537 patients on serotonin specific reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs). MEASURES: We stratified individual patients by the number of visits in the baseline year for each medication class. For each stratum, we created a dichotomized variable YK: Yk = 1 if there is a reduction of K visits or more and 0 if there is no reduction. We calculated the odds of reduction of psychiatric visits among the 3 classes of antidepressants. RESULTS: TCAs and SSRIs were associated with greater odds of reduction compared with SNRIs at the level of 1 through 10 or 11 visits, respectively. SNRIs were associated with greater odds of reduction in visits at the level of 14, 16, or more visits compared with SSRIs and TCAs, respectively (P <0.05). SSRIs were associated with greater odds of reduction compared with TCAs at the level of 1 to 11 visits (P <0.05); there were no significant differences between the 2 classes above 11 visits. CONCLUSION: Effectiveness research using databases should consider how medications are prescribed within systems. Treatment guidelines result in differences in severity and utilization among users of different medications.

Adolescent↗
PubMed2004

Differential effects of two types of antidepressants, amitriptyline and fluoxetine, on anorectal motility and visceral perception.

BACKGROUND: Although antidepressants are used for functional gastrointestinal disorders, the mechanisms of their effects on gut are incompletely understood. AIM: To assess the effects of two types of antidepressants (tricyclic, serotoninergic) on anorectal motility and visceral perception. METHODS: A placebo-controlled, randomized, double-blind, crossover study was performed in 12 healthy male volunteers who received a single oral dose of amitriptyline (80 mg), fluoxetine (40 mg) or placebo. Drug effects were assessed using phasic isobaric distensions of the rectum with an electronic barostat (11 levels from 1 to 51 mmHg) 4 h after drug intake. Maximal rectal volume and pressure, mean and residual pressures at upper anal canal, mean pressure at lower anal canal, defecation sensation (5-level scale) and visceral perception (visual analogue scale) were recorded at each level of distending pressure. RESULTS: Ten subjects completed the study. Compared with placebo, neither amitriptyline nor fluoxetine modified rectal compliance or visceral perception. Compared with placebo, antidepressants significantly reduced mean and residual pressures at upper anal canal (-18%, P = 0.0019, and -27%, P = 0.0002, respectively, for amitriptyline; -26%, P = 0.0001, and -33%, P = 0.0001, respectively, for fluoxetine) whereas only amitriptyline significantly reduced mean pressure at lower anal canal (-16%, P = 0.0008). CONCLUSION: Both antidepressants similarly relaxed the internal anal sphincter, probably through a non-specific mechanism, without modifying visceral perception. Only amitriptyline relaxed the external anal sphincter.

Adolescent↗
PubMed1999

Prevalence of antidepressant use among older people: population-based observations.

OBJECTIVE: To assess the prevalence of antidepressant use with respect to age, gender, and time during a 5-year period from 1993 to 1997. DESIGN: A retrospective, population-based study in which data regarding a cross-sectional series of annual antidepressant use were obtained from administrative claims and census databases for more than 1.4 million older persons during calendar years 1993 through 1997. PARTICIPANTS: All residents of Ontario aged 65 or older. MAIN OUTCOME MEASURES: Changes in the prevalence of antidepressant users as a function of age group, gender, and time. RESULTS: A general, positive, linear trend in the prevalence of antidepressant users with increasing age group was consistently detected regardless of gender and year assessed (P < .001 for both genders and all years). The age-adjusted relative risk of women being dispensed an antidepressant relative to men was significantly higher during each year but seemed to decrease slightly over time: 1.74 (95% CI, 1.72-1.76) in 1993 and 1.65 (95% CI, 1.63-1.67) in 1997. The multiple linear regression model revealed significant relationships between the prevalence of antidepressant users and increasing age group, female gender, and increasing year of assessment (P < .001 for each variable). The prevalence was observed to range from a low of 5.6% in 65 to 69-year-old men in 1993 to a high of 17.2% among 85 to 89-year-old women in 1997. CONCLUSIONS: Our findings reveal that the prevalence of antidepressant users is dynamic and is significantly and independently associated with age, gender, and time of assessment.

Age Factors↗
PubMed1997

Designing a new generation of antidepressant drugs.

Although longer-term adaptive changes in receptor sensitivity may better explain the delayed onset of action of antidepressants, the mechanism based on acutely elevated noradrenaline (NA) and serotonin (5-HT) synaptic levels remains the basis for new drug design. The dual action concept, which postulates that effects on both NA and 5-HT are more advantageous than a selective action on serotonin reuptake (SSRI), has been used to design new antidepressants such as venlafaxine and mirtazapine. Both drugs enhance NA and 5-HT neurotransmission with little affinity for receptors mediating tricyclic-like side effects. Mirtazapine, the prototype noradrenergic and specific serotonergic antidepressant (NaSSA), specifically enhances 5-HT1 neurotransmission and blocks 5-HT2 and 5-HT3 receptors, and in contrast to venlafaxine lacks SSRI-like and adverse cardiovascular side effects. The unique pharmacological action of mirtazapine is a result of implementation of two concepts: dual action as a basis of efficacy combined with receptor-specific action as a basis of tolerability.

Adrenergic Uptake Inhibitors↗