Trends in the prescribing of antidepressant pharmacotherapy: office-based visits, 1990-1995.

Sclar DA, Robinson LM, Skaer TL, Galin RS.

College of Pharmacy and Program in Statistics, Washington State University, Pullman 99164-6510, USA.

Data from the National Ambulatory Medical Care Survey for the period 1990 through 1995 were used to discern the population-adjusted rate of office-based physician-patient encounters at which the prescribing or continuation of antidepressant pharmacotherapy (tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs], or others), a diagnosis of depression (International Classification of Diseases, 9th Revision, Clinical Modification codes 296.2 through 296.36, 300.4, or 311), or both were documented. National estimates of the number of office-based visits resulting in a prescription for or continuation of antidepressant pharmacotherapy for any purpose escalated from 16,534,268 in 1990 to 28,664,796 in 1995, a 73.4% increase. Although the number of office-based visits at which a diagnosis of depression was documented increased 23.2% during this period, the proportion of patients with a diagnosis of depression who were prescribed or continued antidepressant pharmacotherapy increased only 14.9%, from 52.1% in 1990 to 67.0% in 1995. Among patients with a diagnosis of depression, use of a TCA declined from 42.1% in 1990 to 24.9% in 1995. In contrast, use of an SSRI for the treatment of depression increased from 37.1% in 1990 to 64.6% in 1995. The rate of office-based visits at which the use of antidepressant pharmacotherapy for any purpose was documented increased from 6.7 per 100 US population in 1990 to 10.9 in 1995, a 62.7% increase; documentation of a diagnosis of depression increased from 6.1 per 100 US population in 1990 to 7.1 in 1995, a 16.4% increase; and the recording of a diagnosis of depression in concert with the prescribing or continuation of antidepressant pharmacotherapy increased from 3.2 per 100 US population in 1990 to 4.8 in 1995, a 50.0% increase. Further research is required to elucidate the effect of observed trends on clinical and financial outcomes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9737843&dopt=Abstract antidepressant




Antidepressants and the risk of falls among nursing home residents.

Thapa PB, Gideon P, Cost TW, Milam AB, Ray WA.

Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

BACKGROUND: In nursing home residents, the use of tricyclic and other heterocyclic antidepressants is associated with an increased risk of falls. The newer selective serotonin-reuptake-inhibitor antidepressants are largely free of the side effects of the tricyclic agents thought to cause falls and so have been hypothesized to be safer for those at high risk for falls. METHODS: We retrospectively identified an inception cohort of 2428 nursing home residents in Tennessee who were new users of tricyclic antidepressants (665 subjects), selective serotonin-reuptake inhibitors (612 subjects), or trazodone (304 subjects) or nonusers of antidepressants (847 subjects). We ascertained the number of falls during therapy and during a similar follow-up period for nonusers, then calculated the rate ratios for falls with adjustments for an extensive set of potential confounding factors. RESULTS: The new users of each type of antidepressant had higher rates of falls than the nonusers, with adjusted rate ratios of 2.0 (95 percent confidence interval, 1.8 to 2.2) for tricyclic antidepressants, 1.8 (1.6 to 2.0) for selective serotonin-reuptake inhibitors, and 1.2 (1.0 to 1.4) for trazodone. The rate ratios increased with the daily dose for tricyclic antidepressants, reaching 2.4 (95 percent confidence interval, 2.1 to 2.8) for doses of 50 mg or more of amitriptyline or its equivalent, and for the serotonin-reuptake inhibitors, reaching 1.9 (1.7 to 2.2) for 20 mg or more of fluoxetine or its equivalent. The elevated rates of falls persisted through the first 180 days of therapy and beyond. CONCLUSIONS: In this large study of nursing home residents, there was little difference in rates of falls between those treated with tricyclic antidepressants and those treated with selective serotonin-reuptake inhibitors. Hence, the preferential use of the newer antidepressants is unlikely to reduce the higher rate of falls among nursing home residents taking antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9744971&dopt=Abstract antidepressant




Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain. A quantitative in situ hybridization study.

Boyer PA, Skolnick P, Fossom LH.

Laboratory of Neuroscience, NIDDK, National Institutes of Health, Bethesda, MD, USA.

Chronic administration of antidepressants produces region-specific adaptive changes in the radioligand binding properties of N-methyl-D-aspartate (NMDA) receptors. We hypothesized that this effect of chronic antidepressant administration was owing to an alteration in NMDA receptor subunit composition. This hypothesis was examined using in situ hybridization with [35S]-labeled riboprobes to quantify the impact of chronic (16 d) injection with either imipramine (15 mg/kg) or citalopram (20 mg/kg) on the levels of transcripts encoding NMDA receptor subunits in mouse brain. These antidepressants altered the levels of mRNA encoding the zeta-subunit in a parallel fashion, with both drugs either reducing transcript levels (e.g., in the cortex, cerebellum, thalamus, and striatum) or producing no substantial effects (e.g., hippocampus). In contrast, these antidepressants often produced distinct, region-specific effects on mRNA levels encoding the epsilon family of subunits. For example, citalopram treatment produced widespread reductions in epsilon 1-subunit mRNA levels (e.g., in frontal cortex, CA2 of hippocampus, and amygdala), whereas imipramine reduced levels of this transcript only in the amygdala. Conversely, imipramine treatment produced widespread reductions in epsilon 2-subunit mRNA levels (e.g., in cortex, CA1-4 of hippocampus, and amygdala), whereas the effects of citalopram on levels of this transcript were largely restricted to amygdala. These findings indicate that long-term antidepressant treatment produces region-specific changes in expression of transcripts for NMDA receptor subunits, presumably altering NMDA receptor composition. Because subunit composition determines the physiological and pharmacological properties of NMDA receptors, these changes may play a critical role in the therapeutic actions of structurally diverse antidepressants.

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Testosterone-dependent antidepressant-like effect of noradrenergic but not of serotonergic drugs.

Martinez-Mota L, Fernandez-Guasti A.

Subdireccion de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatria Ramon de la Fuente Muniz, Calzada Mexico-Xochimilco 101, San Lorenzo Huipulco, Tlalpan 14370 D.F., Mexico.

The main objective of this study was to analyze the effect of testosterone on the actions of antidepressant drugs in the forced swimming test (FST), an animal model that predicts antidepressant effects. In addition, the effect of testosterone propionate (TP) supplementation was evaluated in the same animal model using orchidectomized male rats. Initially, different doses (2.5, 5.0, and 10.0 mg/kg sc, three injections before the test) of desipramine (DMI), fluoxetine (FLX), and clomipramine (CMI) were administered to intact male rats to detect the effective dose in the FST. All drugs (at 10 mg/kg) produced an antidepressant effect, reflected as a reduction of immobility behavior. Neither orchidectomy per se nor TP supplementation (0.5 and 1.0 mg/rat sc, for 10 days) modified the behaviors evaluated in the FST. Orchidectomy blocked the antidepressant effect of DMI, FLX, and CMI (10 mg/kg), while TP supplementation (0.5 mg/rat, for 10 days) restored the antidepressant action of DMI, but not that of CMI or FLX. These findings indicate that testosterone participates in the antidepressant actions of DMI, a noradrenaline reuptake inhibitor, while other gonadal hormones might be involved in the antidepressant effects of the serotonin reuptake inhibitors (SSRIs) like FLX and CMI. Copyright 2004 Elsevier Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15301926&dopt=Abstract antidepressant




GABAB receptor antagonist-mediated antidepressant-like behavior is serotonin-dependent.

Slattery DA, Desrayaud S, Cryan JF.

Neuroscience Research, Novartis Institutes for BioMedical Research WSJ 386.344, Novartis, Basel, CH-4002, Switzerland.

There is an emerging body of data purporting a role of gamma-aminobutyric acid (GABA) in the pathophysiology of mood disorders. However, the role of metabotropic GABA(B) receptors in depression is not well defined. The modified forced swim test has recently emerged as an excellent tool to assess behaviorally the role of monoamines in antidepressant action. To assess the role of GABA(B) receptors in antidepressant-related behavior, we examined a number of selective GABA(B) receptor ligands (novel positive modulators and antagonists) on behavior in the modified forced swim test. We demonstrate that the selective GABA(B) receptor antagonists CGP56433A [[3-{1-(S)-[{3-cyclohexylmethyl)hydroxy phosphinyl}-2-(S) hydroxy propyl]amino}ethyl]benzoic acid; 1-10 mg/kg] and [3-[[1-(S)-3-dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]phenylmethyl-phosphinic acid hydrochloride; 3-10 mg/kg] had a similar profile to the selective serotonin reuptake inhibitor fluoxetine; they decreased immobility and increased swimming behavior. The tricyclic antidepressant desipramine decreased immobility but increased climbing behavior. In contrast, the novel GABA(B) receptor-positive modulator GS39783 (10-40 mg/kg) did not display antidepressant-like activity in the modified forced swim test. To further assess the possible interaction between GABA(B) receptor antagonism and serotonin, rats were pretreated with the tryptophan hydroxylase inhibitor para-chlorophenylalanine. 5-Hydroxytryptamine depletion (>90%) abolished the antidepressant-like behavior of CGP56433A (10 mg/kg) by attenuating the increase in swimming. Together, these data demonstrate that GABA(B) receptor antagonists via an interaction with the serotonergic system display antidepressant-like properties and therefore represent a novel approach for the treatment of depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15333677&dopt=Abstract antidepressant




Sexual dysfunction associated with antidepressant drugs.

Baldwin DS.

University Department of Mental Health, RSH Hospital, RSH Hospital, Graham Road, Southampton, SO14 0YG, UK. dsb1 soton.ac.uk

The term 'sexual dysfunction' describes a disturbance in sexual desire and the psychophysiological changes that characterise the normal sexual response cycle, and cause marked personal distress and interpersonal difficulty. Epidemiological studies indicate that sexual dysfunction is common in the general population, but more common in depressed individuals in community settings and clinical samples. Most antidepressant drugs have adverse effects on sexual function, but accurate identification of the incidence of treatment-emergent dysfunction has proved troublesome. Futhermore, investigations of sexual dysfunction associated with antidepressants have one or more methodological flaws. There may be some advantages for bupropion, moclobemide, nefazodone and reboxetine over other antidepressants. Many approaches have been adopted for management of patients with sexual dysfunction associated with antidepressant treatment, including waiting for the problem to resolve, behavioural strategies to modify sexual technique, individual and couple psychotherapy, delaying the intake of antidepressants until after sexual activity, reduction in daily dosage, 'drug holidays', use of adjuvant treatments, and switching to a different antidepressant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15335301&dopt=Abstract antidepressant




Prediction of antidepressant response to milnacipran by norepinephrine transporter gene polymorphisms.

Yoshida K, Takahashi H, Higuchi H, Kamata M, Ito K, Sato K, Naito S, Shimizu T, Itoh K, Inoue K, Suzuki T, Nemeroff CB.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, USA. cxw01076 nifty.com

OBJECTIVE: With a multitude of antidepressants available, predictors of response to different classes of antidepressants are of considerable interest. The purpose of the present study was to determine whether norepinephrine transporter gene (NET) and serotonin transporter gene (5-HTT) polymorphisms are associated with the antidepressant response to milnacipran, a dual serotonin/norepinephrine reuptake inhibitor. METHOD: Ninety-six Japanese patients with major depressive disorder were treated with milnacipran, 50-100 mg/day, for 6 weeks. Severity of depression was assessed with the Montgomery-Asberg Depression Rating Scale. Assessments were carried out at baseline and at 1, 2, 4, and 6 weeks of treatment. The method of polymerase chain reaction was used to determine allelic variants. RESULTS: Eighty patients completed the study. The presence of the T allele of the NET T-182C polymorphism was associated with a superior antidepressant response, whereas the A/A genotype of the NET G1287A polymorphism was associated with a slower onset of therapeutic response. In contrast, no influence of 5-HTT polymorphisms on the antidepressant response to milnacipran was detected. CONCLUSIONS: The results suggest that NET but not 5-HTT polymorphisms in part determine the antidepressant response to milnacipran.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15337646&dopt=Abstract antidepressant




Effects of acute treatment with antidepressant drugs on sensorimotor gating deficits in rats.

Pouzet B, Andersen MP, Hogg S.

Department of Psychopharmacology, H. Lundbeck A/S, Ottiliavej 7, 2500, Valby, Denmark. brp lundbeck.com

RATIONALE: Schizophrenic patients have a deficit in prepulse inhibition (PPI) which can be modelled in rats by administration of direct or indirect dopamine (DA) receptor agonists and N-methyl-D-aspartate (NMDA) receptor antagonists. Moreover, antipsychotics reverse the disruptive effect of DA agonists and NMDA receptor antagonists in this rat model. Consequently, this model is considered as predictive of antipsychotic action in the clinic. However, the effect of compounds, such as antidepressants, used for other psychiatric disorders but also administered to patients with schizophrenia has not been well investigated in this model. Antidepressants have been suggested not to affect PPI in humans. Thus, antidepressants are not expected to antagonise PPI disruption in rats, and should normally be used as negative controls in this model. OBJECTIVES: To investigate the effects of three antidepressant compounds, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, and a noradrenaline reuptake inhibitor in the rat PPI model. METHODS: The effect of acute treatment with citalopram, bupropion and desipramine on d-amphetamine-disrupted and phencyclidine (PCP)-disrupted PPI in rats was investigated. Ziprasidone was tested as a positive control. RESULTS: None of the antidepressants, in contrast to ziprasidone, reversed PCP-disrupted PPI in rats. Both desipramine and ziprasidone normalised d-amphetamine-disrupted PPI, while citalopram and bupropion were inactive. CONCLUSIONS: PCP-disrupted PPI in rats was less sensitive to false positives than the d-amphetamine-disrupted PPI model, based on the antidepressants tested in this study.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15338101&dopt=Abstract antidepressant