Placental passage of antidepressant medications

OBJECTIVE: This study determined the placental transfer of antidepressants and their metabolites. METHOD: A total of 38 pregnant women taking citalopram, fluoxetine, paroxetine, or sertraline participated. Maternal and umbilical cord blood samples were obtained to determine antidepressant and metabolite concentrations. RESULTS: Antidepressant and metabolite concentrations were detectable in 86.8% of umbilical cord samples. The mean ratios of umbilical cord to maternal serum concentrations ranged from 0.29 to 0.89. The lowest ratios were for sertraline and paroxetine; the highest were for citalopram and fluoxetine. Maternal doses of sertraline and fluoxetine correlated with umbilical cord concentrations of these medications. CONCLUSIONS: Umbilical cord concentrations of antidepressants and their metabolites were almost invariably lower than corresponding maternal concentrations. Maternal doses predicted umbilical concentrations of fluoxetine and sertraline. Mean umbilical cord to maternal serum ratios were significantly lower for sertraline than fluoxetine, suggesting that sertraline may produce less fetal medication exposure than fluoxetine near delivery.     

Lack of adverse pharmacodynamic drug interactions with rivastigmine and twenty-two classes of medications

Alzheimer's disease (AD) is often associated with multiple comorbidities and subsequent polypharmacy. Treatment of AD with acetylcholinesterase (AChE) inhibitors can carry a risk of drug interaction with multiple medications often prescribed for other co-existing illnesses. Rivastigmine is an AChE inhibitor that is enzymatically cleaved by AChE, minimally metabolized by cytochrome P450 enzymes, has low protein binding, has a short plasma half-life, and a relatively short duration of action. Such properties make it ideal for use in this patient population. A pharmacodynamic analysis of rivastigmine administered concomitantly with other medications (22 different therapeutic classes) did not reveal any significant pattern of increase in adverse events that would indicate a drug interaction. In summary, rivastigmine was well tolerated and safely administered to a population receiving multiple medications for 'real-world' comorbidities.     

Mechanism of action of antidepressant medications

The psychopharmacology of depression is a field that has evolved rapidly in just under 5 decades. Early antidepressant medications--tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)--were discovered through astute clinical observations. These first-generation medications were effective because they enhanced serotonergic or noradrenergic mechanisms or both. Unfortunately, the TCAs also blocked histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this action brought about unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness. MAOIs can interact with tyramine to cause potentially lethal hypertension and present potentially dangerous interactions with a number of medications and over-the-counter drugs. The newest generation of antidepressants, including the single-receptor selective serotonin reuptake inhibitors (SSRIs) and multiple-receptor antidepressants venlafaxine, mirtazapine, bupropion, trazodone, and nefazodone, target one or more specific brain receptor sites without, in most cases, activating unwanted sites such as histamine and acetylcholine. This paper discusses the new antidepressants, particularly with regard to mechanism of action, and looks at future developments in the treatment of depression.     

Adherence to antidepressant medications in black and Latino elderly patients.

OBJECTIVE: The purpose of this pilot study was to identify ethnic group differences in nonadherence and to determine predictors of nonadherence to antidepressant medications in older minority-group members. METHODS: Participants were 49 black and 52 Latino subjects over the age of 55 who had been prescribed antidepressant medications within the past 12 months. RESULTS: We found a distinction between intentional nonadherence (e.g., alteration of medication regimen to fit one's needs) and unintentional nonadherence (e.g., forgetfulness/difficulties keeping track of medication regimen). Results suggested that older Latino subjects reported significantly more unintentional nonadherence than older black subjects. However, once other predictors were entered into the model, ethnicity did not remain a significant predictor. No ethnic group differences in intentional nonadherence were suggested. After controlling for ethnicity and medication type, intentional nonadherence was associated with concerns about the side effects of antidepressant medications, the stigma associated with antidepressant medications, and the attribution of lesser importance to antidepressant medications than other medications. Unintentional nonadherence was associated with greater cognitive impairment. CONCLUSIONS: Results suggest that the two ethnic minority groups face similar barriers to adherence to antidepressant medications. Interventions to increase adherence should target the specific type of nonadherence presented by the elderly patients. Some may benefit from memory aids and the assistance of family and friends, others from specific educational interventions about the nature of depression and antidepressant medications.     

Measurement of levetiracetam drug levels to assist with seizure control and monitoring of drug interactions with other anti-epileptic medications (AEMs)

PurposeLevetiracetam (LEV) therapeutic range (20–40 mg/L) and potential drug interactions were assessed in people with epilepsy (PWE).MethodFifty-two PWE had LEV and concomitant medications [carbamazepine (CBZ); valproate (VPA); lamotrigine (LTG)] blood levels measured and compared to seizure activity. Lacosamide (LCM) levels were unavailable. Adopted therapeutic ranges were: 20–40 mg/L – LEV; 25–50 μmol/L – total CBZ; 6–13 μmol/L – free CBZ; 300–750 μmol/L – total VPA; 30–75 μmol/L – free VPA; and 40–60 μmol/L – LTG. Seizure-freedom was assessed and patients followed for almost two years.Results23 of 52 PWE (44%) used LEV monotherapy and 16/23 (70%) had ‘therapeutic’ LEV with 13/16 (81%) seizure-free. 29 of 52 (56%) used polytherapy and 16/29 (55%) had ‘therapeutic’ LEV with 7/16 (44%) seizure-free. 11 of 29 (38%) used CBZ: 4/11 (36%) had therapeutic mean LEV levels and 7/11 (64%) were seizure-free. Fourteen (48%) used VPA: 9/14 (64%) had therapeutic mean LEV levels and 8/14 (57%) were seizure-free. 13 of 29 (45%) used LTG: 8/13 (62%) had therapeutic mean LEV levels and 5/13 (38%) were seizure-free. LEV did not alter CBZ, but CBZ affected LEV. LEV elevated VPA free levels but not VPA total levels. Dosage/concentration was lowered with polytherapy.ConclusionLEV range (20–40 mg/L) assisted epilepsy management and anti-epileptic medication interactions were suggested with polytherapy thus possibly explaining the impaired efficacy of LEV with polytherapy.     

Major depressive disorder and panic disorder. Effects of comorbidity on treatment outcome with antidepressant medications

Recent studies suggest that major depressive disorder (MDD) and panic disorder (PD) may coexist in a significant number of patients. The relevance of this association may be such that patients with the simultaneous diagnosis are at risk for more severe psychopathology and poorer treatment outcome. To explore this possibility further, we compared treatment outcome of two groups of patients: one with comorbidity of MDD and PD (N = 19) and another with MDD only (N = 22). Patients with comorbidity of MDD and PD scored significantly worse on a number of outcome assessments.     

Changing time perception with antidepressant drug therapy

A pilot study on the time sense of ten depressed patients was performed before and during, as well as after, antidepressant therapy with tricyclic compounds. Short time spans were measured by two methods, giving then two different tasks. Measurements were performed in the morning as well as evening hours, in order to take into account diuranl variations. Accuracy of time estimation was considerably deviant. All except one patient overestimated time. With improvement, time sense also improved. Errors were still greater in the morning. The value of the results are discussed.     

Falling spells associated with antidepressant drug treatment

Summary Six patients experienced falling spells concurrent with the intake of antidepressant drugs in high doses or in moderate doses combined with other psychotropic drugs. The close temporal correlation between drug ingestion and the falling spells and their immediate termination after reduction or discontinuation of medication suggests that these drugs caused the falls. Further factors predisposing to the falling spells remain to be defined.     

Psychoactive drug interactions.

Interactions can arise from serial or simultaneous administration of 2 or more drugs. Interactions with other medications can enhance or diminish either the clinical usefulness of a drug, or its toxic effects. Interactions can arise from changes in absorption, protein binding, metabolism, excretion or activity at a common site of action. Drug interactions of clinical interest to psychiatrists are described. The drugs include: stimulants, neuroleptics, tricyclic antidepressants, monoamine oxidase inhibitors, lithium, anticonvulsants, and sedatives and hypnotics.     

Depression symptomatology as a non-requisite for successful treatment of panic with antidepressant medications

Studies were reviewed to address the question of whether antidepressant medications were effective in the treatment of panic attacks, and whether this effect was primary or secondary to their effect on depression. Evidence was gathered from studies examining comorbidity of panic and depression, level of depression in panic-disordered patients responsive to antidepressant drugs, and the correlation of initial level of depression to change in panic in patients treated with antidepressants. These lines of evidence converge to demonstrate that there is no support for a link between depressive symptomatology and change in panic symptoms as a consequence of treatment with antidepressant medications.     

Redesigning antidepressant drug discovery

Antidepressant drug discovery and development have been put on hold by many pharmaceutical companies. The main reason for this is the negative efficacy studies with novel specific drugs. Here I argue that the main obstacles are the absence of gene tests and biomarkers as an integral part of a diagnostic process. Further, too much emphasis has been put on validating drug candidates in animal models of psychiatric disorders. A more rapid transfer of drug candidates into human research is necessary to overcome current obstacles that prevent the discovery of next-generation antidepressants.     

Recent developments in the use of antidepressant and anxiolytic medications

In this article the authors review recent research contributions to the knowledge regarding the role of antidepressant and anxiolytic medications in the treatment of child psychiatry disorders. For each of the two classes of drug, recent data regarding a range of indications are evaluated. In addition, general methodologic issues and future research priorities are discussed.     

Nocebo effects with antidepressant clinical drug trial placebos

We describe an individual who experienced unusual negative effects while taking a placebo during a clinical drug trial. A 26-year-old male took 29 inert capsules, believing he was overdosing on an antidepressant. Subsequently, he experienced hypotension requiring intravenous fluids to maintain an adequate blood pressure until the true nature of the capsules was revealed. The adverse symptoms then rapidly abated. The nocebo effect (undesirable symptoms following administration of an inert substance that the patient believes to be an active drug) may have significant negative impacts on certain patients. Further research is warranted to better understand this phenomenon.     

Weight gain in breastfed infants of mothers taking antidepressant medications

BACKGROUND: Little is known about the physical development of infants who are exposed to antidepressant medications through breast milk. METHOD: Seventy-eight breastfeeding women taking antidepressant medications were included in the study. Maternal mood was prospectively evaluated at 6, 12, and 18 months postpartum. Infants' weights were obtained from review of pediatric records. Data were gathered from 1997 to 2002. RESULTS: Infants' weights were not significantly different from weights of 6-month-old breastfed infants from normative populations. However, infants of mothers who relapsed to relatively long-lasting major depressive episodes (lasting 2 months or more) following delivery weighed significantly (p =.002) less when compared with infants of mothers who relapsed to brief depressive episodes (< 2 months) and infants of mothers who did not relapse to depression in the postpartum period. This finding remained after including medication dosage and infant birth weight as covariates. CONCLUSION: Exposure to antidepressant medications through breast milk does not appear to affect infants' weight. However, infants exposed to maternal depression lasting 2 months or more appear to experience significantly lower weight gain than infants of euthymic mothers or mothers who experience brief (< 2 months) major depressive episodes. Maternal depression following delivery may influence behaviors that, over the course of 2 months or more, affect infants' weight gain.     

Transient mood elevation associated with antidepressant drug decrease

The development of hypomania, mania and transient mood elevation within 2-3 days of antidepressant discontinuation, and lasting days to several weeks has been reported in unipolar depressed patients. Imipramine and desipramine are the antidepressants most frequently associated with the above phenomena. A reported case of transient mood elevation following abrupt reduction but not discontinuation of desipramine therapy in a woman with unipolar depression is described. The phenomenon was observed and documented on two separate occasions. Mood elevation occurred despite decreased plasma levels of the drug. Relapse followed despite maintenance of dose and similar drug plasma levels. Factors which could account for the transitory improvement of mood are examined. It is suggested that the patient's improvement in mood may have occurred due to a rebound paradoxical therapeutic effect. The features of the presented case history which appear to support this hypothesis are discussed. Also the clinical implications of this phenomenon are reviewed.     

Placebo-controlled antidepressant drug trials. Considering the ethical implications

For the approval of a new antidepressant for clinical use drug authorities still demand the proof of a significantly superior efficacy of the compound over placebo shown in controlled comparison studies. On the other side serious ethical concerns have been raised upon the use of placebos in clinical trials with depressed patients in that this would implicitly mean a withholding of an efficacious treatment from patients in the control groups of such trials. This article summarises frequently quoted arguments for and against placebo use in antidepressant clinical trials focussing on the specific issues involved in the therapeutic effect of antidepressants and placebos in depressed patients and discusses measures that might contribute to study designs that may better evaluate the true efficacy of a new drug while keeping the risk for the individual patient at the lowest possible level. A worldwide solution of the problem is clearly called for. A ban of placebos in antidepressant trials as it might be derived from the Declaration of Helsinki should be postponed until antidepressants with a more convincing superiority over placebo have been developed.