Pharmacokinetics of second generation antidepressants

This paper presents the pharmacokinetic properties of newer second generation antidepressants, with an emphasis on the main metabolic pathways of drugs and metabolites as well as their effects on the cytochrome P450 enzymes. Except for Milnacipran all newer antidepressants are biotransformed in the presence of at least one cytochrome P450 izoenzyme. Drugs and their metabolites may be the substrates or inhibitors of cytochromes P450. The knowledge of drugs' metabolic pathways as well as the knowledge of substrates and inhibitors of izoenzymes assists in choice of a proper drug and its dose. It is particularly important in case of polypharmacotherapy when there is a high risk of adverse events. It is also important to remember about genetic polymorphism of some cytochrome P450 izoenzymes (CYP2D6, CYP2C19) that underlies the marked inpatient variability in drug metabolism.     

Selectivity of antidepressants: from the monoamine hypothesis of depression to the SSRI revolution and beyond

In 2003, available pharmacotherapy for mood disorders was based almost entirely on observations from the 1950s and 1960s that agents that enhance monoamine transmitter function are effective antidepressants. Preclinical studies show that chronic administration of all effective antidepressants increases the efficiency of post-synaptic 5-HT transmission. Many antidepressants also modify nor-adrenergic function in the central nervous system. For the majority of antidepressants, these long-term changes in serotonergic and/or noradrenergic function result from direct antagonism of serotonin and/ or norepinephrine transporters (also termed "uptake sites"). Pharmacotherapy that is highly selective for one transporter over another has been demonstrated to be effective and tolerable, whereas agents that act on multiple transporters may not necessarily achieve better efficacy and may be associated with additional adverse events. Nevertheless, the rationale is in place to suggest that antidepressants that block both the serotonin and norepinephrine transporters might provide better efficacy, which can only be determined by empirical testing.     

A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia

Selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRI; SNRI) are the first choice pharmacological treatment options for major depression. It has long been assumed that the primary therapeutic mechanism of action of these drugs involves the modulation of monoaminergic systems. However, contemporary investigations have revealed that depression is linked with inflammation, and that SSRI/SNRIs possess significant anti-inflammatory actions. While these anti-inflammatory properties initially only related to work undertaken on cells of the peripheral immune system, it has recently become apparent that these drugs also exert anti-inflammatory effects on microglia, the principal cells within the CNS that regulate and respond to inflammatory factors. The aim of the current study was to compare SSRI/SNRIs in terms of their anti-inflammatory potency, and to determine the specific mechanisms through which these effects are mediated. Accordingly, the current study evaluated the ability of five different SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram) and one SNRI (venlafaxine) to suppress microglial responses to an inflammatory stimulus. Specifically, we examined their ability to alter tumour necrosis factor-α (TNF-α) and nitric oxide (NO) production after 4 and 24 h stimulation with lipopolysaccharide. Our results indicated that the SSRIs potently inhibited microglial TNF-α and NO production. We then investigated whether these effects might involve either β-adrenoceptor or cAMP signalling. Using the protein kinase A inhibitor Rp-CAMPs, we found evidence to suggest that cAMP signalling is involved in regulating the anti-inflammatory response. These findings suggest that antidepressants may owe at least some of their therapeutic effectiveness to their anti-inflammatory properties.     

Current status of antidepressants: clinical pharmacology and therapy

Effective antidepressants, including imipramine and monoamine oxidase (MAO) inhibitors, were discovered serendipitously in the 1950s. Many additional agents have been introduced since then, but most are chemically or pharmacologically similar to those known for nearly four decades. Some recently introduced antidepressants offer either lesser or dissimilar side effects, but none exceeds older treatments in efficacy. Selective serotoninpotentiating agents and short-acting MAO-A inhibitors promise efficacy with greater safety. Progress is made difficult because atypical or treatment-resistant patients are more often available for study than typical patients, and because most studies must rely heavily on potentially misleading "standard drug versus new drug" comparisons. Rational development of novel or better agents is slow, in part, due to limited understanding of the biological basis of major affective disorders and some circularity in relating actions of known drugs to pathophysiologic hypotheses. Action mechanisms of antidepressants are subtle and complex: adaptive changes occur in brain monoaminergic neurotransmission following repeated administration of agents of the tricyclic antidepressant (TCA) type that may lead to net facilitation of alpha 1-adrenergic transmission. Important advances have been made in using plasma TCA levels to guide individualization of dosing, in exploring higher doses of antidepressants when ordinary doses prove ineffective, and in recognizing a broadening spectrum of possible indications for antidepressants in adults and children. These indications include panic disorder, obsessive compulsive disorder, attention deficit disorder, and bulimia. Evidence for the prophylactic effects of antidepressants after the first months following recovery from an index episode of major depression is weak, and the treatment of common recurrent or chronic depression remains unsatisfactory. Gains have been made in increasing clinicians' and the general public's awareness of the common occurrence and appropriate treatment of major depression, even when the depression is associated with other medical or psychiatric disorders.     

Validity of clinical trials of antidepressants

OBJECTIVE: Recent reports have criticized the design of antidepressant studies and have questioned their validity. These critics have concluded that antidepressants are no better than placebo treatment and that their illusory superiority depends on methodologically flawed studies and biased clinical evaluations. It has been suggested that the blind in randomized trials is penetrable-since clinician's guesses exceed chance-and that only active placebo can appropriately camouflage the difference between drug and placebo response. Furthermore, evidence has been cited to suggest that psychotherapy is as effective as antidepressants in both the acute and maintenance treatment of depression. These positions are often accepted as valid and have been broadly discussed in both the lay press and scientific literature. The purpose of this review is to reassess the cited data that support these assertions. METHOD: The authors examined the specific studies that were cited in these reports, evaluated their methodology, and conducted aggregate analyses. RESULTS: Analyses of the original sources failed to substantiate 1) that standard antidepressants are no more effective than placebo, 2) that active placebo offers an advantage over inactive placebo, or 3) that substantial evidence of a medication bias is suggested by raters' treatment guesses exceeding chance. The authors also note that some researchers have suggested that the interpretation of psychotherapy trials can be complicated by "allegiance effects." CONCLUSIONS: The issue of bias or allegiance effects for both antidepressant and psychotherapy research is real. Investigators of all orientations must guard against potential bias. However, studies cited as supporting the questionable validity of antidepressant trials fail upon closer examination to support assertions that these trials are invalid.     

How antidepressants help depression: mechanisms of action and clinical response

The monoamine hypothesis of depression suggests that depressive symptoms can be moderated by enhancing monoamine neurotransmission. Targeted neurotransmitters include serotonin and norepinephrine, and a number of medications are available that can selectively enhance the actions of one or both of these substances. Although laboratory tests have validated the pharmacologic effects of these compounds, much less is known about how these effects translate into clinical response. Therapeutic research and experience show clearly that the medications help patients, although the individual and potential cooperative or complementary effects of stimulating each neurotransmitter system remain unclear. Depletion studies have reinforced the validity of targeting these systems and, at the same time, underscored that monoamines most likely are not the only factor driving the clinical presentation of depression.     

Course of clinical response to antidepressants

1. The postulated pharmacological mechanisms of antidepressant effect are reviewed.

2. The clinical profile of response to antidepressants are linked to the pharmacological mechanisms.

3. The limitations of presently available instruments for diagnosis and measurement of change in depression are discussed.     

Assessment of adverse drug reactions in psychiatric inpatients with the AMSP drug safety program: methods and first results for tricyclic antidepressants and SSRI

The AMSP (Arzneimittelsicherheit in der Psychiatrie) study is a new program for continuous assessment of adverse drug reactions (ADR) in psychiatric inpatients under naturalistic conditions of routine clinical treatment. It is based on the preceding drug surveillance study AMUP (Arzneimittelüberwachung in der Psychiatrie). Currently, 29 hospitals are participating in the study. This paper reports on the methods of the AMSP study and the first findings on the comparative risks of tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors (SSRI) . Data assessment is restricted to "severe" ADR as defined in the study protocol. Drug use is estimated from reference day data. From 1993 to 1997, 896 cases of severe ADR were observed in 48,564 patients (1.84%). SSRI and the new substances mirtazapine and venlafaxine were increasingly used as antidepressants (AD), but TCA were still the most common AD in 1997 (52.1% of all AD patients). Similar rates of ADR were observed for SSRI and TCA (1.7% and 1.5%, respectively, for all cases, 0.9% and 1.0%, respectively, only for cases rated as probable). However, different types of ADR occurred with the two AD subgroups; whereas toxic delirium and increased liver enzymes were the most frequent ADR related toTCA, nondelirious psychic and neurologic ADR predominated with SSRI. The duration of inpatient treatment was considerably longer in patients who experienced an ADR due to TCA or SSRI than in those who did not. The AMSP study promises to contribute greatly to drug safety by providing the relative frequencies of severe ADR from a large-scale database and by improving our knowledge of ADR.     

Methodologic problems of clinical investigations of antidepressants

This paper discusses actual, often controversial, problems related to clinical investigations of antidepressants. Such problems include: inclusion and exclusion criteria (the investigated groups of patients are not representative for the population of depressed patients treated by psychiatrists), criteria of results' evaluation (50% reduction of pre-treatment number of points in the scale for measuring of depression severity is not satisfactory from a clinical point of view, this criterion could be replaced by remission), duration of treatment (4-6 weeks observation period is too short for adequate evaluation of treatment effects). The problem of using placebo is controversial from an ethical and legal point of view. This procedure could be replaced by other acceptable methodology.     

Changes in prefrontal activity characterize clinical response in SSRI nonresponders: a pilot study

Previous studies in unipolar depression have shown that early decreases in prefrontal values of the QEEG cordance measure identified responders to pharmacotherapy. These studies have all examined individuals who were drug-free prior to the first physiologic assessment, yet in the clinical management of treatment resistant depression (TRD), many patients undergo changes in treatment without a drug-free interval between treatments. Here, we investigated whether cordance decreases were associated with response in Stage I TRD subjects without wash-out between treatment trials. Awake EEGs were recorded from 12 adults with unipolar depression. Subjects were receiving naturalistic treatment, had failed SSRI monotherapy, and were starting a new treatment prescribed by their treating psychiatrists. EEG data were recorded before starting the new treatment and after approximately 1 week. Six of the 12 subjects responded to treatment after 8--10 weeks. Five of the six responders showed an early cordance decreases, compared with two of the six nonresponders (accurate characterization in 75% of the cases). Consistent with previous treatment trials, decreases in prefrontal cordance differentiated responders from nonresponders in this setting as well. These findings suggest that cordance biomarkers may be a useful tool in effectiveness trials that parallel clinical practices in SSRI nonresponders, and may not require a wash-out period between treatments.     

Monoamine oxidase-inhibiting antidepressants. A clinical update

This article outlines the latest information on the clinical efficacy of MAOIs and provides the physician with guidelines for their safe use. The important side effects of this class of drugs are also summarized along with an up-to-date account of their possible molecular mechanism of action.     

SSRI Antidepressant Medications: Adverse Effects and Tolerability

Side effects of antidepressants can be predicted by receptor selectivity and site of action. Although the selective serotonin reuptake inhibitors (SSRIs) have better overall safety and tolerability than older antidepressants, broad-based experience with SSRIs has shown the frequency and type of side effects to be increased relative to clinical trial data. The author explores the reasons for the different profiles and discusses adverse effects, especially sexual dysfunction, weight gain, and sleep disturbance, the most troubling adverse events seen during long-term SSRI therapy. The informed management of these side effects by primary care practitioners supports successful treatment of depression.     

抗抑郁药物用于双相抑郁的治疗：一个有争议的临床问题

双相障碍是一种慢性致残性疾病。以往治疗的重点在于控制躁狂或轻躁狂症状,然而由于双相障碍患者处于抑郁状态的时间远多于躁狂或轻躁狂状态,近期更多关注的是双相抑郁状态。很多双相障碍患者持续存在阈下抑郁症状。然而,有关双相抑郁药物治疗的循证依据十分有限。     

Diurnal lamotrigine plasma level fluctuations: clinical significance and indication of shorter half-life with chronic administration

For therapeutic monitoring of antiepileptic drugs (AEDs), morning trough levels (MTLs) are generally used. For specific questions like verification of breakthrough seizures or reported toxicity, however, other measures such as minimal and maximal concentrations (C(min), C(max)) can be important and may require daily profiles. For clinical reasons, 20 daily profiles of lamotrigine (LTG) plasma levels were determined in nine patients. The results revealed fluctuations exceeding those expected from its elimination half-life (t(1/2)) of 22h as reported in the literature. Patients on twice-daily regimens without pharmacokinetic interactions exhibited C(min)/C(max) ratios between 0.62 and 0.69. Fluctuations were smaller in those co-medicated with valproate, and reached a ratio of 0.55 in those co-medicated with phenobarbital. The C(max) was as much as 58% above the MTL. Therefore, verification of complaints indicating toxicity requires determination of drug levels when the symptoms are present. Our findings indicate that the t(1/2) of LTG with chronic treatment is shorter than generally assumed, and suggest that a slow-release formulation could be helpful in achieving full seizure control in patients with a narrow individual therapeutic index for LTG.