Second generation antidepressants: a comparative review

The authors review four "second generation" antidepressants (maprotiline, amoxapine, trazodone, and nomifensine) in terms of action on biogenic amines and receptors, antidepressive efficacy, and adverse effects. Doxepin is used as a comparative agent and is similar to the prototypical tricyclic agents in all the above categories. Maprotiline is a selective noradrenergic agent, but shares a similar adverse effect profile with doxepin and may be associated with a high frequency of seizures in overdose. Amoxapine is a mixed action antidepressant with significant neuroleptic activity in vivo. Its adverse effect profile is highlighted by symptoms related to its neuroleptic activity, and seizures and acute renal failure in overdose. Trazodone is a selective serotonergic agent with low anticholinergic activity, and minimal morbidity/mortality in overdose. Reports of priapism, leading to impotence in some men, however, is of concern. Nomifensine is a potent noradrenergic and dopaminergic agent with low anticholinergic activity, and minimum cardiotoxicity and low morbidity/mortality in overdose. Its most important adverse effects include overstimulation and infrequent, usually reversible, immunologic hypersensitivity reactions. Trazodone and nomifensine have favorable profiles for use in the elderly. Trazodone may be more favorable in the anxious/agitated patient due to its sedative effects, whereas nomifensine may be more beneficial in the retarded, apathetic patient.     

抗抑郁药物治疗的起效与疗效评价

本文综述抗抑郁药物治疗过程中有关疗效评估的指标和标准,以及早期起效的临床意义,强调临床治愈是抗抑郁治疗的关键,同时从循证医学的角度评估不同抗抑郁药物治疗急性期抑郁症的疗效,并探讨难治性抑郁症的治疗策略及疗效。     

Effects of antidepressants on human performance: a review

Despite widespread use of antidepressants, major gaps remain in our knowledge of the effects of antidepressants on human performance. While most single-dose studies with normal subjects have suggested that the more sedating tricyclic antidepressants tend to produce impairment, the effects of antidepressant treatment in clinical populations have been less thoroughly examined, with both drug-induced impairment and improvement reported. This review suggests that factors such as age, diagnosis, drug plasma concentration, and length of treatment need to be explored to establish the effects of antidepressants on performance in clinical populations.     

Effects of analgesics and antidepressants on TREK-2 and TRESK currents

TWIK-related K⁺ channel-2 (TREK-2) and TWIK-related spinal cord K⁺ (TRESK) channel are members of two-pore domain K⁺ channel family. They are well expressed and help to set the resting membrane potential in sensory neurons. Modulation of TREK-2 and TRESK channels are involved in the pathogenesis of pain, and specifi c activators of TREK-2 and TRESK may be benefi cial for the treatment of pain symptoms. However, the effect of commonly used analgesics on TREK-2 and TRESK channels are not known. Here, we investigated the effect of analgesics on TREK-2 and TRESK channels. The effects of analgesics were examined in HEK cells transfected with TREK-2 or TRESK. Amitriptyline, citalopram, escitalopram, and fluoxetine significantly inhibited TREK-2 and TRESK currents in HEK cells (p<0.05, n=10). Acetaminophen, ibuprofen, nabumetone, and bupropion inhibited TRESK, but had no effect on TREK-2. These results show that all analgesics tested in this study inhibit TRESK activity. Further study is needed to identify the mechanisms by which the analgesics modulate TREK-2 and TRESK differently.     

Effects of obstetric analgesics and anesthetics on the neonate : a review

Most anesthetic and analgesic agents in current use traverse the placental barrier in varying degrees, but are well tolerated by the fetus if judiciously administered. For labor analgesia, many options are available. Systemic administration of opioids and sedatives is one such option. Repeated maternal administration of opioids such as pethidine (meperidine) results in significant fetal exposure and neonatal respiratory depression. Patient-controlled analgesia with synthetic opioids such as fentanyl, alfentanil, and the new ultra-short-acting remifentanil may be used for labor analgesia in selected patients. Other options for labor analgesia include epidural and combined spinal-epidural techniques. With such techniques, neonatal exposure to opioids and sedatives can be minimized or totally avoided. While limiting the fetal exposure to the harmful effects of depressant drugs, epidural anesthesia and/or analgesia improves placental perfusion and oxygenation of the fetus, which is beneficial, especially in conditions such as pregnancy-induced hypertension. Regional blocks are also administered for the majority of cesarean deliveries because of the overwhelming and unequivocal evidence of maternal and fetal safety compared with general anesthesia for this indication. However, in some instances, administration of general anesthesia is unavoidable. Neonatal respiratory depression with low Apgar scores, and umbilical arterial and venous pH associated with general anesthesia, is often transient. A properly administered anesthetic, whether regional or general, has no significant adverse fetal or neonatal effects.     

Antidepressants as analgesics

Depression is a common accompaniment of pain, particularly when pain is unremitting. The use of a variety of antidepressant medications is associated with pain reduction, an effect that is independent of the mood-enhancing qualities of these drugs. This pain relief is a consequence of a wide variety of actions of antidepressants on the neuroregulatory mechanisms associated with pain perception and transmission.The older tricyclic antidepressants (TCAs) and the newer 'balanced' reuptake inhibitors (such as duloxetine) seem to be more efficacious in terms of providing pain relief than the selective serotonin reuptake inhibitors (SSRIs). Unfortunately, adverse effects are not uncommon during antidepressant use, particularly with TCAs. It is now becoming apparent that TCAs can have an analgesic effect when applied topically and that this effect is produced by peripheral mechanisms rather than systemic uptake.Antidepressants remain a major therapeutic tool in the management of chronic pain.     

Efficacy of venlafaxine compared with tricyclic antidepressants in depressive disorder: a meta-analysis

With respect to the pharmacological characteristic, venlafaxine is comparable with tricyclic antidepressants (TCAs), and venlafaxine might be comparable in efficacy. We performed a systematic review investigating the relative efficacy and tolerability of venlafaxine compared with TCAs (imipramine, clomipramine, amitriptyline, nortriptyline and desipramine). Relevant double-blind randomised trials were identified from systematic searches of electronic databases. An exact analysis of the estimated odds ratios of response of the TCA relative to venlafaxine showed no overall significance of treatment effect (P = 0.38). The odds ratios were not homogenous across studies (P = 0.0213). The average dose of venlafaxine was 103.5 mg/day and for the TCA 106.1 mg/day. An exact analysis of the estimated odds ratios of the withdrawals and side effects in the trials with a TCA relative to venlafaxine showed no overall significance of withdrawal. From our review, no significant difference in treatment effect between low dose of both venlafaxine and the TCAs could be found. In our opinion, because of the heterogeneity of the odds ratios, one cannot conclude that they are of equal efficacy.     

The prescription of antidepressants in general practice: I a critical review

This review critically examines the literature which is available on the way in which general practitioners use antidepressants, the kind of depressed patients who they choose to treat, and the trials of antidepressants which have specifically been carried out in general practice. General practitioners tend to use a ‘low-dose strategy’ of prescribing tricylics (75 mgs or less per day), which are the most commonly used antidepressants. While this is a subtherapeutic dose in psychiatric hospital patients there is evidence that GP's patients are less serverely depressed, and the low-dose strategy might be effective in such cases. A review of trials in general practice revealed only one study capable of addressing this question, which suggested a lack of efficacy of the low-dose strategy.     

Efficacy and tolerability of milnacipran in the treatment of major depression in comparison with other antidepressants : a systematic review and meta-analysis

BACKGROUND: Milnacipran, a dual serotonin-noradrenaline reuptake inhibitor, is one of the newer antidepressants that clinicians use for the routine care of patients with major depression. We undertook a systematic review and meta-analysis of randomized controlled trials that compared the efficacy and tolerability of milnacipran with other antidepressants. OBJECTIVE: To assess the efficacy and tolerability of milnacipran in comparison with TCAs, SSRIs and other drugs in the acute phase of treatment for major depression. METHODS: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials registers, journals, conference proceedings, trial databases of the drug-approving agencies and ongoing clinical trial registers for all published and unpublished randomized controlled trials that compared the efficacy and adverse events of milnacipran versus any other antidepressant. The search was conducted in December 2006 and updated in May 2007. No language restrictions were applied. All relevant authors were contacted to supplement any incomplete reporting in the original papers. Randomized controlled trials comparing milnacipran with any other active antidepressants as monotherapy in the acute phase of treatment for major depression were selected. Participants were aged > or =18 years, of both sexes and with a primary diagnosis of unipolar major depression. Studies were excluded when the participants had specific psychiatric and medical co-morbidities.Two independent reviewers assessed the quality of trials for inclusion, and subsequently extracted data. Disagreements were resolved by consensus. Meta-analyses were conducted for efficacy and tolerability outcomes. Sixteen randomized controlled trials (n = 2277) were included in the meta-analyses. RESULTS: No differences were found in achieving clinical improvement, remission or overall tolerability when comparing milnacipran with other antidepressants. However, compared with the TCAs, fewer patients taking milnacipran were early treatment withdrawals due to adverse events (number needed to harm (NNH) = 15; 95% CI 10, 48). Significantly more patients taking TCAs experienced adverse events compared with milnacipran (NNH = 4; 95% CI 3, 7). CONCLUSIONS: The overall effectiveness and tolerability of milnacipran versus other antidepressants does not seem to differ in the acute phase of treatment for major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of premature withdrawal due to adverse events and the rates of patients experiencing adverse events. Milnacipran may benefit some patient populations who experience adverse effects from other antidepressants in the acute phase of treatment for major depression.     

Dosage regimen design for cyclic antidepressants: a review of pharmacokinetic methods.

One of the difficulties in pharmacotherapy of depression is the frequent need to make several dosage titrations before reaching the optimal therapeutic dosage. This problem has led to several experimental approaches for predicting a stable antidepressant maintenance dose from plasma concentration data collected shortly following a test dose. The theoretical basis for these methods is reviewed along with the results of clinical trials. It is concluded that accurate steady-state concentrations of cyclic antidepressants can be predicted from kinetic analysis of plasma concentrations obtained early in therapy. The most applicable drug for prospective dosing methods is nortriptyline with its widely accepted therapeutic plasma concentration range. Other drugs that also have substantial evidence for predicting the optimal dose from an early point in therapy include desipramine and imipramine. Predictive dosing methods are easily applied in the inpatient setting. Multiple data points obtained between 12 and 48 hours after the first dose are likely to give accurate predictions and provide clinically useful information. More widespread application of predictive approaches to dosage regimen design of antidepressant pharmacotherapy may lead to reduced hospitalization and cost savings.     

Comparative risk for harms of second-generation antidepressants : a systematic review and meta-analysis

BACKGROUND: Evidence indicates that only minor differences in efficacy exist among second-generation antidepressants for the treatment of major depressive disorder (MDD). However, a comprehensive assessment of both benefits and harms is crucial to evaluate the net benefit. OBJECTIVE: To review systematically the comparative harms of second-generation antidepressants for the treatment of MDD in adults by including both experimental and observational evidence. DATA SOURCES: We searched MEDLINE((R)), EMBASE, PsychLit, The Cochrane Library and the International Pharmaceutical Abstracts from 1980 to April 2007. We manually searched reference lists of pertinent review articles and explored the Center for Drug Evaluation and Research database to identify unpublished research. STUDY SELECTION: Eligible study designs were trials and observational studies comparing one drug of interest with another. DATA EXTRACTION: Two persons independently reviewed abstracts and full-text articles. One investigator extracted relevant data. A senior reviewer checked data for completeness and accuracy. DATA SYNTHESIS: We included 104 experimental and observational studies. If data were sufficient, we conducted meta-analyses of randomized controlled trials on the relative risk of specific adverse events. Findings indicate that the spectrum of adverse events is similar. The frequency of specific adverse events, however, differed across drugs. Venlafaxine was associated with a significantly higher rate of nausea and vomiting than selective serotonin reuptake inhibitors. Compared with other drugs, paroxetine frequently led to more sexual adverse effects and bupropion to fewer such effects; mirtazapine and paroxetine was associated with more weight gain and sertraline with a higher rate of diarrhoea. Overall, however, these differences did not lead to different discontinuation rates. The evidence is insufficient to draw conclusions about rare but severe adverse events. CONCLUSIONS: Adverse event profiles are similar among second-generation antidepressants. However, different frequencies of specific adverse events might be clinically relevant and influence the choice of a treatment.     

Experimental human pain models: a review of standardised methods for preclinical testing of analgesics

Treatment of pain is one of the major challenges in clinical medicine. However, it is often difficult to evaluate the effect of a treatment, as the many symptoms of the underlying diseases often confound this assessment. Furthermore, as the pain mechanisms in many diseases are poorly understood, the limited successful trial and error approach is most often used in the selection of analgesics. Hence, there is a need for new methods in the characterization and treatment of pain. Human experimental pain models offer the possibility to explore the pain system under controlled settings. The models can also be used to screen the analgesic profiles of drugs targeted to treat pain. This review gives a brief introduction to the methods used to evoke and assess pain in the skin, muscle and viscera. New methods using multimodal stimulation and activation of central pain mechanisms can to a higher degree mimic the clinical situation, and such methods are recommended in the future screening of analgesics. Examples of the use of experimental pain models in the testing of analgesics are given. With these models the therapeutic spectrum may be defined from a differentiated knowledge on the effect of drugs on the pain system. Such information may be used in the future guidelines for trials and clinical use of analgesics.