Frontal EEG predictors of treatment outcome in major depressive disorder

ObjectiveTo investigate the role of frontal EEG as predictor of clinical response to SSRIs or venlafaxine in major depressive disorder (MDD).Method82 subjects (age 35.9 ± 13.0; 47.6% female) meeting DSM-IV criteria for MDD entered an 8-week prospective treatment with SSRIs or venlafaxine. At baseline and week 1 we recorded serial, 4-channel EEGs (F7-Fpz, F8-Fpz, A1-Fpz, A2-Fpz). We evaluated prospectively the relative theta power as predictor of treatment outcome. We also developed an Antidepressant Treatment Response (ATR) index using EEG parameters assessed at baseline and week 1.Results45 subjects (54.9%) responded to treatment (HAM-D-17 reduction ≥ 50%). At baseline, frontal relative theta power (i.e., 4–8 Hz power/2–20 Hz power) was significantly (p = 0.017) lower (21%) in treatment responders than in non-responders (24%). Baseline relative theta power predicted treatment response with 63% accuracy [64% sensitivity, 62% specificity, 66% area under the receiver operator curve (AUROC) (p = 0.014)]. Relative theta power at week 1 predicted treatment response with 60% accuracy [62% sensitivity, 57% specificity, 61% AUROC (p = 0.089)]. ATR predicted response with 70% accuracy [82% sensitivity, 54% specificity, 72% AUROC (p = 0.001)].ConclusionUsing automated analysis of frontal EEG collected during the first week of antidepressant treatment it may be possible to facilitate prediction of SSRI or venlafaxine efficacy in MDD.     

The novel nicotinic receptor antagonist, N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked [H]norepinephrine overflow from rat hippocampal slices

Smoking is a significant health concern and strongly correlated with clinical depression. Depression is associated with decreased extracellular NE concentrations in brain. Smokers may be self-medicating and alleviating their depression through nicotine stimulated norepinephrine (NE) release. Several antidepressants inhibit NE transporter (NET) function, thereby augmenting extracellular NE concentrations. Antidepressants, such as bupropion, also inhibit nicotinic receptor (nAChR) function. The current study determined if a recently discovered novel nAChR antagonist, N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked NE release from superfused rat hippocampal slices. Previous studies determined that bPiDDB potently (IC₅₀ = 2 nM) inhibits nicotine-evoked striatal [³H]dopamine (DA) release in vitro, nicotine-evoked DA release in nucleus accumbens in vivo, and nicotine self-administration in rats. In the current study, nicotine stimulated [³H]NE release from rat hippocampal slices (EC₅₀ = 50 μM). bPiDDB inhibited (IC₅₀ = 430 nM; I_max = 90%) [³H]NE release evoked by 30 μM nicotine. For comparison, the nonselective nAChR antagonist, mecamylamine, and the α7 antagonist, methyllycaconitine, also inhibited nicotine-evoked [³H]NE release (IC₅₀ = 31 and 275 nM, respectively; I_max = 91% and 72%, respectively). Inhibition by bPiDDB and mecamylamine was not overcome by increasing nicotine concentrations; Schild regression slope was different from unity, consistent with allosteric inhibition. Thus, bPiDDB was 200-fold more potent inhibiting nAChRs mediating nicotine-evoked [³H]DA release from striatum than those mediating nicotine-evoked [³H]NE release from hippocampus.     

“There are always two sides to these things”: Managing the dilemma of serious adverse effects from SSRIs

Over the past two decades, evidence and regulatory responses have surfaced regarding associations between selective serotonin reuptake inhibitors (SSRIs) and serious adverse effects, especially akathisia, aggression and suicidality. Given increasing concern about depression prevalence and harm, the dominance of biomedical approaches, and the normalisation of antidepressant use, reports about the potential for serious adverse effects from SSRIs present a dilemma for people working in depression intervention: the drugs are linked to “two conflicting claims” that they may either decrease or increase harm. We present data from in-depth semi-structured interviews with nine professionals in New Zealand working in fields relating to depression and supportive of SSRIs, to investigate the negotiation of this dilemma. We analysed participants’ talk about akathisia, aggression and suicidality associated with SSRIs, and found the use of rhetorical strategies that minimised the significance of risks, countered risks with notions of benefit and/or questioned the validity of risks. These discursive resources provided ways of mitigating the dilemma otherwise posed by evidence of adverse drug effects. However in doing so they referenced notions of SSRI benefit that relied upon assumptions about the efficacy of the drugs, risks of untreated depression, and the impact of adverse effects. Overall, our analysis highlights ways in which evidence of serious adverse effects from SSRIs can be rhetorically contained and undermined.     

抗抑郁剂的应用情况调查

目的：了解抗抑郁剂的应用情况。方法：将我院１９９７年６月至１９９９年２月期间应用的抗抑郁剂的患者进行分组，分成三环类抗抑郁剂（ＴＣＡｓ）组，选择性５羟色胺再摄取抑制剂（ＳＳＲＩｓ）组和其它抗抑郁剂组，比较用药频度和脱落率。结果：ＴＣＡｓ的用药频度显著下降，而ＳＳＲＩｓ的用药频度显著上升；目前，ＳＳＲＩｓ的应用率显著高于ＴＣＡｓ；ＴＣＡｓ的脱落率显著高于ＳＳＲＩｓ。结论：ＳＳＲＩｓ和ＴＣＡｓ已共同成     

Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine

The new antidepressant mirtazapine was tested in two experimental procedures which can reveal direct or indirect 5-HT_1A receptor agonistic effects. These procedures were observation for induction of lower lip retraction in rats and comparison of stimulus properties in cross-familiarization experiments with conditioned taste aversion in mice. Mirtazapine induced lower lip retraction in rats, as did the 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). However, the response to mirtazapine at doses up to 22 mg/kg remained below the maximum score obtained with 8-OH-DPAT (0.46 mg/kg). Blockade of the 5-HT_1A receptors with pindolol (10 mg/kg) caused a strong reduction of the lower lip retraction induced both with mirtazapine and 8-OH-DPAT. In the cross-familiarization conditioned taste aversion experiments it was found that the conditioned taste aversion induced by mirtazapine (0.32 mg/kg) could be prevented if the mice were pre-exposed to injections with mirtazapine (0.22 and 0.46 mg/kg), 8-OH-DPAT (0.22 and 0.46 mg/kg) and after pre-exposure to the 5-HT reuptake inhibitor fluoxetine (22 mg/kg). No familiarization for the mirtazapine stimulus was obtained by pre-exposure to (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) (0.46–4.6 mg/kg) and MK212 (2.2–22 mg/kg), being agonists for the 5-HT_2A and 5-HT_2C receptors, respectively. With the reversed sequence, the conditioned taste aversion induced by 8-OH-DPAT (0.22 mg/kg), DOI (1.0 mg/kg) and fluoxetine could be prevented only partially by pre-exposure to mirtazapine in a dose of 1 mg/kg. The conditioned taste aversion induced by MK 212 (4.6 mg/kg) was not affected by pre-exposure to mirtazapine (0.1–1.0 mg/kg). On the basis of these results, it can be concluded that mirtazapine has indirect 5-HT_1A receptor agonistic properties which may play an important role in the therapeutic effect of this compound. Received: 24 January 1997/Final version: 24 April 1997     

In vivo evidence for the reversible action of the monoamine oxidase inhibitor brofaromine on 5-hydroxytryptamine release in rat brain

We have used intracerebral microdialysis to examine the reversibility of the action of brofaromine, a selective inhibitor of monoamine oxidase-A (MAO, E.C. 1.4.3.4.), on 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) output in rat frontal cortex. Brofaromine significantly increased the 5-HT output to about 200% of basal values 4 h after the s.c. administration of 10 and 30 mg/kg (but not 3 mg/kg) and reduced the concentration of 5-HIAA in the dialysate dose-dependently (61%, 53% and 41% of basal value with doses of 3, 10 and 30 mg/kg, respectively). At this time, cortical 5-HT concentration was increased and cortical 5-HIAA concentration was decreased in a dose-dependent manner.Treatment of rats with 10 mg/kg brofaromine plus 2.5 mg/kg of the irreversible MAO-B inhibitor l-deprenyl increased the concentration of 5-HT in the dialysate more than did brofaromine alone (503% vs 206% of the basal value, 4 h after administration). Similarly, clorgyline (5 mg/kg) plus l-deprenyl (2.5 mg/kg) increased the concentration of 5-HT in the dialysate to 461 % of the control value. This indicates that the concurrent inhibition of both types of MAO increases 5-HT output more than the selective blockade of either enzyme subtype. We have used this characteristic to examine, in vivo, the reversibility of the interaction of brofaromine with MAO-A. The output of 5-HT and 5-HIAA was examined 19–21 h after treatment with l-deprenyl plus clorgyline or l-deprenyl plus brofaromine. At this time, the concentration of 5-HT in the dialysate was increased six-fold in the clorgyline plus l-deprenyl group, as compared to pre-treatment values, but did not differ significantly from these in the brofaromine plus L-deprenyl group. Also, 5-HIAA concentration in the dialyste was still reduced (48% of basal value) in the clorgyline plus l-deprenyl group but not in the brofaromine plus l-deprenyl group. Cortical 5-HT and 5-HIAA concentrations in these animals, measured at the end of the microdialysis experiments (21 h after treatment), displayed changes that paralleled those in the extracellular compartment.These results indicate that: (a) as with clorgyline, the inhibition of MAO-A with brofaromine has a more pronounced effect on tissue 5-HT concentrations than on extracellular 5-HT concentrations; (b) the simultaneous inhibition of both forms of MAO with l-deprenyl and either brofaromine or clorgyline increased the concentration of 5-HT in the dialysate shortly (1–4 h) after administration more than did treatment with either of the MAO-A inhibitors alone; (c) dialysate and tissue 5-HT concentrations were greatly increased one day after the irreversible inhibition of MAO by clorgyline plus l-deprenyl, whereas they had returned to pretreatment values in those animals treated with brofaromine plus l-deprenyl. These transient effects on 5-HT and 5-HIAA in vivo provide further support for the conclusion that the interaction of brofaromine with brain MAO-A is reversible.     

Randomized double-blind comparison of serotonergic (Citalopram) versus noradrenergic (Reboxetine) reuptake inhibitors in outpatients with somatoform, DSM-IV-TR pain disorder.

OBJECTIVES: Whether the effect of tricyclic antidepressants on Pain Disorder arises from their noradrenergic or serotonergic actions or both remains unclear. We compared the selective serotonin reuptake inhibitor (SSRI) citalopram and the noradrenergic reuptake inhibitor (NARI) reboxetine in outpatients with Pain Disorder. We also distinguished the drugs' analgesic and antidepressant effects. METHODS: In this 8-week, randomized double-blind study, 35 patients with a DSM-IV-TR diagnosis of Pain Disorder were randomly assigned to receive either citalopram 40 mg/day (N=17 patients) or reboxetine 8 mg/day (N=18). The Present Pain Intensity (PPI) scale and the Total Pain Rating Index (tPRI) of the McGill Pain Questionnaire were used to measure the effect on pain symptoms. Changes in the Zung Self-Rating Depression Scale (Zung-D) scores were evaluated to monitor a possible antidepressant effect. For all patients who had at least one assessment, an intent-to-treat analysis was performed. RESULTS: No significant differences were found in the demographic variables or clinical characteristics of the two treatment groups. In the citalopram group, PPI and tPRI scores measured at baseline decreased after treatment (tPRI: 41.9 vs. 30.0, p=.004; PPI: 3.5 vs. 2.8, p=.045) whereas in the reboxetine group differences were not statistically significant (tPRI: 35.2 vs. 31.5; PPI: 3.7 vs. 3.1). The Zung-D showed no significant changes between baseline and endpoint assessment in either group. CONCLUSIONS: Our study suggests that the SSRI citalopram may have a moderate analgesic effect in patients with Pain Disorder, and that this analgesic activity appears to be not correlated to changes in depressive scores. If confirmed in a larger sample, this evidence suggests that patients who are intolerant or resistant to tricyclic antidepressants, may be treated with SSRIs.     

Trimipramine in the Treatment of Active Duodenal Ulceration

Forty-five patients with endoscopically proven uncomplicated active duodenal ulcers were placed in a randomised double-blind trial. Six patients were lost to follow-up. Twenty patients received 50 mg trimipramine (Surmontil®) at night, and 19 patients received placebo. Complete healing was defined as disappearance of the ulcer, with or without a scar; partial healing was defined as a reduction of ulcer size to 25% of its size, or a large deep ulcer that became flat, if erosions were present even if the ulcer had gone. After 4 weeks of trimipramine treatment 35% had completely healed and 50% had partly healed, compared with 21% completely and 21% partly healed with placebo (chi-square 7.9; p < 0.025 in favour of trimipramine). There were no side effects. Trimipramine, 50 mg at night, is a safe and effective treatment for active duodenal ulceration.