Adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines

Adjuvant use of nutritional and herbal medicines has potential to increase the efficacy of synthetic pharmaceuticals, and perhaps also decrease their side-effects by allowing lower doses to be prescribed. We evaluated current evidence for adjuvant use of nutritional and herbal medicines with antidepressants, mood stabilizers and benzodiazepines; and explored novel future areas of research. The paper also critiques current evidence for co-administration of St. John’s wort with synthetic antidepressants. We performed a systematic search of MEDLINE, CINAHL, PsycINFO, The Cochrane database, China National Knowledge Infrastructure and the Chinese Science Citation Database. Search results were supplemented by a review of reference lists and a forward search using the Web of Science. Where possible we calculated effect sizes. Encouraging evidence exists for the use of omega-3 fatty acids, SAMe, folic acid and l-tryptophan adjuvantly with antidepressants to enhance response and improve efficacy. Various nutrients also have emerging evidence as effective adjuncts with antipsychotics and mood stabilizers. While some evidence supports nutritional adjuvancy with various psychopharmacotherapies, adjuvant use of herbal therapies has not been sufficiently studied to warrant standard clinical application. This remains a promising area of research via robust, safety-conscious studies.

Antidepressants, but not antipsychotics, modulate GR function in human whole blood: An insight into molecular mechanisms

Clinical studies have demonstrated an impairment of glucocorticoid receptor (GR)-mediated negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis in patients with major depression (GR resistance), and its resolution by antidepressant treatment. Recently, we showed that this impairment is indeed due to a dysfunction of GR in depressed patients (Carvalho et al., 2009), and that the ability of the antidepressant clomipramine to decrease GR function in peripheral blood cells is impaired in patients with major depression who are clinically resistant to treatment (Carvalho et al. 2008). To further investigate the effect of antidepressants on GR function in humans, we have compared the effect of the antidepressants clomipramine, amytriptiline, sertraline, paroxetine and venlafaxine, and of the antipsychotics, haloperidol and risperidone, on GR function in peripheral blood cells from healthy volunteers (n=33). GR function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. Compared to vehicle-treated cells, all antidepressants inhibited dexamethasone (DEX, 10-100nM) inhibition of LPS-stimulated IL-6 levels (p values ranging from 0.007 to 0.1). This effect was specific to antidepressants, as antipsychotics had no effect on DEX-inhibition of LPS-stimulated IL-6 levels. The phosphodiesterase (PDE) type 4 inhibitor, rolipram, potentiated the effect of antidepressants on GR function, while the GR antagonist, RU-486, inhibited the effect of antidepressants on GR function. These findings indicate that the effect of antidepressants on GR function are specific for this class of psychotropic drugs, and involve second messenger pathways relevant to GR function and inflammation. Furthermore, it also points towards a possible mechanism by which one maybe able to overcome treatment-resistant depression. Research in this field will lead to new insights into the pathophysiology and treatment of affective disorders.

Neurotrophins and neuronal plasticity in the action of antidepressants and morphine

Neuronal plasticity is a well characterized phenomenon in the developing and adult brain. It refers to capasity of a single neuron to modify morphology, synaptic connections and activity. Neuronal connections and capacity for plastic events are compromised in several pathological disorders, such as major depression. In addition, neuronal atrophy has been reported in depressive patients. Neurotrophins are a group of secretory proteins functionally classified as neuronal survival factors. Neurotrophins, especially brain derived neurotrophic factor (BDNF), have also been associated with promoting neuronal plasticity in dysfunctional neuronal networks. Chronic antidepressant treatment increases plastic events including neurogenesis and arborization and branching of neurites in distinct brain areas, such as the hippocampus. One suggested mode of action is where the antidepressants elevate the synaptic levels of BDNF thus further activating several signaling cascades via trkB-receptor. In our studies we have tried to clarify the mechanisms of action for antidepressants and to resolve the role of BDNF in this process. We found that chronic antidepressant treatment increases amount of markers of neuronal plasticity in both hippocampus and in the medial prefrontal cortex, both of which are closely linked to the etiology of major depression. Secondary actions of antidepressants include rapid activation of the trkB receptor followed by a phosphorylation of transcription factor CREB. In addition, activation of CREB by phosphorylation appears responsible for the regulation of the expression of the BDNF gene. Using transgenic mice we found that BDNF-induced trkB-mediated signaling proved crucial for the behavioral effects of antidepressants in the forced swimming test and for the survival of newly-born neurons in the adult hippocampus. Antidepressants not only increased neurogenesis in the adult hippocampus but also elevated the turnover of hippocampal neurons. During these studies we also discovered that another trkB ligand, NT-4, is involved in morphine-mediated anti-nociception and tolerance. These results present a novel role for trkB-mediated signaling in plastic events present in the opioid system. This thesis evaluates neuronal plasticity and trkB as a target for future antidepressant treatments.

A retrospective case-control study on the prescribing practices of antidepressants administered to cancer patients and non-cancer patients in Australia

Comorbidity of depression risks is common among cancer patients. The pharmacological treatment of depression is antidepressants. However, antidepressants may interact with anticancer drugs or cause adverse reactions. The prescription practice of antidepressants to cancer patients in Australia is not well documented. Our systematic review and meta-analysis identified that the overall prevalence rate of antidepressants was 15.6% varied widely by world-region and gender. A retrospective case-control study was undertaken to determine the recent prescription practice of antidepressants to cancer and non-cancer patients in Australia. Mirtazapine was the highly prescribed antidepressants to cases, whereas Desvenlafaxine was prescribed to controls. Considerable variation in the prescribing patterns of antidepressants was identified. Prospective studies are needed to ascertain whether patients are being treated optimally.

P-glycoprotein inhibition as a strategy to increase drug delivery across the blood-brain barrier: focus on antidepressants

Depression is among the leading causes of disability worldwide. Currently available antidepressant drugs have unsatisfactory efficacy, with up to 60% of depressed patients failing to respond adequately to treatment. Emerging evidence has highlighted a potential role for the efflux transporter P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), in the aetiology of treatment-resistant depression. In this thesis, the potential of P-gp inhibition as a strategy to enhance the brain distribution and pharmacodynamic effects of antidepressant drugs was investigated. Pharmacokinetic studies demonstrated that administration of the P-gp inhibitors verapamil or cyclosporin A (CsA) enhanced the BBB transport of the antidepressants imipramine and escitalopram in vivo. Furthermore, both imipramine and escitalopram were identified as transported substrates of human P-gp in vitro. Contrastingly, human P-gp exerted no effect on the transport of four other antidepressants (amitriptyline, duloxetine, fluoxetine and mirtazapine) in vitro. Pharmacodynamic studies revealed that pre-treatment with verapamil augmented the behavioural effects of escitalopram in the tail suspension test (TST) of antidepressant-like activity in mice. Moreover, pre-treatment with CsA exacerbated the behavioural manifestation of an escitalopram-induced mouse model of serotonin syndrome, a serious adverse reaction associated with serotonergic drugs. This finding highlights the potential for unwanted side-effects which may occur due to increasing brain levels of antidepressants by P-gp inhibition, although further studies are needed to fully elucidate the mechanism(s) at play. Taken together, the research outlined in this thesis indicates that P-gp may restrict brain concentrations of escitalopram and imipramine in patients. Moreover, we show that increasing the brain distribution of an antidepressant by P-gp inhibition can result in an augmentation of antidepressant-like activity in vivo. These findings raise the possibility that P-gp inhibition may represent a potentially beneficial strategy to augment antidepressant treatment in clinical practice. Further studies are now warranted to evaluate the safety and efficacy of this approach.

Prenatal effects of selective serotonin reuptake inhibitor antidepressants, serotonin transporter promoter genotype (SLC6A4), and maternal mood on child behavior at 3 years of age

To investigate whether prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure affects behavior in 3-year-olds of antenatally anxious or depressed mothers and whether risk was moderated by the serotonin transporter promoter (SLC6A4) genotype.

Are older people prescribed antidepressants on the basis of fewer symptoms of depression, and for longer periods of time? A survey of 1825 New Zealanders

Aims: To determine whether older people are prescribed antidepressants at lower levels of depression and with fewer symptoms, and whether they are more likely to engage in chronic usage. Methods: An online survey about experiences with, and opinions about, depression and antidepressants, was completed by 1,825 New Zealand adults who had been prescribed antidepressants in the preceding five years. Results: Participants over 55 were prescribed antidepressants with significantly fewer symptoms and were significantly less likely to meet DSM criteria for depression. They were also significantly more likely to have used the drugs for three years and still be using them. Conclusions: Prescribing physicians and their older patients might benefit from discussing the pros and cons of antidepressants (including the additional risk factors with this age group) and the alternatives; and, if prescription does occur, careful monitoring to avoid unnecessary, potentially damaging, long-term use is recommended.

Understanding the non-pharmacological correlates of self-reported efficacy of antidepressants

Objective: To explore the non-pharmacological correlates of the perceived effectiveness of antidepressants (ADs), thereby enhancing understanding of the mechanisms involved in recovery from depression while taking ADs. Method: An online survey was completed by 1781 New Zealand adults who had taken ADs in the previous 5 years. Results: All 18 psychosocial variables measured were associated with depression reduction, and 16 with improved quality of life (QoL). Logistic regression models revealed that the quality of the relationship with the prescriber was related to both depression reduction and improved QoL. In addition, depression reduction was related to younger age, higher income, being fully informed about ADs by the prescriber, fewer social causal beliefs for depression and not having lost a loved one in the 2 months prior to prescription. Furthermore, both outcome measures were positively related to belief in ‘chemical’ rather than ‘placebo’ effects. Conclusion: There are multiple non-pharmacological processes involved in recovery while taking ADs. Enhancing them, for example focusing on the prescriber–patient relationship and giving more information, may enhance recovery rates, with or without ADs.

A Retrospective Claims Analysis of Medication Adherence and Persistence Among Patients Taking Antidepressants for the Treatment of Major Depressive Disorder (MDD)

Thesis (Master's)--University of Washington, 2015

Chirality in the new generation of antidepressants: stereoselective analysis of the enantiomers of mirtazapine, N-demethylmirtazapine, and 8-hydroxymirtazapine by LC-MS.

Mirtazapine is an antidepressant that acts specifically on noradrenergic and sertonergic receptors. A LC-MS method was developed that allows the simultaneous analysis of the R-(-)- and S-(+)-enantiomers of mirtazapine (MIR), demethylmirtazapine (DMIR), and 8-hydroxymirtazapine (8-OH-MIR) in plasma of MIR-treated patients. The method involves a 3-step liquid-liquid extraction, an HPLC separation on a Chirobiotic V column, and MS detection in electrospray mode. The limit of quantification (LOQ) for all enantiomers was 0.5 ng/mL, and the intra- and interday CVs were within 3.3% to 11.7% (concentration ranges 5-50 ng/mL). A method is also presented for the quantitative analysis of glucuroconjugated MIR and 8-OH-MIR. S-(+)-8-OH-MIR is present in plasma mainly as its glucuronide. Preliminary data suggest that in all patients, except in those comedicated with CYP2D6 inhibitors such as fluoxetine and thioridazine, R-(-)-MIR concentrations were higher than those of S-(+)MIR. Moreover, fluvoxamine seems also to inhibit the metabolism of MIR. Therefore, this method seems to be suitable for the stereoselective assay of MIR and its metabolites in plasma of patients comedicated with MIR and other drugs for routine and research purposes.

New Generation Antidepressants in Painful Diabetic Neuropathy

The incidence of diabetic neuropathy increases with the duration of diabetes and the degree of hyperglycaemia. Pain is one of the most common and incapacitating symptoms of diabetic neuropathy and its pharmacological control is complex. The effectiveness of antidepressive agents has been described in different types of neuropathic pain, but their effectiveness, when used as analgesics in painful diabetic neuropathy, still remains controversial. Objective: To review the possible role of new-generation antidepressive agents in the treatment of pain in diabetic peripheral neuropathy. This work has thus consisted of a meta-analysis for determining which antidepressive agent had the best analgesic potential in managing pain in patients suffering from painful diabetic neuropathy. Methods: This search covered the Cochrane, MEDLINE, EMBASE and LILACS databases, between January 2000 and August 2007. The following information was obtained from each article: criteria for diagnosing diabetic neuropathy, patients' age average, antidepressant drug received and dose, sample size, duration of the disease and treatment follow-up, outcome measurement, evaluation of pain and rescue medication. Results: A combined RR: 1.67 (95% CI 1.38 - 2.02) was obtained; this result indicated that the antidepressive agent duloxetine, was effective for controlling pain in diabetic neuropathy. The corresponding NNT for Duloxetine was established, according to our interests; NNT = 6 (95% CI 5- 8) for achieving greater than 50% analgesia in patients suffering from painful diabetic neuropathy. Discussion: Antidepressive agents are frequently employed in the specific case of diabetic neuropathy; their analgesic benefit has been demonstrated.

Effect of antidepressants on melatonin metabolite in depressed patients

Antidepressants increase melatonin levels, but it is still unclear whether this effect is related to the improvement of depressive symptoms or to unrelated pharmacological action of antidepressants. To answer this question, the effect of antidepressants on 6-sulphatoxymelatonin (aMT6s), the main melatonin urinary metabolite, was examined in drug-free depressed patients - most of them antidepressant-naive. aMT6s was evaluated in 34 depressed patients, before and after 8 weeks of placebo (n = 12) or antidepressant (n = 22; fluoxetine, duloxetine or Hypericum perforatum). Both groups showed an improvement of depressive symptoms after treatment compared to baseline (Hamilton Depression scores): 17.0 +/- 1.4 vs. 9.0 +/- 2.8, P = 0.007 for placebo, and 18.6 +/- 1.1 vs. 11.8 +/- 1.6, P < 0.001 for antidepressants). After treatment, aMT6s levels increased after antidepressants (P < 0.01), but not after placebo (P > 0.05). As depressive symptoms improved both in patients taking antidepressant and in those taking placebo, but an effect of antidepressants could only be seen in those taking antidepressants, we suggest that melatonin changes after antidepressants are more likely due to a pharmacological action of these drugs on melatonin secretion.