International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets.

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.

Depression and cardiovascular risk-association among Beck Depression Inventory, PCSK9 levels and insulin resistance.

BACKGROUND: Depression and cardiovascular disease (CVD) are among the most common causes of disability in high-income countries, depression being associated with a 30% increased risk of future CV events. Depression is twice as common in people with diabetes and is associated with a 60% rise in the incidence of type 2 diabetes, an independent CVD risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein cholesterol, has been related to a large number of CV risk factors, including insulin resistance. Aim of this study was to investigate whether the presence of depression could affect PCSK9 levels in a population of obese subjects susceptible to depressive symptoms and how these changes may mediate a pre-diabetic risk. RESULTS: In 389 obese individuals, the Beck Depression Inventory (BDI-II) was significantly associated with PCSK9 levels. For every one-unit increment in BDI-II score, PCSK9 rose by 1.85 ng/mL. Depression was associated also with the HOMA-IR (homeostatic model assessment index of insulin resistance), 11% of this effect operating indirectly via PCSK9. CONCLUSIONS: This study indicates a possible mechanism linking depression and insulin resistance, a well-known CV risk factor, providing evidence for a significant role of PCSK9.

Non-insulin anti-diabetic drugs: An update on pharmacological interactions.

Nowadays, the goal in the management of type 2 diabetes mellitus (T2DM) remains personalized control of glucose. Since less than 50% of patients with T2DM achieve glycemic treatment goal and most of them take medications for comorbidities associated to T2DM, drug interactions, namely pharmacokinetic and pharmacodynamic interactions, may enhance or reduce the effect of compounds involved in hyperglycemia. Hence, clinicians should be aware of the severe complications in T2DM patients in case of a concomitant use of these medications. It is within this context that this review aims to evaluate the effect of a second drug on the pharmacokinetic of these compounds which may lead, along with several pharmacodynamic interactions, to severe clinical complications, i.e., hypoglycemia. Available drugs already approved in Europe, USA and Japan have been included.

Stress and corticosterone increase the readily releasable pool of glutamate vesicles in synaptic terminals of prefrontal and frontal cortex.

Stress and glucocorticoids alter glutamatergic transmission, and the outcome of stress may range from plasticity enhancing effects to noxious, maladaptive changes. We have previously demonstrated that acute stress rapidly increases glutamate release in prefrontal and frontal cortex via glucocorticoid receptor and accumulation of presynaptic SNARE complex. Here we compared the ex vivo effects of acute stress on glutamate release with those of in vitro application of corticosterone, to analyze whether acute effect of stress on glutamatergic transmission is mediated by local synaptic action of corticosterone. We found that acute stress increases both the readily releasable pool (RRP) of vesicles and depolarization-evoked glutamate release, while application in vitro of corticosterone rapidly increases the RRP, an effect dependent on synaptic receptors for the hormone, but does not induce glutamate release for up to 20 min. These findings indicate that corticosterone mediates the enhancement of glutamate release induced by acute stress, and the rapid non-genomic action of the hormone is necessary but not sufficient for this effect.

Pharmacological characterization of BDNF promoters I, II and IV reveals that serotonin and norepinephrine input is sufficient for transcription activation.

Compelling evidence has shown that the effects of antidepressants, increasing extracellular serotonin and noradrenaline as a primary mechanism of action, involve neuroplastic and neurotrophic mechanisms. Brain-derived neurotrophic factor (BDNF) has been shown to play a key role in neuroplasticity and synaptic function, as well as in the pathophysiology of neuropsychiatric disorders and the mechanism of action of antidepressants. The expression of BDNF is mediated by the transcription of different mRNAs derived by the splicing of one of the eight 5' non-coding exons with the 3' coding exon (in rats). The transcription of each non-coding exon is driven by unique and different promoters. We generated a gene reporter system based on hippocampal and cortical neuronal cultures, in which the transcription of luciferase is regulated by BDNF promoters I, II, IV or by cAMP response element (CRE), to investigate the activation of selected promoters induced by monoaminergic antidepressants and by serotonin or noradrenaline agonists. We found that incubation with fluoxetine or reboxetine failed to induce any activation of BDNF promoters or CRE. On the other hand, the incubation of cultures with selective agonists of serotonin or noradrenaline receptors induced a specific and distinct profile of activation of BDNF promoters I, II, IV and CRE, suggesting that the monoaminergic input, absent in dissociated cultures, is essential for the modulation of BDNF expression. In summary, we applied a rapidly detectable and highly sensitive reporter gene assay to characterize the selective activation profile of BDNF and CRE promoters, through specific and different pharmacological stimuli.

Serine/threonine kinases as molecular targets of antidepressants: implications for pharmacological treatment and pathophysiology of affective disorders.

It is currently a widely accepted opinion that adaptive, plastic changes in the molecular and cellular components of neuronal signaling systems correlate with the effects on mood and cognition observed after long-term treatment with antidepressant drugs. Protein phosphorylation represents a key step for most signaling systems, and it is involved in the regulation of virtually all cellular functions. Two serine/threonine kinases, Ca2+ /calmodulin-dependent protein kinase II and cyclic AMP-dependent protein kinase, have been shown to be activated in the brain following antidepressant treatment. The changes in kinase activity are mirrored by changes in the phosphorylation of selected protein substrates in subcellular compartments (presynaptic terminals and microtubules), which, in turn, may contribute to the modulation of synaptic transmission observed with antidepressants. The molecular consequences of protein kinase activation may account for some of the alterations in neural function induced by antidepressants, and may suggest novel possible strategies of pharmacological intervention.

Abnormalities of cyclic adenosine monophosphate signaling in platelets from untreated patients with bipolar disorder.

BACKGROUND: Abnormalities in the cyclic adenosine monophosphate (cAMP)-dependent phosphorylation system have been recently reported in patients with bipolar disorder. We evaluated the immunoreactivity of the regulatory and catalytic subunits of cAMP-dependent protein kinase (protein kinase A) and 1 of its substrates, Rap1, in platelets from untreated euthymic, manic, and depressed patients with bipolar disorder and healthy subjects. METHODS: Platelets were collected from 112 drug-free patients with bipolar disorder (52 euthymic, 29 depressed, and 31 manic) and 62 healthy subjects. The levels of cAMP-dependent protein kinase and Rap1 were assessed by Western blot analysis, immunostaining, and computer-assisted imaging. RESULTS: The immunolabeling of the catalytic subunit of cAMP-dependent protein kinase was significantly different among groups (P<.001), with higher values in untreated depressed and manic patients with bipolar disorder compared with untreated euthymic patients with bipolar disorder and healthy subjects. No significant differences were found in the immunolabeling of the regulatory subunits (type I and type II) of cAMP-dependent protein kinase. The immunolabeling of Rap1 was significantly higher (P<.001) in untreated euthymic, depressed, and manic patients than in healthy persons. CONCLUSIONS: Levels of Rap1 and the catalytic subunit of cAMP-dependent protein kinase are altered in the platelets of bipolar patients. These findings may provide clues toward understanding the involvement of cAMP signaling in the pathogenesis of bipolar disorder.

Possible involvement of ovarian mechanisms other than estrogen-progesterone secretion in the regulation of glutamic acid decarboxylase activity of the rat fallopian tubes.

This study was performed to clarify the physiological role of the ovary in regulating the glutamic acid decarboxylase (GAD) activity in rat Fallopian tubes. To this purpose, GAD activity of the oviduct was evaluated in the following experimental conditions: immature or adult castrated (CX) rats; immature or adult CX rats treated with graded doses of estradiol benzoate (EB) or a fixed dose of EB and progesterone; adult CX rats bearing Silastic implants able to produce steady state estradiol plasma levels in the range of diestrous values; and prepubertal rats treated with ovulatory or anovulatory doses of exogenous gonadotropins (PMS and hCG). Moreover, the possible fluctuations of both gamma-aminobutyric acid (GABA) concentrations and GAD activity in the Fallopian tubes were studied during the estrous cycle. The results show that the prepubertal rat oviduct possesses a GABA content and a GAD activity analogous to those of normal diestrous rats. The GAD activity measured with the CO2 formation method was well correlated with the formation of labeled GABA, indicating that tubes of prepubertal rats are able to form the neurotransmitter by means of specific decarboxylation of glutamate. GAD activity, but not GABA levels, was increased over control values by the administration of exogenous gonadotropins. The role of the ovary in both adult and prepubertal rats to regulate this enzymatic activity is further stressed by the results of the experiments performed in CX animals which showed that ovariectomy produced a 4- to 5-fold decrease in GAD activity independent of the age of the animals. However, implantation of Silastic estradiol-containing capsules in adult CX animals or the administration of EB for 5 days in a dose range from 0.001-6.4 micrograms/day to adult ovariectomized animals and from 0.001-0.2 microgram/day to prepubertal animals did not modify GAD activity in spite of marked peripheral estrogenization of the animals evidenced by increases in uterine weight. Moreover, no variation of the enzymatic activity was observed at puberty (assessed by the age at vaginal opening). The administration of progesterone (0.2 mg) plus EB (0.01 microgram) did not produce any significant variation in GAD activity. GABA content and GAD activity of the tubes did not change during the estrous cycle. We, therefore, believe that other ovarian, still unidentified, secretions might be involved in the regulation of GAD activity in rat Fallopian tubes.

Role of central nervous system-derived or circulating gamma-aminobutyric acid on prolactin secretion in the rat.

To investigate the respective role in PRL secretion of gamma-aminobutyric acid (GABA), either derived from the central nervous system or circulating in plasma, experiments were performed using ethanolamine-O-sulfate (EOS), a specific inhibitor of GABA catabolism. Intracerebroventricular injection of EOS (2 mg/kg) induced in unanesthetized male rats 2-8 h post injection a clear-cut rise in hypothalamic, anterior pituitary (AP), and plasma GABA concentrations. Rises in GABA titers occurred earlier in the hypothalamus and AP (2 h) than in the plasma (4 h). Concomitant to alterations of GABA, there was a striking lowering of plasma PRL evident at 2 h and still present 24 h after EOS administration. In contrast, systemic administration of graded doses of EOS (200-400 mg/kg, iv) did not induce significant changes in plasma GABA concentrations 4 h post injection; only the 600 mg/kg dose of EOS increased GABA concentrations 4 h post injection in the hypothalamo-AP system and decreased plasma PRL concentrations. Finally, in hypophysectomized rats bearing ecotopic pituitaries, despite the occurrence of rises in the hypothalamic GABA after intracerebroventricular or systemic (600 mg/kg) administration of EOS, AP, plasma GABA, and plasma PRL concentrations were not altered. In all these findings indicate that: 1) changes in plasma PRL are best correlated to variations in the amino acid titers occurring in the hypothalamo-AP systems; and 2) circulating GABA does not play a functional role in the control of PRL secretion. Finally, since alterations in blood GABA levels after central or systemic administration of EOS appear to reflect primary changes occurring in the brain concentration of the amino acid, circulating GABA may be a reliable indicator of central nervous system GABAergic function.