Biological rationale and potential clinical use of gabapentin and pregabalin in bipolar disorder, insomnia and anxiety: protocol for a systematic review and meta-analysis

Houghton, Kerensa T; Forrest, Alexandra; Awad, Amine; Atkinson, Lauren Z; Stockton, Sarah; Harrison, Paul J.; Geddes, John; Cipriani, Andrea

doi:10.1136/bmjopen-2016-013433

Cited by 42 publications

(43 citation statements)

References 60 publications

(34 reference statements)

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“…Despite the many uncertainties, these findings led to Ltype voltage-gated calcium channel (VGCC) antagonists, with existing indications in angina and hypertension, being evaluated for the treatment of BD [25]. Antiepileptic drugs, such as pregabalin, which act via VGCC a 2 d subunits (Box 2) have also been tested [26], and lamotrigine, another antiepileptic drug that may block calcium channels, among its various actions [27], is an effective treatment for bipolar depression [28].…”

Section: Calcium Signalling In Bipolar Disorder: Linking Genetics Pamentioning

confidence: 99%

The Emerging Neurobiology of Bipolar Disorder

Harrison¹,

Geddes²,

Tunbridge³

2019

FOC

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Bipolar disorder (BD) is a leading cause of global disability. Its biological basis is unknown, and its treatment unsatisfactory. Here, we review two recent areas of progress. First, the discovery of risk genes and their implications, with a focus on voltage-gated calcium channels as part of the disease process and as a drug target. Second, facilitated by new technologies, it is increasingly apparent that the bipolar phenotype is more complex and nuanced than simply one of recurring manic and depressive episodes. One such feature is persistent mood instability, and efforts are underway to understand its mechanisms and its therapeutic potential. BD illustrates how psychiatry is being transformed by contemporary neuroscience, genomics, and digital approaches. Bipolar Disorder and the New Psychiatry Psychiatry still relies largely on 19th-Century diagnostic categories. These are based on clusters of symptoms rather than biological markers, and are treated with drugs discovered serendipitously several decades ago. BD typifies this unsatisfactory state of affairs. Although its name has changed [it was formerly known as manic depression (see Glossary)], its cardinal features, and how it is assessed and treated (Box 1) have barely altered. An important reason for this stagnation has been the lack of any real traction on its causes and underlying biology, beyond its well-established high heritability [1]. Although there is evidence for altered structural and functional brain connectivity [2-4], and changes in markers of oxidative stress [5], mitochondrial function [6], inflammation [7], circadian rhythms [8], and dopamine [9], it remains difficult to integrate these diverse findings, and to disentangle causative changes from those that are secondary to the disorder and its treatment. The situation is belatedly improving. While optimism must be tempered by appreciation of the many complexities, there are realistic prospects for a transformation in our understanding of BD and how it is diagnosed and treated. Here, we highlight two areas of current interest: the discovery of the first BD risk genes and their implications, and the application of novel technologies with the potential to refine, or redefine, the BD phenotype. These developments exemplify how genomics, neuroscience, and digital technologies are heralding a new era for psychiatry. For broader reviews of BD, see [10,11].

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Section: Calcium Signalling In Bipolar Disorder: Linking Genetics Pamentioning

confidence: 99%

The Emerging Neurobiology of Bipolar Disorder

Harrison¹,

Geddes²,

Tunbridge³

2019

FOC

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“…Over the past decade the study of Ca 2+ in bipolar disorder has been received new impetus from the increasingly compelling evidence that voltage-gated calcium channels (VGCCs) are part of the genetic aetiology [12,13]. Interest is enhanced by the therapeutic opportunities which VGCCs provide, given their known druggability by existing calcium channel blockers and the gabapentinoids [14][15][16][17]. However, despite multiple studies and several narrative reviews, there is no consensus as to the specific Ca 2+ abnormality-if any -which characterises bipolar disorder, nor is the robustness of the evidence clear [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Cellular calcium in bipolar disorder: systematic review and meta-analysis

et al. 2019

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Calcium signalling has long been implicated in bipolar disorder, especially by reports of altered intracellular calcium ion concentrations ([Ca 2+ ]). However, the evidence has not been appraised critically. We carried out a systematic review and metaanalysis of studies of cellular calcium indices in bipolar disorder. 2281 records were identified and 117 screened, of which 32 were eligible and 21 were suitable for meta-analyses. The latter each involved up to 642 patients and 404 control subjects. We found that basal free intracellular [Ca 2+ ] is increased in bipolar disorder, both in platelets and in lymphocytes. The effect size is 0.55, with an estimated elevation of 29%. It is observed in medication-free patients. It is present in mania and bipolar depression, but data are equivocal for euthymia. Cells from bipolar disorder individuals also show an enhanced [Ca 2+ ] response to stimulation with 5-HT or thrombin, by an estimated 25%, with an effect size of 0.63. In studies which included other diagnoses, intracellular basal [Ca 2+ ] was higher in bipolar disorder than in unipolar depression, but not significantly different from schizophrenia. Functional parameters of cellular Ca 2+ (e.g. calcium transients), and neuronal [Ca 2+ ], have been much less investigated, and no firm conclusions can be drawn. In summary, there is a robust, medium effect size elevation of basal and stimulated free intracellular [Ca 2+ ] in bipolar disorder. The results suggest altered calcium functioning in the disorder, and encourage further investigations into the underlying mechanisms, and the implications for pathophysiology and therapeutics.

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“…We also highlight that currently, systematic revisions to understand the effects of pregabalin and gabapentin in the treatment of bipolar disorder, insomnia and anxiety are taking place [11], but it seems that polysomnographic parameters are not being taken into account which as the systematic review states are also important co-morbid disorders in fibromyalgia patients.…”

Section: Commentarymentioning

confidence: 99%

“…This is especially important in patients with anxiety and symptoms of depression as it has recently been published that the sleep cycle plays a role in emotion regulation and sleep disturbances may play a role in the emotion dysregulation observed in anxiety and depressive disorders [10]. These pathologies also can favor abuse of such medication which is also an issue that must be taken into accountWe also highlight that currently, systematic revisions to understand the effects of pregabalin and gabapentin in the treatment of bipolar disorder, insomnia and anxiety are taking place [11], but it seems that polysomnographic parameters are not being taken into account which as the systematic review states are also important co-morbid disorders in fibromyalgia patients.We consider that these type of studies are of upmost importance in daily clinical practice and their dissemination among professionals that treat patients with sleep disorders must be mandatory since it is very common to see prescription of these type of drugs in patients with sleep disorders and unknowingly we can actually be favoring the development of respiratory problems that can affect bed rest and overall wellbeing being more of a nightmare than a favorable dream. [Crossref]…”

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confidence: 99%

GABA agonists truly helping sleep or is it just a dream?

Robles-Martínez¹,

Sturchio²

2017

Clin Case Rep Rev

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We present a commentary in order to reflect about the use of GABA agonists in clinical practice to treat sleep disorders. Noticing that drugs like GABA agonists are used frequently as alternatives in patients with sleep disturbances and respiratory problems as well as in fibromyalgia patients where is also common to see respiratory disorders with truly few objectified tests on respiratory parameters, we believe more studies must be done in the matter and will like to publish the article in the journal to raise awareness and make clinical professionals reflect about the use of polysomnography for such purpose. The fact that GABA agonists can cause an increase of the apnea-hypopnea index as it is recently being discussed is also important to be aware of. We also highlight the fact that it is worth studying if this drugs could cause obstructive sleep apnea by themselves and also that sleep disturbances must be studied and looked at before attributing them to psychiatric causes. CommentaryIn clinical psychiatry it is usual to daily encounter patients that suffer from insomnia that demand hypnotic medication. It's also common for our patients to have serious respiratory problems, due to nicotine dependence among other factors that contraindicate the use of hypnotic medications or benzodiazepines. It is also a common practice in clinical rheumatology to use neuroleptic and hypnotic medication to aid pain in fibromyalgia patients where it is frequent to see obesity and associated obstructive sleep apnea (OSA). Under these situations it is a common practice to use alternative drugs like GABA agonists such as pregabalin or gabapentin.As clinical professionals we have found that few studies truly focus on how to increase sleep quality in patients with fibromyalgia. This is important to look at since a relation can be made between the patient's pain and poor quality of sleep and not many studies have been done with objective tests [1]. GABA agonists are a common management strategy used in fibromyalgia inspired by such theory. It has recently been found though that the use of 300 mg daily of gabapentin in healthy adult men increases the risk of OSA due to raises in the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) seen by polysomnography [2]. It is also evidenced that these negative effects during sleep are also superior to the ones seen in studies with flurazepam [3] and antipsychotic medications [4].Despite this, there are other studies that recognize the beneficial effect of gabapentin in insomnia and fibromyalgia [5][6][7] without reporting significant adverse effects, yet these studies did not perform a polysomnography. This could be quite troublesome since it is common to see respiratory problems during sleep in fibromyalgia patients [8,9]. It´s why we believe that it is convenient to confirm the beneficial effects of sleep medications with complementary tests that objectify not only their benefit but also the possible adverse effects that could have repercussions in sleep and other paramete...

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Biological rationale and potential clinical use of gabapentin and pregabalin in bipolar disorder, insomnia and anxiety: protocol for a systematic review and meta-analysis

Cited by 42 publications

References 60 publications

The Emerging Neurobiology of Bipolar Disorder

The Emerging Neurobiology of Bipolar Disorder

Cellular calcium in bipolar disorder: systematic review and meta-analysis

GABA agonists truly helping sleep or is it just a dream?

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