Scribd Logo
Upload

Welcome to Scribd!

  • 7 views

    2022 - Antidepressant Medications in Dementia Evidence and Potential Mechanisms of Treatment Resistence - 14p

    Uploaded by

    Ana Borges

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content

    You might also like

    2022 - Antidepressant Medications in Dementia Evidence and Potential Mechanisms of Treatment Resistence - 14p

    Uploaded by

    Ana Borges
    7 views14 pages

    Original Title

    2022_Antidepressant medications in dementia Evidence and potential mechanisms of treatment resistence_14p

    Copyright

    © © All Rights Reserved

    Available Formats

    PDF or read online from Scribd

    Did you find this document useful?

    Is this content inappropriate?

    Report this Document

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    7 views14 pages

    2022 - Antidepressant Medications in Dementia Evidence and Potential Mechanisms of Treatment Resistence - 14p

    Uploaded by

    Ana Borges

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    of 14
    Psychological Medicine Antidepressant medications in dementi evidence and potential mechanisms of cambridge orgipem i treatment-resistance Review Article Harry Costello ®, Jonathan P. Reiser! and Robert Howard? cha this arcs Coneto Hoses, Howard _ "hs of Cote Nurcadence, Unie Clg London, Landon UK an von of Pha, Uae BO) eres medestotin”"Callee London, Londo, Ut meri: evince aed potent rechansms flteaientresiance Pyctobga Medkioe Abstract 1-4 tps door 10,011) seosszairancaane Depression in dementia is common, disabling and causes significant distress to patients and carers. Despite widespread use of antidepressants for depression in dementia, there is no evi- Receive 12 May 002 ence of therapeutic efficacy, and their use is potentially harmful in this patient group. Reese 13 Ocober 2022 pees aera Depression in dementia has poor outcomes and effective treatments are urgently needed, ‘Understanding why antidepressants are ineffective In depression in dementia could provide Key words Insight into theie mechanism of action and ald Identification of new therapeutic targets. In {epson ements orders this review we discuss why depression in dementia may bea dsint entity, current theories ancien of how antidepressants work and how these mechanisms of action may be affected by disease ator op processes in dementia. We also consider why clinicians contine to prescribe antidepressants try cs {in dementia, and novel approaches to understand and kent effective teatments for patents Crmat ha contlogva ack ig oda aerae cer em Introduction Depression in dementia is common. Individuals with dementia are twice as likely as age- matched controls to develop mejor depresive disorder and up to one-third of all-cause dementia patients develop depresion (Asmer tal, 2018). Despite the widespread use of antidepressants in patents with dementia (Breining etal, 2017; Jester, Molina, Zalbor, & Volicer, 2021) there i itl evidence of therapeutic efficacy (Gee Fg. 1) (Dudas, Malouf, McCleery, & Dening, 2018) Though elavey few trials of ant- depressants for depression in dementia have been conducted to date and most have studied depression in Alnheimers dementia (AD), the largest and best quality studies have shown limite signal of any clinically meaningful difference (Banerjee etal, 2011). The lack of thera- peutic effect cannot be explained by age effets as depresed older adults without dementia respond as well to antidepressants as other age groups (Gerson, Belin, Kaufman, Mint, & Jaevik, 1999; Gildengers et aly 2002), though the effective dase range difers (Furukawa etal, 2019) In fact, antidepressant use in dementia is not onl ineffective but potentially harmful as it is associated with increased sk of falls, hospitalisation and higher rsk of mortality (Banerjee et al, 2021; Jobnell etal, 2017) ‘easly further high-quality trials of antidepressants in dementia types other than AD are needed. To date only one randomised controlled trial (RCT) of a selective serotonin reuptake ‘inhibitor (SSR) in 14 patients has been conducted in Lewy body dementia (LBD) which did not show efiacy and found high overall burden of sideefects (Calo eta, 2010). Vascular dementia has siary been neglected. Antidepressants are elective for poststroke depression ‘n patients without dementia (Li & Zhang, 2020). However, the overlap of vascular dementia with AD pathology (Attems & Jellinger, 2014) and evidence that higher vascular risk factor Scores predict reduced response to antidepressants in lte life depression (Sheline etal, 2010) doesnot suggest this patent group wil bck the trend ofa disappointing lack of efficacy © The tor, 202 Published by of antidepressants in dementia, Even in fontotemporal dementia (FTD) where clinical use of Cambridge Uierty Pres. Th san Open SSRs is widely advocated and sen as an effective therapy for depresion and disinhibition in ices ale, beg ander te this patent group (Triew eal, 2020) the evidence supporting its seis mixed (Huey, Putnam, ie coats Comms motion Mee, 8 Grafman, 2006 Kaye, Petrovie-Pljak, Verhoef, & Freedman, 2010). Most studies in FID ‘heh pemis umes ease daibuton ate open-label or case series designs, and the only RCTs of SSRIs (RCTS) found opposing Uncrepeaeion pvded he ongalarice results in terms of elcacy (Deakin, Rahman, Nestor, Hodges, & Sabakian, 200%; Moret is propery te ‘Tore, Antonello, Cazzat, & Bava, 2003), though one trial of trazodone in 26 patients reported reduced depresive symptoms (Leber, Siekke, Hasenbrockx, & Pasquier, 2004). In the UK over « quarter ofall people living with dementia take an antidepressant and the CAMBRIDGE rates of prescription are increasing (Martine, Jones, & Rielbrock, 2013). There is hte eve UNIVERSITY PRESS dence to support thi rate of prescription and the lack of replication of the efcacy seen in seid orga or7sgaase 700874 rbd ole Cane Urea Pes Harry Costello et ot ised Mean ‘Study (Dementia type, AD class) Difference Weight Lyketsos 2003 (AD, SSRI) —_— . 11.2% Petracea 1996 (AD, TCA) —— 0.53 [-0.92;-0.14] 8.4% ‘An 2017 (AD, SSRI) = 0.99 [-0.52; -0.26] 11.9% Rosenberg 2010 (AD, SSRI) 0.14 [-0.20; -0.08] 12.4% Petracca 2001 (AD, SSRI) — + 0.11 [-0.31; 0.09] 11.1% de Vasconcelos 2007 (AD/VD/M, SNRI) fe 0.09 [-0.35; 0.16] 10.3% Banerjee 2011 (AD, NASSA) = 0.02 [-0.08; 0.04] 12.4% Banerjee 2011 (AD, SSRI) = 0.19 [0.13; 0.26] 12.4% Reifler 1989 (PDD, TCA) +a 0.19 [-0.09; 0.48] 9.9% 05 ~0.16 [-0.36; 0.03] 100.0% 0 05 Fie 1 Repos ere plot of met naa of nce Cachan ew rancomies contra il of atdeprstans fo depreson in deme. (Ose et sia) RD Asnemerdementi YD (or TCA oi tiepresant, SNR Sertonivnrerealie eupate nity, MASSA neatenlie a specif seetnerge oneprsen depression without dementia could point to important mechanis- tic differences underlying depression in dementia. ‘Though there is evidence for the efficacy of some non-drug interventions in people with dementia (Orgets, Qazi, Spector, & Orel, 2015; Watt etal, 2021), therapeutic outcomes for patients with depression and dementia are poor (Fritz, Hhrt, Hortobagy, Ballard, & Aarsland, 2011). Depression in dementia hastens cognitive decline, increases mortality, causes significant carer siress and accelerates admission to long-term care facilites (Asmer et aly 2018; Feng et aly 2010; Lavretsky et al, 2010; Rapp et al, 2011) ‘Substantial evidence supports the hypothesis that depression is an early prodromal symptom of dementia, commonly occurring ‘up to 10 years prior to diagnosis, and a consequence of the distinct pathophysiology of individual “dementia syndromes (Singh-Manous et al, 2017). In cognitively normal older adults, biomarkers of Alzheimer’s disease pathology are associated with subsequent depression and presence of depression accelerates cognitive decline (Babulal et al, 2016; Snowden et al, 2015). “The underlying aetiology of depression asa prodrome of demen- tia is therefore likely to differ from depression in the general population. Effective treatments for depression in dementia are urgently required. Understanding why standard antidepressants are unsuc- cesifil in dementia has the potential to provide insight into both their mechanisms of action in typical depressed patients and the ‘mechanisms driving depression in dementia, 2s well as aiding ‘identification of new therapeutic targets In this review we summarise the reasons why depression in dementia may be a distinct entity, current understanding of how antidepressants work and how these mechanisms of action are flected by disease process in dementia, We also discus why ant depressants will continue to be used in dementia and the attendant clinical dilemmas faced by clinicians, patients and carers. A different syndrome of depression in dementia? Depression is @ heterogeneous and aetiologically complex syn- drome. There are a leat 256 possible unique symptom profiles seid orga or7sgaase 700874 rbd ole Cane Urea Pes that meet DSM-V ete for a diagnosis of major depressive dis- onder (Buch 8 Liston, 2021) This degre of clinical heterogeneity has led to efforts to define subtypes based on symptom profs (uch & Liston, 2021). The reliably of different depression sub- {ypes has not been established inthe general population, largely due to transition between symptom profes across and within depressive episodes (Lamers etal, 2012). However, this has led to studies highlighting how specific symptoms of depression respond differently 10 interventions and may predict overall response to teatment (Buch & Liston, 2021). For example, network analysis of individual depressive symptoms in anti depressant RCTs has identified improvement in low mood and insomnia as having greatest impact on subsequent remision and recovery (Komulainen et al, 202). Few studies have investigated how depressive symptoms differ across dementia types oF in comparison with the non-dementia depression (Ehrt, Bronnick, Leentjens, Larsen, & Aaland, 2006; Riedel, Heuser, Klotche, Dodel, & Wittchen, 2010; Verdelho, Hénon, Lebert, Pasquier, & Ley, 2008) However, the clinical complety of making a distinction between & diagnosis of depression from some of the other behavioural and paycho- logial symptoms of dementia (BPSD) can be challenging as shown by the overlap between depression rating scales with, other symptoms captured by BPSD measures (See Table 1), ‘This raises the question of whether antidepressants are ineffective because they have been used to treat different syndromes. ‘Studies of depressive symptom profle in dementia in long- term care facies highlight how motivational symptoms such a apathy are common (Janzing, Hooie, van ‘t Hot, & Zitman, 2002), and clnician-rated inital is the most prevalent depres. sive symptom (Borza etal, 2015) However both apathy and init ability are common in dementia in the absence of depression, and highly infuenced by environmental factors Jao, Li Willams, Chaudhry, & Paral, 2019) “Apathy alects 49% (Zhao et al, 2016) and 72% (Chow etal, 2003) of Alaheimer’ disease (AD) and FTD patients respectively, smarkedly higher than that reported in older adults with depres: sion without dementia (38%) (Yuen et al, 2015). Lesion studies have identified thatthe functional anatomy of apathy is associated Psychological Medicine 3 “able 1. Depressive symptoms rss seven deprestion rating scales that are lio capured by measues father BPSD symptoms ot depression ems} on fur ‘o-ccuence of smptms in four BPSD measures (ot nding depeson ters) Depression symptoms across seven depression rating sales: Ne Behave uses ouseeno ty insomnia lace incomn ate ison yparomnla ewes lo |e je |e le |e je le le |e Je |e Sed mood ows Pani ritabie ood reacvty lum variation ret Appetite decease -ppette incense Wight decrease igh Increase Concentration Indecshaness ity ortlesnes ° ° ° Pessimism loo jo |e |e |ele Sul ideation Please los Fatigue Every loss ded tid etrdaton gation Somatic complains Sympathetic arousal Coarointeinl je oJololelo eeleee le teterpersonalsenstity Lzaden paris as fare Punishment ° ° ° setae Seeieaness Coin e e ° one it ° seid orga or7sgaase 700874 rbd ole Cane Urea Pes 4 Harry Costello et ot Table 2. (Contec) ‘o-occurence of poms in four BPSD measure ot inudng depression em) Depression symptoms across sven depression rating scale et Behave AD user MOUSEPAD Tali ess ° Pope a unienaly . ° ° Pope dae me ° . ° ° Feeling bothered ° ° ° o Feeling good Feeling happy Feeling needed eu Inne tension ° . ° ° Inabliyto fee Hypochondiai ° . 2 Loss of night ° ° o ° ‘> newcpneteic merry (amiga 155, SehaveABaadeua Patologia eee’ ae fie, et & Net, CUSAD,Calala Une Sale Povhpuion nae’ ane Bsa ta, HOUSEAD, hance € ord Urey Slr he Papal warinet of omens en Sargon Hap, eames (lured dec for asymp cate tec sss tha ptm whereas phy ccna tht ce nly menue 3 apt The see epson ng ‘lst Bec epson arto ec Sex Bl Rn Cre of mola Suds Open Sc aon Rang Scale Orpen 87; ato ‘Soepensn spt uch clon anne ed 29} Momgonet er epeaon ang ee oer & ber 9) Quinny Depee gns Iau ecatciyZre Stating resin Sale ane Iss) UM of epee rpms opted et Fs Fk, etn, 22 with damage to front-sratal circuits (Levy & Dubois, 2006) Apathy also shares underlying neural and cognitive mechanisms ‘ith anhedoni, a core symptom of depression primarily charac: terised by loss of interest in engaging in pleasurable activities “Motivational symptoms incading apathy and anhedonia contrib. ute to an “interest-actiiy” cluster of depresive symptoms that predicts worse response to antidepressants in depression in the general population (Uher etal, 2012), but respond better than ore mood syptons to behavioural activation (Leontjvas et 2013). The presence of pathy in te onset depression in mild cog tiveimpairment (MC also predicts subsequent development of AD (uthiakahan, Herrmann, Vieira Gallagher, & Lanett, 2019. This {indicates that apa snot only common symptom depression n deren, but is ental othe presentation of depression a8 a pro- Gromal stage of dementia and poor reponse fo antidepestant tweatment. “Agitation is common in dementia affecting half of ptints (vington et al, 2017), and is defined a8 inappropriate verbal, Ya, oF motor activiy that is got thought tobe caused by an unmet ned (Cammings eal, 2013). Intabiltyisa key component of agitation in dementia and strongly associated with depressive Symptoms, both of which worsen with dementia progression Wolcer, Fre, & Van der Sten, 2012). Though agitation is seen across psychiatric disorder, there is a dinieal distinction beeen a patient with dementia and agitation consising of wander- fing due to disorientation and a patent with agitated depresion (Sampogoa, Veechio,Giallonardo, Lucan, & Fiorll, 2020). Ibis ily thatthe prevalence of italy as one ofthe most common symptoms in depression in dementias duet this overlap with ag- tation secondary to cognitive dene, and is diferent entity to the dentability that characterises depresion in the general population. Few studies have asiesed whether the phenomenology of Aepresson in dementia i qualitatively different from depression seid orga or7sgaase 700874 rbd ole Cane Urea Pes {in other populations (Ehrt et al, 2006; Riedel et al, 2010). However, apathy and irritability are examples of how key depres- sive symptoms in dementia, which are captured by most symptom scales, are also common in the context of BPSD without apparent depressed mood. This highlights just how challenging its for clin- ‘cians to reliably disgnose depression in dementia and raises the {question as to whether antidepressants are ineffective due to their being used to treat a diferent syndrome that isn't ‘depression’ Duet the difering pattems of neurodegeneration across demen- tia subtypes it would be anticipated thatthe underlying mechanisms of depression, evolution of symptoms and response to treatment ‘would be diferent in each disorder. However few studies have inves- tigated whether depressive symptom profiles oresponseto treatment shies across neurodeyenerative disorder or tages of disease, Puture research investigating the network dynamics of depressive symptoms ‘overtime could reveal how changes in specific symptoms are related, and which symptoms have the greatest impact on clinical improve- ‘ment and treatment response, Further trials of medications that treat depression as homogen- ‘us across dementia subtypes and stage of disease are likely to be Ineffective. Amalternative approach to understanding depression in dementia i to view it asa complex system of interacting depressive symptoms, which difer across dementia subtypes and stages of dis- cease. Utilising this approach would promote tailored interventions for specific symptoms wit greater importance at different stages of disease, development of depresive-symptom-network matkers for each condition to guide interventions and diagnosis, and provide some mechanistic insights into the causes of depression. Neurodegeneration of monoamine pathways ‘The monoamine hypothesis of depression is over 50 years old (Coppen, 1967). It proposes that diminished activity in Psychological Medicine ‘Table 2 Newodegenetion of monoeineni uct in dementia subi Monoamine nel yer Aimer dementia Lewy body disease Froetotemporal dementia Serotonin (oosal ope ult (0) Phosphostauneurofbllany changes inthe DRW occur early in AD (Braak Stag il and predate entorhinal pathology, on ofthe erlest bain Felons aieced by AD pathlony (Grinberg eta, 200) In Pron’ ese (PD) ew bodes are found in the DRM ano postmortem sucles have reported obs loss of neuron nthe Daw (francis & Pry, 2007; Halls etal, 190) - 4 reduction in ORN neon ie present at autopsy of patents wth FID, 2 sma Level of degeneration to that Seen in AD fang Schmit, 200) Dopamine Substatio Neuronal ssn the SW ard VTA in rig ors campacta (SW) s highly varbe. Over Ral of AD ‘ental tegmental aca” patents hve neuroliblaytagies (vam Inthe Su, but 0% of patents hove ‘severe neuronal oes nti region (Gio, mount, Mano, Lees 158% arom Lys, Mortimer, & Chu, 2003 Noradrenalin (Locus AD pathology ocurs eatin the LG, cers () leading to severe loss of LC neurons (ore 6%) (Gruden ea 2007; Zao et al, 203). Degeneration In ‘he UE conclates wih eopntive decne and has been azote wth developing depression in AD (Gruden et at 2007; zbenko, oo, & Kopp 220) Neuronal loss inthe Sie 2 pxthological halmark of P. Upto | of dopamine projections to the tatu fro the SN are et by the time of egnoss (hong etal, 2010; Kish ea 1952). Duaion of ines careless of reurons inthe SN (Chong ea, 20. Neuronal loss nthe LC is eter than te Si at postrmartem in ED Patents. Over Boe of LE neurons relat compared to contols (aro et aly 203) Though ony mid atopy hasbeen reported inthe SW and VA in FID, Paisonam occurs i 205 of FD Patient ana, South, Some, & Neary, 295; Park Chang, 213) One study found decreased stata dopamine projectors, ad thee are ase reports of reduced pre-sraptic foparine tansperter binding in Patients Muy al, 2006; ine ta 202) There are mite rigs of LC degeneration in FID. One study reported that te CIs relate Spared in FTD (Yanga seh, 2001, However a ager postmortem study found morse tau burden and peredegeneration inthe {UC which as greater in FTO tv than FTotransacte response DNA binding prota (TP) fohm eta, 2020), ‘monoamine pathways (predominantly serotonin, noradrenaline and dopamine) plays a causal role in the development of depression. In the age of complex systems neurobiology and. ‘computational neuroscience, thee isa consensus that such reduc- tionist biochemical theories are over-simplifications (Cowen & Browning, 2015; Harmer, Duman, & Cowen, 2017). However, given that almost all effective antidepressants directly target monoamine system receptors or transporters, predominantly serotonin, monoamine function likely plays a central roe in the therapeutic effect of antidepressants "The monoamine systems project from small brainstem nuclei to widespread brain regions (Sasaki et al, 2008), Combined with an array of post-synaptic receptors, this anatomical distibu- tion enables @ wide variety of functions but is also susceptible to

    You might also like