POLINA EIDELMAN 1, LISA S. TALBOT 1, JUNE GRUBER 1, ILANA

Transcription

1 J. Sleep Res. (2010) 19, Sleep and bipola disode doi: /j x Sleep achitectue as coelate and pedicto of symptoms and impaiment in inte-episode bipola disode: taking on the challenge of medication effects POLINA EIDELMAN 1, LISA S. TALBOT 1, JUNE GRUBER 1, ILANA HAIRSTON 1,2 and ALLISON G. HARVEY 1 1 Depatment of Psychology, Univesity of Califonia, Bekeley, CA, USA and 2 Psychiaty Depatment, Addiction Reseach Cente, Univesity of Michigan, Ann Abo, MI USA Accepted in evised fom 19 Novembe 2009; eceived 7 July 2009 SUMMARY This study was designed to claify the association between inte-episode bipola disode (BD) and sleep achitectue. Paticipants completed a baseline symptom and sleep assessment and, 3 months late, an assessment of symptoms and impaiment. The effects of psychiatic medications on sleep achitectue wee also consideed. Paticipants included 22 adults with BD I o II (inte-episode) and 22 non-psychiatic contols. The sleep assessment was conducted at the Sleep and Psychological Disodes Laboatoy at the Univesity of Califonia, Bekeley. Follow-up assessments 3 months late wee conducted ove the phone. Results indicate that, at the sleep assessment, BD paticipants exhibited geate apid eye movement sleep (REM) density than contol paticipants with no othe goup diffeences in sleep achitectue. Sleep achitectue was not coelated with concuent mood symptoms in eithe goup. In the BD goup, duation of the fist REM peiod and slow-wave sleep (SWS) amount wee positively coelated with manic symptoms and impaiment at 3 months, while REM density was positively coelated with depessive symptoms and impaiment at 3 months. The amount of Stage 2 sleep was negatively coelated with manic symptoms and impaiment at 3 months. In contast, fo the contol goup, REM density was negatively coelated with impaiment at 3 months. SWS and Stage 2 sleep wee not coelated with symptoms o impaiment. Study findings suggest that inte-episode REM sleep, SWS and Stage 2 sleep ae coelated with futue manic and depessive symptoms and impaiment in BD. This is consistent with the poposition that sleep achitectue may be a mechanism of illness maintenance in BD. keywods bipola disode, apid eye movement sleep, sleep achitectue, slowwave sleep, stage 2 sleep INTRODUCTION Individuals with bipola disode (BD) spend appoximately 50% of thei adult lives unwell, with the majoity of this time maked by subsyndomal symptoms pesisting into the inteepisode peiod (Judd et al., 2002). Sleep distubance in the Coespondence: Allison G. Havey, PhD, Depatment of Psychology, Univesity of Califonia, Bekeley, 2205 Tolman Hall #1650, Bekeley, CA , USA. Tel.: ; fax: ; ahavey@bekeley.edu inte-episode peiod has been epoted to be compaable to chonic insomnia and to have a pognostic value in BD (see Havey, 2008 fo eview). Fo instance, deceased sleep has been found to be the most common podome of mania (Jackson et al., 2003) and to pedict depessive symptoms at a 6-month follow-up (Pelman et al., 2006). Hence, the pesent study focused on inte-episode sleep distubance as a mechanism that may contibute to impaiment and be associated with futue illness couse. To the best of ou knowledge, studies utilizing sleep distubance as a pedicto of symptoms 516 Ó 2010 Euopean Sleep Reseach Society

2 Sleep and inte-episode bipola disode 517 and impaiment in BD have elied on subjective peceptions of sleep (e.g. Pelman et al., 2006) o have expeimentally induced sleep depivation in the lab and obseved next-day effects (Weh et al., 1987). We aimed to extend past findings by evaluating the pedictive value of objectively measued sleep achitectue in inte-episode BD. Inceased apid eye movement (REM) activity (i.e. shotened REM latency, longe duation of the fist REM peiod, highe pecentage of REM ove the couse of the night and geate REM density) has been widely epoted in unipola depession (e.g. Benca et al., 1992), and REM sleep has been poposed to have a mood-egulatoy ole that malfunctions in mood disodes (Catwight et al., 1998). REM in BD has eceived less empiical attention than in unipola depession, and the evidence is mixed. Patients with BD who ae manic o depessed have been epoted to exhibit deceased (e.g. Hudson et al., 1992), inceased (e.g. Giles et al., 1986) o equivalent REM latencies (Jenajczyk, 1986) elative to healthy contols and to patients diagnosed with unipola depession. In the inte-episode peiod, patients with BD have shown sleep maked by inceased REM activity (Knowles et al., 1986) and sleep that does not diffe fom that of contols (Sitaam et al., 1982). Studies of healthy elatives of individuals diagnosed with a mood disode point to the possibility that distubances in REM sleep may be a make of affective disode vulneability. Such studies suggest that the sleep of elatives of individuals diagnosed with unipola depession o BD is maked by inceased REM activity compaed with contols (Giles et al., 1998; Modell et al., 2003). In addition, geate REM density has been found to distinguish those elatives who go on to expeience an affective episode fom unaffected elatives and contols (Modell et al., 2007). Slow-wave sleep (SWS), which consists of Stages 3 and 4, is thought to have a estoative function in healthy individuals that includes memoy consolidation and cell egeneation, and has been found to be deceased in unipola depession (e.g. Benca et al., 1992). The two-pocess model of sleep egulation poposes that SWS is an index of the homeostatic pocess (Bobely, 1982), which may be weakened in depession (Bobely, 1987). Deceased SWS has also been epoted in BD (Jovanovic, 1977) and in depessed adolescents who go on to have a BD illness couse (Rao et al., 2002). Howeve, most studies epot SWS in mania and BD to be equivalent to that of healthy contols (Hudson et al., 1988, 1992; Jenajczyk, 1986; Mendelson et al., 1987). Thus, the manne in which SWS is distubed in BD is unclea, paticulaly duing the inteepisode peiod. Stage 2 sleep is also thought to have an impotant estoative and sleep-potective function (De Gennao and Feaa, 2003; Hayashi et al., 2005). Although it is undestudied in mood disodes, deceased Stage 2 sleep has been found in both unipola and BD (de Maetelae et al., 1987). Additionally, in studies of clozapine, teatment esponse in BD was most damatically associated with the enhancement of Stage 2 sleep (Hinze-Selch et al., 1997). The pesent study was designed to claify the association between BD and REM, SWS and Stage 2 sleep. We aimed to investigate whethe thee is a coss-sectional association between symptoms and sleep achitectue, and whethe sleep achitectue pedicts symptoms and mood-associated impaiment at 3-month follow-up in patients with BD duing the inte-episode peiod elative to a non-psychiatic contol goup. Ou fist hypothesis was that highe levels of depessive and manic symptoms at the baseline sleep assessment would be associated with inceased REM activity (shote REM latency, highe REM%, longe duation of fist REM, geate REM density), and that inceased REM activity would be associated with highe levels of depessive symptoms, manic symptoms and impaiment at 3-month follow-up. Second, we hypothesized that inceased Stage 2 sleep would be associated with lowe levels of manic and depessive symptoms, impaiment at the baseline sleep assessment and at the 3-month follow-up. Given the mixed findings fo SWS epoted in the published epots, we included SWS on an exploatoy basis. Ou thid study aim elates to medication effects, an issue that inceasingly equies consideation in neuoscience and psychological eseach on seious mental illness. A lage majoity of patients with BD ae teated with polyphamacy (Ghaemi et al., 2006). Thus, if eseach is conducted on only medication-fee paticipants, pogess will be slow and the esults may not be genealizable to the majoity of patients with BD. Hence, ou thid aim was to devise an appoach to medication effects that balances scientific igo and clinical eality. MATERIALS AND METHODS Paticipants Paticipants wee ecuited fom advetisements and efeals tageting Ôgood sleepesõ and Ôindividuals diagnosed with BDÕ. Of the 266 calles who wee sceened, 51 chose not to paticipate o could not be eached subsequently, 25 did not complete the potocol and a total of 146 wee excluded fom paticipating in eithe the BD o the contol goup. Paticipants wee excluded fom the BD goup fo: not being unde psychiatic cae (equiement of the ethics committee; n = 23); not meeting Stuctued Clinical Inteview fo DSM-IV (SCID- IV; Fist et al., 1994) diagnostic citeia fo BD Type I o II (n = 22); and diagnosis of a cuent substance o alcohol abuse disode (n = 4). In addition, paticipants wee excluded fom the BD goup fo not being inte-episode, as defined by: a scoe geate than 11 on the Clinician Rated Inventoy of Depessive Symptomatology (IDS-C; Rush et al., 1996); a scoe geate than 7 on the Young Mania Rating Scale (YMRS; Young et al., 1978); o meeting SCID-IV citeia fo cuent depessive, manic o hypomanic episode (n = 17). Paticipants wee excluded fom paticipating in the contol goup fo: lifetime histoy of Axis I disode accoding to the SCID-IV (n = 33); subjective sleep complaints accoding to the Duke Stuctued Inteview fo Sleep Disodes (DSISD;

3 518 P. Eidelman et al. Edinge et al., 2004; n = 24); and epoted fist-degee elatives with a diagnosis of BD o schizophenia (n = 6). Paticipants wee excluded fom eithe goup if they had a sevee medical illness (e.g. autoimmune disode, cance; n = 7) o a confounding sleep disode (e.g. sleep apnea, estless leg syndome), based on thei esponses to the DSISD o based on Respiatoy Distess Index (RDI) geate than 5 o Peiodic Limb Movement (PLM) index geate than 15 found ove the couse of 1 night of polysomnogaphy (PSG) sceening in the lab (n = 17). The demogaphics of the BD goup (n = 22) and contol goup (n = 22) ae pesented in Table 1. Thee wee no significant diffeences between the two goups. Paticipants anged in age fom 20 to 61 yeas, and epesented a ange of socioeconomic and ethnic goups. All paticipants in the BD goup met diagnostic citeia fo BD Type I (n = 19) o Type Table 1 Demogaphics, sleep achitectue vaiables, symptoms and impaiment in the BD and contol goups BD (n =22) Contol (n =22) v 2 o t Demogaphics Age (in yeas) (10.09) (12.62) 1.74 Sex (% female) 90.9% 77.3% Maital status (% patneed) 31.8% 27.2% Education (% college gaduate) 72.8% 72.7% Ethnicity (% white) 77.3% 59.1% Employed (%) 72.7% 90.9% Co-mobid diagnoses in BD goup Panic disode 4.5% Agoaphobia 4.5% Social phobia 9.1% Specific phobia 27.3% Obsessive compulsive disode 11.5% Post-taumatic stess disode 4.5% Genealized anxiety disode 9.1% Anoexia nevosa 4.5% Binge eating disode 4.5% Illness histoy in BD goup Age at illness onset (yeas) (9.44) Total past manic episodes 8.81 (7.60) Total past depessive episodes (10.04) Histoy of psychiatic 76.2% hospitalization Time since last mood episode (months) 7.21 (11.54) Mood symptoms at diagnostic visit and baseline sleep assessment YMRS diagnostic visit 3.19 (2.27) 1.80 (2.26) IDS-C diagnostic visit 7.35 (3.77) 5.20 (4.86) YMRS baseline sleep assessment 2.09 (2.20) 0.55 (1.06) -2.97* IDS-C baseline sleep assessment 5.55 (5.11) 2.36 (1.79) -2.76* Sleep achitectue at baseline sleep assessment REM vaiables REM latency (min) (48.42) (54.66) REM% (9.02) (8.03) 0.03 Duation of the 1st REM peiod (min) (17.53) (11.10) 1.56 REM density (12.29) (8.20) -2.30* NREM vaiables Stage 1% 8.20 (6.99) 5.77 (4.46) Stage 2% (16.10) (8.67) SWS% (10.71) (9.46) 1.09 Symptoms and impaiment at 3-month follow-up YMRS (mania) 3.57 (2.62) 1.00 (1.45) -4.03*** IDS-C (depession) (9.07) 2.09 (1.82) -4.85*** WSAS (impaiment) (10.19) 4.41 (5.61) -3.73** Mean values ae pesented with standad deviations in paentheses. BD, bipola disode; IDS-C, Clinician Rated Inventoy of Depessive Symptomatology; NREM, non-apid eye movement; REM, apid eye movement; SWS, slow-wave sleep; WSAS, Wok and Social Adjustment Scale; YMRS, Young Mania Rating Scale. *P 0.05; **P 0.005; ***P

4 Sleep and inte-episode bipola disode 519 II (n = 3) accoding to the SCID-IV, and wee detemined to be inte-episode at the fist visit based on SCID, IDS-C and YMRS citeia. Subsequently, the IDS-C and YMRS wee used to detemine that the paticipant was still inte-episode at all study visits peceding the follow-up. No paticipants in the contol goup wee taking psychotopic o hypnotic medications. Howeve, because the enollment of a medication-fee BD sample would be unfeasible and unepesentative, BD paticipants wee not asked to change o stop taking thei pescibed medications. Thus, 21 of the 22 BD goup paticipants wee taking psychotopic medications. In addition, as BD is typically associated with the pesence of co-mobid diagnoses (Kessle et al., 2005), paticipants wee not excluded on the basis of co-mobid diagnoses othe than cuent alcohol o substance abuse disodes. Detailed illness histoy fo the BD goup was assessed using the National Institute of Mental Health etospective Life-Chating Methodology (NIMH- LCM; Leveich and Post, 1993; one paticipant did not fully complete the NIMH-LCM). Data on cuent co-mobidities and illness histoy in the BD goup ae pesented in Table 1. Pocedues Witten infomed consent was obtained, and the SCID-IV, DSISD, NIMH-LCM, IDS-C, YMRS and demogaphics and medication questionnaies wee administeed at the diagnostic visit. An acclimation sceening night was then conducted as a contol fo fist night effects and to sceen fo sleep disodes (e.g. sleep apnea). The baseline sleep assessment was the second ovenight visit, taking place appoximately 1 month following the acclimation sceening night. Inte-episode status was assessed when paticipants aived using the YMRS and IDS-C. PSG equipment was then attached. The timing of inteviews and PSG set-up was caefully scheduled in ode to allow paticipants to go to bed at thei habitual pefeed bedtime. A neutal mood induction was administeed immediately pio to sleep to minimize the potential impact of tansient pe-sleep affective states on sleep achitectue. The neutal mood was induced using a well-validated pocedue (Eich et al., 1994), which combined continuous music and autobiogaphical ecall techniques. All paticipants epoted being in a neutal mood pio to sleep, and thee wee no goup diffeences in mood pio to (t = -0.50, P > 0.60) o following the mood induction (t = 0.40, P > 0.60). The 3-month follow-up assessment took place an aveage of 82.0 days (SD = 51.4) afte the baseline sleep assessment. It was conducted by phone and consisted of the YMRS, IDS-C and the Wok and Social Adjustment Scale (WSAS; Mundt et al., 2002). Measues Polysomnogaphy Polysomnogaphy involves the continuous and simultaneous ecoding of electoencephalogam (EEG), electooculogam (EOG) and electomyogam (EMG). We used laboatoybased PSG (Compumedics USA Inc., Chalotte, NC, USA; Siesta802) that included fou EEG leads (C3 A2, C4 A1, O1 A2, O2 A1), two EOG leads and two submental EMG leads. On the acclimation sceening night, espiatoy aiflow (using a nasal and oal themisto), thoacic and abdominal displacement, finge pulse oximete, electocadiogam (two EKG leads), and a snoing senso wee added. Data wee scoed using the standad Rechtschaffen and Kales citeia fo sleep staging (Rechtschaffen and Kales, 1968). REM latency coesponds to the time (in minutes) fom sleep onset to the beginning of the fist REM peiod of the night. REM density was calculated as the pecentage of 5-s REM sleep peiods that contained at least one eye movement (Weth et al., 1996). Fo the BD goup, an aveage total sleep time of min (SD = 85.50) was available fo scoing. This was maginally significantly longe than the aveage total sleep time of contol paticipants, which was min (SD = 73.28; t = -2.02, P = 0.05). Pecentages of the vaious sleep stages wee used instead of total minutes spent in each sleep stage due to goup diffeence in total sleep time and because paticipants wee not able to sleep past 09:00 hous because of esouce limitations. Mood symptom measues The IDS-C (Rush et al., 1996) consists of 30 items, scoed on a 0 3 metic, that assess depessive symptom seveity fo the peceding week. Scoes less than 12 coespond to inteepisode status meaning no clinical depession is pesent. The YMRS (Young et al., 1978) consists of 11 items, scoed on a 0 4 metic, that measue the seveity of manic symptoms fo the peceding week. Scoes less than 8 coespond to inteepisode status meaning no clinical mania o hypomania is pesent. The IDS-C and the YMRS have good psychometic popeties, and ae widely used in medical and eseach settings (Rush et al., 1996; Young et al., 1978). Functional impaiment measue The WSAS (Mundt et al., 2002) was used to assess moodelated functional impaiment. This five-item measue has good intenal consistency, test etest eliability and sensitivity to disode seveity (Mundt et al., 2002). Individual items ae ated on a 0 8 metic and assess the extent to which the paticipantsõ mood causes them to be impaied in occupational oles, home management, social leisue, pivate leisue and elationships. Data analysis Independent t-tests and chi-squae tests wee used to examine goup diffeences in pedicto and outcome vaiables. To addess the effects of psychotopic medications on sleep achitectue, we employed a multi-step patient-by-patient appoach. anovas wee used to test the effect of paticipantsõ medication status on sleep achitectue. Coelation analyses

5 520 P. Eidelman et al. wee then used to test ou a pioi hypotheses. Continuous symptom and impaiment measues wee etained as the outcome measues of inteest, as only a small subset of paticipants met citeia fo hypomania o depession at follow-up. Whee medications appeaed to affect sleep achitectue, seconday data analyses of ou hypotheses wee conducted in the medication subgoups. RESULTS As evident in Table 1, thee wee no goup diffeences in symptoms at the diagnostic visit, but the BD goup exhibited moe depessive and manic symptoms than the contol goup at the baseline sleep assessment. At follow-up, the BD goup had significantly moe manic symptoms, depessive symptoms and functional impaiment (based on WSAS total scoe and scoes fo each individual item) than the contol goup (Table 1). At follow-up, both manic (t = -2.66, P < 0.05) and depessive (t = -2.25, P < 0.05) symptoms in the BD goup had inceased since the baseline sleep assessment such that fou paticipants (18.2%) met YMRS citeia fo hypomania and 10 (45.5%) met IDS-C citeia fo depession. With espect to sleep achitectue, as evident in Table 1, the BD goup had significantly geate REM density than the contol goup, though thee wee no othe goup diffeences. To addess medication effects, two of the authos (P. Eidelman and J. Gube) independently classified each medication epoted by paticipants as having no effect, an enhancing effect o a suppessing effect on REM, SWS and o Stage 2 sleep, based on a detailed liteatue seach. In cases whee paticipants epoted taking medications with conflicting sleep effects (e.g. Bupopion is a REM sleep enhance and Fluoxetine is a REM sleep suppesso; Ott et al., 2004; Rush et al., 1998), we easoned that these effects cancelled each othe out. A list of potential medication effects on the sleep of each paticipant was geneated by the two authos fo 33% of paticipants, with a eliability of 100% fo those coded by both authos. As epoted in Table 2, anovas and Tukey post hoc compaisons indicated that paticipants taking a medication that suppessed REM had a significantly longe latency to fist REM than paticipants taking medications with no effect o an enhancing effect on REM. Paticipants taking a medication that suppessed REM also had geate REM density than paticipants taking a medication with no effect on REM. Thee wee no othe significant diffeences in sleep achitectue based on medications (all P > 0.10; Table 2). Table 3 pesents coelations of baseline sleep achitectue with baseline and 3-month follow-up symptoms and impaiment. Sleep achitectue was not significantly coelated with concuent manic and depessive symptoms at the baseline sleep assessment in eithe paticipant goup. Howeve, in the BD goup thee wee fou significant coelations (out of 12) between baseline sleep achitectue and follow-up symptoms. Duation of fist REM and SWS% wee positively coelated with manic symptoms, while REM density was positively coelated with depessive symptoms. Stage 2% was negatively coelated with manic symptoms. Additionally, thee wee thee significant coelations (out of six) between sleep achitectue and follow-up impaiment in the BD goup. REM density and SWS% wee positively coelated with impaiment, while Stage 2% was negatively coelated with impaiment. In the contol goup, sleep achitectue was not significantly coelated with follow-up symptoms. Howeve, thee was one significant coelation (out of six) fo impaiment, indicating that REM density was negatively coelated with impaiment in the contol goup. Thus, seven significant coelations between baseline sleep achitectue and follow-up symptoms and impaiment emeged in the BD goup, while only one significant coelation was found in the contol goup. Coelations between sleep achitectue and follow-up symptoms and impaiment wee epeated in subgoups of BD paticipants based on medication status to examine potential confounds of medication effects on REM latency and density. Fo REM latency all coelations emained Table 2 Medication effects on sleep achitectue in the BD goup Sleep achitectue vaiables Medication effects No effect on REM (n =7) Enhance REM (n =5) Suppess REM (n =10) F REM latency (min) (20.86) (45.36) (48.27) 5.20* REM% (9.28) (11.87) (8.23) 0.11 Duation of 1st REM (min) (12.55) (18.10) (20.78) 0.48 REM density 8.81 (5.99) (13.83) (12.06) 3.67* No effect on SWS (n = 10) Enhance SWS (n = 12) Suppess SWS (n =0) Stage 3% 7.27 (3.93) 9.06 (6.08) 0.64 Stage 4% 3.37 (3.03) 7.85 (8.36) 2.60 No effect on Stage 2 (n = 14) Enhance Stage 2 (n = 7) Suppess Stage 2 (n =1) Stage 2% (17.63) (13.04) Mean values ae pesented with standad deviations in paentheses. REM, apid eye movement; SWS, slow-wave sleep. *P 0.05.

6 Sleep and inte-episode bipola disode 521 Table 3 Coelations between sleep achitectue at baseline sleep assessment and baseline and 3-month follow-up symptoms and impaiment Sleep vaiable Baseline YMRS (mania) Baseline IDS-C (depession) Follow-up YMRS (mania) Follow-up IDS-C (depession) Follow-up WSAS (impaiment) BD goup (n = 22) REM vaiables REM latency )0.06 ) ) REM% )0.05 ) Duation of 1st REM )0.01 ) * REM density )0.11 ) ** 0.54** NREM vaiables Stage 2% )0.13 )0.29 )0.47* )0.15 )0.48* SWS% * * Contol goup (n = 22) REM vaiables REM latency )0.12 )0.11 )0.39 )0.33 )0.19 REM% 0.23 ) Duation of 1st REM )0.18 )0.22 )0.01 )0.12 )0.22 REM density )0.34 )0.32 ) )0.46* NREM vaiables Stage 2% ) ) SWS% ) Seconday analyses in BD medication subgoups fo REM density REM suppessing (n = 10) * 0.75* No effect on REM (n = 7) )0.33 ) SWS%, sum of Stage 3% and Stage 4%; BD, bipola disode; IDS-C, Clinician Rated Inventoy of Depessive Symptomatology; NREM, nonapid eye movement; REM, apid eye movement; SWS, slow-wave sleep; WSAS, Wok and Social Adjustment Scale; YMRS, Young Mania Rating Scale. *P 0.05; **P non-significant in both the BD subgoup taking medications that suppessed REM and the subgoup taking medications with no enhancing effects on REM (all P > 0.10). Howeve, as evident at the bottom of Table 3, while thee wee significant coelations between REM density and follow-up depessive symptoms and impaiment in the BD subgoup taking medications that suppessed REM, these coelations wee not significant in the subgoup taking medications with no effect on REM. DISCUSSION This study examined the coss-sectional and pospective associations of sleep achitectue and symptoms and impaiment in inte-episode BD. At the outset, we ecognize that ou discussion needs to be tempeed due to the potential effects of medications on sleep in the BD goup. Indeed, a pimay aim of this study was to exploe one stategy to manage the medication effects that need to be consideed in neuopsychological and neuobiological eseach on BD, so we will etun to this issue thoughout the discussion that follows. The fist aim was to coss-sectionally examine the association between sleep achitectue and symptoms and impaiment in BD elative to non-psychiatic contols. We found no significant coelations between sleep achitectue and concuent symptoms at baseline in eithe goup, although geate REM density was found in the BD goup elative to the contol goup. These findings ae in contast to ou hypotheses that REM and Stage 2 sleep would coelate with concuent symptoms. One potential explanation may be ou equiement that all paticipants be inte-episode. By definition, this esticts the ange of depessive and manic symptoms in the sample, and deceases a likelihood of finding significant coelations (e.g. Guilfod and Fuchte, 1978). A second potential explanation is that the neutal mood induction administeed pio to sleep may have diffused pe-sleep mood and canceled out the effects inte-episode symptoms may have had on sleep achitectue. Howeve, the lack of significant goup diffeences in mood pio to, and following, the neutal mood induction endes this account unlikely. Ou finding of geate REM density in the BD goup elative to contols is consistent with epots of inceased REM activity in inteepisode BD (e.g. Knowles et al., 1986) and in elatives of individuals with affective illness (e.g. Modell et al., 2003), aising the possibility that inceased REM density is a pesistent sleep distubance in BD. Given that we also found that paticipants who epoted taking REM-suppessing medications demonstated geate REM density, this goup diffeence may also be attibutable to medication effects. We will etun to this possibility below. The second study aim was to pospectively examine coelations between baseline sleep achitectue and futue

7 522 P. Eidelman et al. symptoms and impaiment in BD. A numbe of significant findings emeged. Taking REM fist, seveal significant coelations suppoted the hypothesis that inceased REM activity would be associated with inceased symptoms and impaiment at follow-up in the BD goup. Specifically, in the BD goup longe duation of fist REM was associated with moe manic symptoms at the 3-month follow-up, while geate REM density was associated with moe depessive symptoms and impaiment at the 3-month follow-up. Thus, duation of fist REM and REM density may have pedictive value in inteepisode BD. The negative coelation between REM density and impaiment in the contol goup, along with the findings that REM density is positively coelated with impaiment and depession in the BD goup, is consistent with the suggestion that REM seves a mood-egulatoy ole that is adaptive in non-psychiatic individuals but malfunctions in mood disodes (e.g. Knowles et al., 1986). Seveal findings also suppoted the hypothesis that geate amounts of Stage 2 sleep would be associated with less followup symptoms and impaiment in the BD goup. Specifically, geate Stage 2% was associated with lowe levels of manic symptoms and impaiment in the BD goup at follow-up. This is consistent with theoies that Stage 2 sleep fulfills an impotant estoative function (Hayashi et al., 2005). Although Stage 2 sleep has eceived compaatively little attention in mood disode eseach to date, ou findings aise the possibility that Stage 2 sleep may have some potective value. Studies demonstating positive associations between teatment esponse and inceased Stage 2 sleep in BD (e.g. Hinze-Selch et al., 1997) ae also suggestive of the impotance of Stage 2 sleep. Given the mixed findings in the liteatue to date, we did not make specific hypotheses egading SWS, including it in ou analyses on an exploatoy basis. Results indicated that geate SWS% pedicted moe manic symptoms and impaiment in the BD goup at the 3-month follow-up. This was somewhat supising, given that past eseach has suggested that inceased levels of SWS appea necessay to nomalize depessed mood (e.g. Bobely, 1982; Jovanovic, 1977). Thee ae seveal possible explanations fo ou findings. Fist, in consideation with findings that geate Stage 2% was associated with less manic symptoms and impaiment at the followup, it is impotant to note that the duations of Stage 2 sleep and SWS may change in popotion to each othe. Indeed, while it appeas that distubances in REM and non-apid eye movement (NREM) sleep ae not ecipocal (Amitage, 2007), changes in the diffeent stages of NREM sleep ae likely to impact othe NREM sleep stages. Second, pehaps even pio to the baseline assessment, the paticipants who late developed manic symptoms wee stating to incease thei physical activity. Even a slight incease in execise and physical activity is known to incease SWS (Naylo et al., 2000). Thid, paticipants who late developed manic symptoms may have aleady been displaying educed sleep need pio to the baseline sleep assessment and wee, theefoe, becoming sleep depived. Based on the two-pocess model of sleep egulation and sleep depivation studies, inceased wakefulness is associated with geate SWS ove the couse of the night (e.g. Bobely, 1982; Bunne et al., 1993). Fouth, pehaps thee ae bi-diectional effects. Specifically, pehaps geate SWS may be detimental in BD, ovecompensating fo the need to egulaize depessed mood and inducing a shift to the opposite end of the mood spectum towad manic symptoms. Ou thid aim was to addess the ole of psychotopic medications. To addess potentially confounding effects of medications in ou analyses, we employed a multi-step appoach based on a detailed patient-by-patient liteatue eview of medication sleep achitectue effects. By applying this appoach, in lieu of equesting that all paticipants be medication fee pio to paticipating, we easoned that we would be able to ecuit a paticipant sample that is moe epesentative of the lage population of adults with BD. In the pesent study, the main concen was the association of REM-suppessing medications with geate REM density. It is possible that this medication effect confounded coelations between REM density and symptoms and impaiment at 3 months in the BD goup. If this is the case, this medicationelated finding aises a numbe of possibilities. Fist, BD individuals who ae pone to depession may also be moe likely to espond to REM-suppessing medications. Second, REM-suppessing medications may ende individuals moe susceptible to depession and impaiment, although this seems unlikely as neithe follow-up depessive symptoms (t = -1.74, P > 0.10) no impaiment (t = -1.70, P > 0.10) wee geate in paticipants taking REM-suppessing medications than in paticipants taking medications with no REM effects. Thid, REM-suppessing medications may affect the mood-egulatoy function of REM, theeby intensifying the association of REM density with futue depession and impaiment. Thus, futhe eseach on REM sleep in BD is needed to claify the elationship between medication effects, REM density and depessive symptoms. Thee wee seveal key lessons leaned fom ou appoach to medications that should be addessed in futue studies of BD. Fist, we ecognize that some of the medication subgoups wee small (e.g. only one paticipant was taking a medication that suppesses Stage 2 sleep). Thus, some statistical tests wee undepoweed to detect meaningful goup diffeences in sleep achitectue based on medication egimen. Futue studies with lage samples could addess medication confounds by utilizing medication subgoups as covaiates in statistical analyses. Second, medication usage should be assessed at follow-up to check if a medication change o discontinuation may have occued, potentially influencing the associations obseved between sleep achitectue and follow-up symptoms and impaiment. Thid, we easoned that sleep achitectue effects of medications that enhanced and suppessed the same sleep stage would cancel out. Although this decision makes sense at one level, medication inteaction studies have not yet been conducted to assess the validity of this assumption. Fouth, investigatos had to be awae that medications may be pescibed to paticipants on the basis of undelying factos,

8 Sleep and inte-episode bipola disode 523 such as a tendency to exhibit paticula symptom clustes (e.g. Swann et al., 2002). These undelying factos may affect both sleep achitectue and the paticipantõs medication egimen. In ode to assess this possibility, it may be useful to obtain a moe detailed illness histoy o obtain pemission to contact the pescibing physician in ode to discuss the physicianõs easons fo pescibing the medications taken by paticipants. Finally, the effects of medications on sleep achitectue ae undoubtedly quite complex, and include effects othe than inceasing and deceasing sleep stages. Fo example, benzodiazepine ecepto agonists may incease EEG beta activity while deceasing delta and theta activity (Bastien et al., 2003). While we ecognize the limitations of ou appoach to medications, we aimed to begin a pocess of developing a method fo dealing with phamacological teatments that would allow fo the study of a divese and epesentative sample of individuals diagnosed with BD. We hope that futue investigations will futhe elaboate on ou appoach, utilizing lessons leaned about the issues discussed above. Seveal limitations need to be consideed. Fist, the sample size was elatively small and lagely composed of female paticipants. Replication in lage and moe divese samples is waanted. Second, we did not coect fo multiple compaisons. While this inceases the isk of Type I eo, given that this is a elatively new eseach aea, we wee also concened about deceasing the isk of Type II eo (Nakagawa, 2004) so as to maximize infomation gleaned fom this initial study. The small numbe of significant coelations in the contol goup is notewothy. On the basis of chance, if the esults eflected false positives, moe significant findings had to have emeged in the contol goup. Thid, we acknowledge that the stages of NREM sleep assessed ae not entiely independent, and that we cannot ascetain causal elationships between sleep stages and subsequent symptoms and impaiment. Fouth, we utilized one night of PSG as ou assessment of sleep achitectue. Futue studies should assess sleep achitectue ove multiple nights. Finally, the impact of co-mobid diagnoses should be consideed. In futue studies, it may be useful to include a compaison goup with a diagnostic pofile simila to the co-mobid diagnoses in the BD goup in ode to ascetain the impact of co-mobid disodes on sleep achitectue. Oveall, ou esults point to sleep achitectue as a potential illness-maintaining mechanism in BD. Suppoting the hypothesis that the mood-egulatoy ole of REM may malfunction in mood disodes, REM activity was positively coelated with a futue incease in symptoms and impaiment in ou sample. With espect to NREM sleep, we found that SWS activity was also positively coelated with inceased symptoms and impaiment. In contast, ou esults suggest that Stage 2 sleep may play a potective ole in BD, as it was coelated with deceased symptoms and impaiment at follow-up. Indeed, it may be the case that the ways in which REM and NREM function in BD may be alteed even in the inte-episode peiod, such that sleep achitectue chaacteistics ae pedictive of futue symptoms and impaiment. Futhemoe, by taking a new appoach to medication effects, we wee able to assess sleep in an inte-episode, epesentative, medicated BD sample to demonstate that medications do not have to be inheent and intactable confounding factos in eseach of sevee psychopathology. ACKNOWLEDGEMENTS We would like to thank D. 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