Depression, sleep physiology, and antidepressant drugs

May combine two claims.

Compared to placebo, paroxetine in healthy volunteers produced a significant reduction in actual sleep time, a reduction in sleep efficiency, and an increase in WASO.

“Compared to placebo, subjects receiving paroxetine demonstrated a significant reduction in actual sleep time, a reduction in sleep efficiency, and an increase in WASO.”

• cites Sharpley et al., 1996 sourceNot checked — no full text of the source

May combine two claims.

Sedation with fluoxetine increased linearly up to 40 mg/day and remained stable between 40 and 60 mg/day.

“Sedation increased linearly up to 40 mg/day and remained stable between 40 and 60 mg/day.”

• cites Beasley et al., 1992Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Paroxetine did not influence total sleep time or sleep onset latency, but increased the number of awakenings and reduced sleep efficiency after 4 weeks of treatment.

“Staner et al. [1995] found that paroxetine did not influence total sleep time or sleep onset latency, but increased the number of awakenings and reduced sleep efficiency after 4 weeks of treatment.”

• cites Staner et al., 1995Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

The irreversible MAOIs are potent REM suppressants, with REM suppression observed promptly after initiation of treatment and persisting for months during ongoing therapy.

“The irreversible MAOIs are also potent REM suppressants, with REM suppression being observed promptly after initiation of treatment and persisting for months during ongoing therapy.”

May combine two claims.

Polysomnographic studies of the TCAs generally support the clinical practice of utilizing sedating TCAs for depressed patients with coexisting insomnia and employing more activating TCAs for the hypersomnolent depressive subgroup.

“In summary, polysomnographic studies of the TCAs generally support the clinical practice of utilizing sedating TCAs for depressed patients with coexisting problems with insomnia and employing more activating TCAs for the hypersomnolent depressive subgroup.”

May combine two claims.

In the sertraline study, sleep efficiency was not reduced, nor was WASO increased; sleep continuity measures remained undisturbed following high-dose sertraline administration.

“In contrast to some studies with other SSRIs, however, sleep efficiency was not reduced in the sertraline group, nor was WASO increased.Thus, sleep continuity measures remained undisturbed following highdose sertraline administration.”

• cites Winokur et al., 1991Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Paroxetine exhibits greater potency in inhibiting presynaptic reuptake of serotonin than other SSRIs and is relatively more potent in inhibiting muscarinic cholinergic receptors and histaminic H1 receptors.

“Paroxetine, for example, exhibits greater potency in inhibiting presynaptic reuptake of serotonin than other SSRIs and is also relatively more potent in inhibiting muscarinic cholinergic receptors and histaminic H 1 receptors.”

Probably not a substantial claim: may not pass S2 (checkable).

These observations support the clinical relevance of obtaining specific information regarding effects of antidepressant drugs on sleep architecture.

“These observations support the clinical relevance of obtaining specific information regarding effects of antidepressant drugs on sleep architecture.”

• AssumptionRests on an assumption: Approximately 80% of hospitalized depressed patients have objective findings of alterations in sleep electroencephalogram (EEG) patterns.
• AssumptionRests on an assumption: Insomnia is the most commonly encountered subjective complaint of sleep difficulty in depressed patients, while a subset report complaints of hypersomnia.

May combine two claims.

Other TCAs, such as desipramine or protriptyline, prolong sleep onset latency, reduce sleep efficiency, and increase WASO or awakenings/arousals after sleep onset.

“Other TCAs, such as desipramine or protriptyline, prolong sleep onset latency, reduce sleep efficiency, and increase WASO or awakenings/arousals after sleep onset [Kupfer et al., 1991].”

• cites Kupfer et al., 1991 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Several TCAs, such as amitriptyline and trimipramine, are viewed as predominantly sedating drugs, most likely due to their potent antihistaminic properties.

“Based on clinical observations and patient self-report data, several of the TCAs (e.g., amitriptyline and trimipramine) are viewed as predominately sedating drugs, most likely due to their potent antihistaminic properties.”

May combine two claims.

SSRIs potently inhibit presynaptic uptake of serotonin, while exerting relatively weak effects on other neurotransmitter/receptor systems.

“Pharmacologically, the SSRIs potently inhibit presynaptic uptake of serotonin, while exerting relatively weak effects on other neurotransmitter/receptor systems [Richelson, 1996].”

• cites Richelson, 1996 sourceNot checked — no full text of the source

May combine two claims.

Sertraline produced a prominent suppression of REM sleep, a significant increase in Stage II sleep, and no alterations in Stage I or slow wave sleep.

“Examination of sleep architecture parameters revealed a prominent suppression of REM sleep following sertraline, consistent with other studies of SSRIs, a significant increase in Stage II sleep, and no alterations in Stage I or slow wave sleep.”

• cites Winokur et al., 1991Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

REM suppression with paroxetine occurred at a level similar to that of amitriptyline, with REM latency remaining significantly prolonged compared to baseline 1 week after withdrawal.

“REM suppression occurred at a level similar to that of amitriptyline, with REM latency remaining significantly prolonged compared to baseline 1 week after withdrawal.”

• cites Staner et al., 1995Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Fluoxetine is relatively more potent in vitro in inhibiting presynaptic uptake of norepinephrine, and sertraline is more potent in inhibiting presynaptic uptake of dopamine.

“Additionally, fluoxetine is relatively more potent in vitro in inhibiting presynaptic uptake of norepinephrine, and sertraline is more potent in inhibiting presynaptic uptake of dopamine.”

May combine two claims.

In the same study, REM sleep minutes were significantly reduced and REM latency significantly prolonged at all time points examined (days 1, 6, and 16) for the paroxetine-treated group.

“REM sleep minutes were significantly reduced and REM latency significantly prolonged at all time points examined (days 1, 6, and 16) for the paroxetine-treated group.”

• cites Sharpley et al., 1996 sourceNot checked — no full text of the source

May combine two claims.

Compared to placebo-treated patients, patients on sertraline demonstrated significantly prolonged sleep latency and a reduced total sleep time.

“Compared to the placebo-treated group, patients on sertraline demonstrated significantly prolonged sleep latency and a reduced total sleep time.”

• cites Winokur et al., 1991Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Certain TCAs, including amitriptyline and trimipramine, shorten sleep onset latency, improve sleep continuity or sleep efficiency, and decrease wake time after sleep onset (WASO).

“Consistent with clinical experience, certain TCAs, including amitriptyline and trimipramine, are reported to shorten sleep onset latency, improve sleep continuity or sleep efficiency (the proportion of time in bed during which the subject is actually recorded asleep), and decrease wake time after sleep onset (WASO) [Kupfer, 1982;Shipley et al., 1984;Ware et al., 1989].”

• cites Kupfer, 1982Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Shipley et al., 1984 sourceNot checked — no full text of the source
• cites Ware et al., 1989 sourceNot checked — no full text of the source

May combine two claims.

Cholinergic systems exert significant effects on the initiation of a REM interval, while norepinephrine and serotonin play important roles in terminating a REM period.

“Cholinergic systems exert significant effects on the initiation of a REM interval, while the monoamine neurotransmitters norepinephrine (NE) and serotonin (5-HT) play important roles in terminating a REM period [McCarley and Hobson, 1975;Velazquez-Moctezuma et al., 1991].”

• cites McCarley and Hobson, 1975 sourceNot checked — no full text of the source
• cites Velazquez-Moctezuma et al., 1991 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Basic investigations of the neurobiological mechanisms regulating sleep implicate several neurotransmitter systems in the control of REM onset and offset.

“Finally, basic investigations of the neurobiological mechanisms regulating sleep implicate several neurotransmitter systems in the control of REM onset and offset [Hobson, 1983] (Fig. 1).”

• cites Hobson, 1983 sourceNot checked — no full text of the source

May combine two claims.

TCAs, with the exception of trimipramine, suppress REM sleep, with clomipramine exerting the most potent effect in standard antidepressant dosage.

“With the exception of trimipramine [Ware et al., 1989;Wiegand et al., 1986], all of the TCAs examined suppress REM sleep, with clomipramine exerting the most potent effect in standard antidepressant dosage [Thase and Kupfer, 1987].”

• cites Ware et al., 1989 sourceNot checked — no full text of the source
• cites Wiegand et al., 1986 sourceFetching the cited paper…
• cites Thase and Kupfer, 1987Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

In a study of fluoxetine at multiple fixed doses (5-60 mg/day), activation and sedation were both significant with fluoxetine compared to placebo.

“Beasley et al. [1992] examined activating and sedating effects of fluoxetine at multiple fixed doses (5-60 mg/ day).Activation and sedation were both significant with fluoxetine compared to placebo.”

• cites Beasley et al., 1992Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

SSRIs consistently suppress REM sleep; this effect has been observed after a single dose and, in many cases, continues after several weeks of SSRI therapy, with rebound effects often noted following withdrawal.

“Consistent effects have been reported for the SSRIs with respect to suppression of REM sleep.This effect has been observed after a single dose of an SSRI and, in many cases, continues to be observed after several weeks of SSRI therapy, with rebound effects often noted following withdrawal.”

May combine two claims.

In a comparison of trazodone and fluoxetine, more sedation was reported with trazodone, and more activation with fluoxetine.

“In a similar study comparing trazodone and fluoxetine, Beasley et al. [1991] found more sedation reported with trazodone, and more activation with fluoxetine.”

• cites Beasley et al., 1991Not checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Specific TCAs demonstrate wide intraclass variability with respect to effects on nocturnal sleep and daytime sleepiness.

“Clinicians have long recognized that specific TCAs demonstrate wide intraclass variability with respect to effects on nocturnal sleep and daytime sleepiness.”

May combine two claims.

In another study, trazodone suppressed REM sleep, while nefazodone increased REM sleep.

“In another study, trazodone suppressed REM sleep, while nefazodone increased REM sleep [Ware et al., 1994].”

• cites Ware et al., 1994 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Inhibitory REM-off aminergic neurons terminate REM sleep, after activation by REM-on neuronal activity.

“Inhibitory REM-off aminergic neurons terminate REM sleep, after activation by REM-on neuronal activity.”

May combine two claims.

In the citalopram study, no changes in sleep continuity measures were noted and Stage II sleep increased.

“No changes in sleep continuity measures were noted and Stage II sleep increased [van Bemmel et al., 1993].”

• cites van Bemmel et al., 1993 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

The ability of venlafaxine to produce similar effects on sleep physiology to SSRIs may logically relate to its inhibition of serotonin reuptake.

“The ability of venlafaxine to produce similar effects on sleep physiology to those produced by the SSRIs may logically relate to venlafaxine's identified pharmacological profile of inhibiting serotonin reuptake.”

May combine two claims.

Trazodone reduces the number of awakenings and arousals, increases slow wave sleep, prolongs REM latency, and produces a reduction of total REM sleep time.

“Trazodone reduces the number of awakenings and arousals, increases slow wave sleep, prolongs REM latency, and produces a reduction of total REM sleep time.”

May combine two claims.

Patients receiving nefazodone demonstrated increased sleep efficiency, while patients on fluoxetine demonstrated a significant reduction in sleep efficiency and a significant increase in number of awakenings compared to baseline scores.

“With respect to sleep parameters, patients receiving nefazodone demonstrated increased sleep efficiency, while patients on fluoxetine demonstrated a significant reduction in sleep efficiency and a significant increase in number of awakenings compared to baseline scores [Gillin et al., 1997].”

• cites Gillin et al., 1997 sourceNot checked — no full text of the source

May combine two claims.

In Nofzinger et al.'s study, REM latency tended to decrease from baseline to remission in bupropion-treated patients, in contrast to no change in cognitive therapy-treated patients and an increase in the fluoxetine group.

“REM latency tended to decrease from baseline to remission in patients treated with bupropion, in contrast to no change in cognitive therapy-treated patients and an increase in the fluoxetine group.”

• cites Nofzinger et al., 1995 sourceNot checked — no full text of the source

May combine two claims.

In normal volunteers, venlafaxine (75 mg on nights 3-4 and 150 mg on nights 5-6) significantly increased WASO and Stage I sleep from baseline on all four drug nights.

“They found WASO and minutes in Stage I were significantly increased from baseline on all four drug nights, while minutes in Stages II and III were reduced.”

• cites Salin-Pascaul et al., 1997Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Nefazodone exerts minimal effects in altering sleep continuity measures; it either decreases awake and movement time and number of awakenings, increases sleep efficiency, or has no effect on these parameters, thus preserving sleep continuity.

“First, nefazodone exerts minimal effects in altering sleep continuity measures.In this regard, nefazodone either decreases awake and movement time and number of awakenings, increases sleep efficiency, or has no effect on these parameters, thus preserving sleep continuity [Armitage et al., 1994[Armitage et al., , 1997;;Gillin et al., 1997;Sharpley et al., 1992Sharpley et al., , 1996;;Rush et al., 1”

• cites Armitage et al., 1994 sourceNot checked — no full text of the source
• cites Gillin et al., 1997 sourceNot checked — no full text of the source
• cites Sharpley et al., 1996 sourceNot checked — no full text of the source

May combine two claims.

Other antidepressants may be less sedating and less likely to shorten sleep latency, but may still be associated with a preservation of sleep continuity.

“Other antidepressants may be less sedating and less likely to shorten sleep latency, but may still be associated with a preservation of sleep continuity.”

May combine two claims.

Venlafaxine inhibits presynaptic uptake of 5-HT and NE and also exhibits some potency in inhibiting dopamine uptake.

“In addition to inhibiting presynaptic uptake of 5-HT and NE, venlafaxine also exhibits some potency in inhibiting dopamine uptake [Stahl, 1996].”

• cites Stahl, 1996Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

In Nofzinger et al.'s study, percentage of REM sleep and total REM time increased from baseline to treatment response in the bupropion group, whereas these measures were not significantly altered in the cognitive therapy or fluoxetine groups.

“Percentage of REM sleep and total REM time increased from baseline to treatment response in the bupropion group, whereas these measures were not significantly altered in either the cognitive therapy or fluoxetine groups.”

• cites Nofzinger et al., 1995 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Prospective data demonstrating differential responsiveness on the basis of sleep-effect profiling have yet to be reported.

“It must be emphasized, however, that prospective data demonstrating differential responsiveness on the basis of such profiling have yet to be reported.”

May combine two claims.

In normal volunteers, venlafaxine reduced REM sleep on all four drug nights and completely suppressed REM sleep in all subjects by the fourth night.

“More importantly, due to decreases in both frequency and duration, REM sleep was reduced on all 4 nights of drug and was completely absent in all subjects by the fourth night.”

• cites Salin-Pascaul et al., 1997Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Ware and Pittard reported that trazodone significantly increased deep sleep while preserving normal sleep architecture.

“Ware and Pittard [1990] reported that trazodone significantly increased deep sleep while preserving normal sleep architecture.”

• cites Ware and Pittard, 1990Not checked — no full text of the source

May combine two claims.

Nefazodone and fluoxetine both modulate serotonin activity, although through different mechanisms.

“As noted above, nefazodone and fluoxetine both modulate serotonin activity, although through different mechanisms.”

May combine two claims.

In that study, there was no change in REM percentage but REM latency increased 28%.

“There was no change in REM percentage but REM latency increased 28% [Scharf and Sachais, 1990].”

• cites Scharf and Sachais, 1990Not checked — no full text of the source

May combine two claims.

Citalopram may be less activating and therefore less likely to disrupt sleep continuity.

“It may be less activating, however, and therefore less likely to disrupt sleep continuity.”

May combine two claims.

Bupropion represents one of the few antidepressant drugs studied to date that does not suppress REM sleep, and similar to nefazodone, it increases REM and shortens REM latency.

“Thus, bupriopion represents one of the few antidepressant drugs studied to date that does not suppress REM sleep, and similar to nefazodone, it increases REM and shortens REM latency.”

• AssumptionRests on an assumption: The majority of antidepressant drugs produce a decrease in REM sleep associated with a prolongation of REM latency.

May combine two claims.

Other antidepressant drugs may be classified as being substantially activating, and may be associated with direct effects of disrupting sleep continuity in some cases.

“Finally, other antidepressant drugs may be classified as being substantially activating, and may be associated with direct effects of disrupting sleep continuity in some cases.”

May combine two claims.

In patients receiving nefazodone, total REM sleep time increased, in contrast to the expected REM suppression associated with fluoxetine treatment.

“study demonstrated an increase in total REM sleep time in patients receiving nefazodone in contrast to the expected REM suppression associated with fluoxetine treatment [Rush et al., 1998].”

• cites Rush et al., 1998 sourceFetching the cited paper…

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Cholinergic activation of the reticular formation produces REM sleep.

“Cholinergic activiation of the reticular formation produces REM sleep.”

May combine two claims.

Others, such as bupropion (an NE/DARI) and nefazodone (an SARI), lack REM suppressant effects.

“Others, such as bupropion (an NE/DARI) and nefazodone (an SARI), lack REM suppressant effects.”

• AssumptionRests on an assumption: The majority of antidepressant drugs produce a decrease in REM sleep associated with a prolongation of REM latency.

May combine two claims.

In a double-blind, placebo-controlled, crossover study of six healthy volunteers, a single 30 mg dose of mirtazapine decreased sleep latency, wake time, awakenings, and Stage I sleep, and increased slow wave sleep and the latency between sleep onset and the first REM episode.

“Mirtazapine ad-ministration decreased sleep latency, wake time, and awakenings and Stage I sleep, and increased slow wave sleep and the latency between sleep onset and the first REM episode.”

• cites Ruigt et al., 1990 sourceNot checked — no full text of the source

May combine two claims.

Bupropion has been characterized pharmacologically to inhibit reuptake of both NE and DA, and it is currently the only available antidepressant compound to demonstrate this unique profile.

“As noted above, bupropion has been characterized pharmacologically to inhibit reuptake of both NE and DA, and it is currently the only available antidepressant compound to demonstrate this unique profile.”

May combine two claims.

Mouret et al. noted increased total sleep time, decreased sleep latency, fewer awakenings, and an increase in delta sleep with increased REM latency associated with trazodone treatment in depressed inpatients.

“Mouret et al. [1988] noted increased total sleep time, decreased sleep latency, fewer awakenings, and an increase in delta sleep with increased REM latency associated with trazodone treatment in depressed inpatients.”

• cites Mouret et al., 1988 sourceNot checked — no full text of the source

May combine two claims.

Trazodone potently inhibits the α1 adrenergic receptor and the histamine H1 receptor.

“Trazodone, for example, potently inhibits the α 1 adrenergic receptor and the histamine H 1 receptor [Stahl, 1996].”

• cites Stahl, 1996Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

The relative contributions of bupropion's NE and DA effects to its clinical efficacy have not been established.

“While it is generally proposed that the antidepressant effects of bupropion are mediated by some combination of its effects on NE and DA, the relative contributions of these neuropharmacological effects to the clinical efficacy of buproprion have not been established.”

May combine two claims.

Results from Nofzinger et al. indicate that the primary effects of bupropion on sleep architecture relate to changes in REM parameters, including a tendency towards shortened REM latency and an increase in REM time and REM percent.

“Results from the Nofzinger et al. [1995] study indicate that the primary effects of bupropion treatment on sleep architecture relate to changes in REM parameters, including a tendency towards shortened REM latency and an increase in REM time and REM percent.”

• cites Nofzinger et al., 1995 sourceNot checked — no full text of the source

May combine two claims.

In a pilot study of six depressed patients with insomnia, mirtazapine (15 mg/day for one week then 30 mg/day for one week) significantly reduced sleep latency and significantly increased total sleep time and efficiency compared to baseline.

“There was a significant reduction in sleep latency and significant increases in total sleep time and efficiency as compared to baseline.”

• cites Winokur et al., 2000 sourceNot checked — no full text of the source

May combine two claims.

In Luthringer et al.'s study, the maximum dose employed was 225 mg/day, a moderate dose by clinical standards.

“In the Luthringer et al. [1996] study, the maximum dose employed was 225 mg/day, a moderate dose by clinical standards.”

• cites Luthringer et al., 1996Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

The differences between nefazodone and fluoxetine were observed both with respect to sleep continuity measures and to REM sleep.

“These differences were observed both with respect to sleep continuity measures and to REM sleep.”

May combine two claims.

Venlafaxine's dopaminergic effect is markedly less pronounced than its effects on 5-HT and NE, occurs only at higher doses, and is not generally considered significantly involved in its antidepressant mechanism.

“This dopaminergic effect is markedly less pronounced than effects on 5-HT and NE, only occurs at higher doses, and is not generally considered to be significantly involved in the presumed mechanism of action of antidepressant efficacy.”

• cites Stahl, 1996Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

This preliminary study suggests that mirtazapine improves sleep continuity, sleep efficiency, and clinical signs of depression without suppressing REM sleep.

“This preliminary study suggests that mirtazapine improves sleep continuity, sleep efficiency, and clinical signs of depression without suppressing REM sleep.”

May combine two claims.

Trazodone did not influence sleep continuity or slow wave sleep, but significantly suppressed REM sleep and increased REM latency in depressed patients.

“Trazodone did not influence sleep continuity or slow wave sleep, but significantly suppressed REM sleep and increased REM latency in depressed patients [van Bemmel and Havermans, 1992].”

• cites van Bemmel and Havermans, 1992 sourceNot checked — no full text of the source