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with amoxapine. There are no studies objectively measur-
ing sleepiness. Minimal data suggest little cognitive impair-
ment with maprotiline. 15  In healthy individuals, mianserin 
impaired driving and tracking performance as well as reac-
tion time and other psychomotor measures. 12 , 44  Agomela-
tine,  recently  approved  for  treatment  of  depression  in 
Europe,  is  a  potent  agonist  at  both  melatonin MT 1   and 
MT 2   receptors  as  well  as  an  antagonist  at  serotonergic 
5-HT 2C   receptors. Limited  non-placebo-controlled  PSG 
data  in  depressed  patients  showed  increases  in  sleep  efi-
ciency and SWS without effects on REM sleep compared 
with baseline. 59
but  insomnia  has  also  been  reported.  Among  the  older 
drugs, chlorpromazine and thioridazine appear to be more 
sedating than haloperidol. Clozapine is even more sedating 
than these drugs (with transient sedation reported by 54% 
of  patients,  persistent  sedation  by  46%,  and  sedation 
requiring  drug  discontinuation  by  24%) 66 ;  aripiprazole  is 
the  least  sedating.  Whereas  ziprasidone  and  quetiapine 
would  be  expected  to  be  sedating  given  their  pharmaco-
logic proiles,  they appear  less sedating  than other drugs, 
possibly because of their short half-lives. Insomnia occurs 
at variable rates with these drugs. Although the mechanism 
is not clear, options include 5-HT 1A  receptor agonism and 
restless legs symptoms secondary to dopaminergic antago-
nism. 64   Restless  legs  syndrome  symptoms  have  been 
reported as case reports  for olanzapine, risperidone, que-
tiapine, and clozapine. 67
There  are  few  double-blind  placebo-controlled  PSG 
studies  of  antipsychotics  in  healthy  normals  and  none  in 
schizophrenia  patients.  Small-sample  controlled  studies 
indicate  that  olanzapine,  quetiapine,  and  ziprasidone 
decrease  sleep  latency and  improve  sleep continuity. 64,67,68
Uncontrolled  studies  suggest  that  clozapine,  haloperidol, 
and risperidone also improve sleep. 69  REM suppression is 
variable,  whereas  increased  SWS  is  typical,  except  for 
quetiapine. 64 , 67
There  are  no  MSLT  or  other  studies  that  objectively 
evaluate daytime sleepiness.
Although antipsychotics cause cognitive  impairment  in 
healthy subjects, 70  these drugs may have no negative effects 
in patient populations. 71  Some of the newer drugs, in par-
ticular, appear to be more likely to improve cognitive func-
tion in patients despite significant sedation.65 65
LITHIUM
Lithium,  which  is  used  primarily  in  the  treatment  of 
manic-depressive  illness,  is  subjectively  associated  with 
improved  nocturnal  sleep  and  increased  daytime  sleepi-
ness,  at  least  initially. 60   Sleep  disturbance  is  a  prominent 
feature of mania and similar polysomnographically to that 
observed  in  major  depression. 61   In  healthy  volunteers, 
lithium increases SWS and decreases REM sleep 62 ; it pro-
duces  cognitive  and  psychomotor  deicits,  including  pro-
longed reaction times, decreased vigilance, and impairment 
of semantic reasoning. 61  Similar deicits have been shown 
in  psychiatric  patients  taking  lithium  for  periods  ranging 
from  2  weeks  to  longer  than  3  months, 63   although  it  is 
difficult  to  determine  whether  the  deficits  seen  in  the 
patient  population  are  caused  by  the  medication  or  the 
psychiatric  illness.  Degree  of  cognitive  deficit  increases 
with age, severity of disease, and lithium concentration.
Antipsychotic Drugs
Table 46-2   summarizes  the  effects of  antipsychotic drugs 
on sleep and waking behavior. Sedating drugs used as hyp-
notics  (olanzapine,  quetiapine)  are  covered more  fully  in 
Chapter 43.
Antipsychotic  drugs  have  complex  pharmacologic  pro-
iles. Their  antipsychotic  effects  are  thought  to be medi-
ated primarily by antagonism of dopamine D 2  receptors in 
the  mesolimbic  dopamine  pathway. 64   These  drugs  also 
block  dopamine  receptors  in  other  neural  pathways, 
leading to unwanted effects such as anhedonia, extrapyra-
midal symptoms, and hyperprolactinemia, which are com-
monly seen with the older or “typical” antipsychotics (e.g., 
chlorpromazine,  haloperidol,  thioridazine). These  effects 
are  decreased  with  the  newer  or  “atypical”  antipsychotic 
drugs, which  in addition  to blockade of dopamine  recep-
tors  also  antagonize  serotonin  receptors  (especially 
5-HT 2A ), have the ability to dissociate from D 2  receptors, 
may  have  partial  agonist  activity  at D 2   receptors,  or may 
act  as  partial  agonists  at  serotonin  5-HT 1A   receptors. 50
These  drugs  differ  in  their  specificity  for  dopamine  D 2
versus D 1  receptors and also differ in the degree to which 
they  block muscarinic  cholinergic,  histamine,  and  alpha-
adrenergic  receptors  (see  Table 46-2 ). 65  Sedation  is more 
likely  in drugs with relatively more potent antagonism of 
histamine,  alpha-adrenergic,  or  5-HT 2   receptors  com-
pared with antagonism of dopamine receptors. 66
Patients  with  schizophrenia  commonly  have  insomnia 
and  circadian  rhythm  disturbances  as  well  as  cognitive 
impairment, complicating evaluation of the effects of anti-
psychotic medications. Sedation  is  a  common  side  effect, 
Anxiolytic Drugs
The primary drugs used in the treatment of anxiety disor-
ders  include  antidepressants  (particularly  SSRIs  and 
SNRIs), benzodiazepines, and buspirone, a 5-HT 1A  recep-
tor partial agonist. Antiepileptics and atypical antipsychot-
ics are also sometimes used. Prazosin, an antihypertensive 
with alpha 1 -adrenergic antagonism, has been used to treat 
nightmares in posttraumatic stress disorder. 72  Antidepres-
sants,  antiepileptics,  and  antipsychotics  are  covered  else-
where  in  this  chapter.  Benzodiazepines  approved  for 
treatment  of  anxiety  disorders  (e.g.,  alprazolam,  clonaze-
pam,  diazepam,  lorazepam)  have  pharmacologic  profiles 
similar to those of benzodiazepines used to treat insomnia 
and  thus  similar  side  effects.  Given  that  these  drugs 
enhance GABA at the GABA A  receptor, their most common 
side  effect  is  sedation. 60   In  nonanxious  subjects,  daytime 
administration  of  alprazolam  and  diazepam  produced 
decreased  sleep  latencies  as measured  by MSLT  on  both 
day 1 and day 7 of treatment, with alprazolam producing 
greater sleepiness than diazepam on the first day of treat-
ment. 73  Performance impairment, including impairment of 
actual driving performance, 74  is common with benzodiaz-
epines in studies of normal subjects and patient groups for 
treatment periods of up to 3 weeks, particularly at higher 
doses.  Well-controlled  studies  are  needed  to  determine 
whether  longer  term  use  of  benzodiazepine  anxiolytics 
results in tolerance to these performance-impairing effects 
and whether there are differential effects between younger 
and older individuals.
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