What to do when comorbid depression and sleep disorders are resistant to treatment  

Please follow this instruction

To prepare for this Discussion:

Case 1: Volume 2, Case #16: The woman who liked late-night TV

The Case: The woman who liked late-night TV  The Question: What to do when comorbid depression and sleep disorders are resistant to treatment  The Dilemma: Continuous positive airway pressure (CPAP) may not be a reasonable option for treating apnea; polypharmacy is needed but complicated by adverse effects.

Review the patient intake documentation, psychiatric history, patient file, medication history, etc. As you progress through each section, formulate a list of questions that you might ask the patient if he or she were in your office.

· Based on the patient’s case history, consider other people in his or her life that you would need to speak to or get feedback from (i.e., family members, teachers, nursing home aides, etc.).

· Consider whether any additional physical exams or diagnostic testing may be necessary for the patient.

· Develop a differential diagnoses for the patient. Refer to the DSM-5 in this week’s Learning Resources for guidance.

· Review the patient’s past and current medications. Refer to Stahl’s Prescriber’s Guide and consider medications you might select for this patient.

· Review the posttest for the case study.

Learning Resources

Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY: Cambridge University Press.

Stahl, S. M. (2014b). The prescriber’s guide (5th ed.). New York, NY: Cambridge University Press.

Review the following medications:

For insomnia

· alprazolam

· amitriptyline

· amoxapine

· clomipramine

· clonazepam

· desipramine

· diazepam

· doxepin

· flunitrazepam

· flurazepam

· hydroxyzine

· imipramine

· lorazepam

· nortriptyline

· ramelteon

· temazepam

· trazodone

· triazolam

· trimipramine

· zaleplon

· zolpidem

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: Author.

Davidson, J. (2016). Pharmacotherapy of post-traumatic stress disorder: Going beyond the guidelines. British Journal of Psychiatry, 2(6), e16-e18. doi:10.1192/bjpo.bp.116.003707. Retrieved from http://bjpo.rcpsych.org/content/2/6/e16

The case Study

PATIENT FILE

The Case: The woman who liked late-night TV

The Question: What to do when comorbid depression and sleep disorders

are resistant to treatment

The Dilemma: Continuous positive airway pressure (CPAP) may not be a

reasonable option for treating apnea; polypharmacy is needed but

complicated by adverse effects

Pretest self-assessment question (answer at the end of the case)

Which of the following hypnotic agents is less likely to be addictive, impair

psychomotor function, or cause respiratory suppression?

A. Ramelteon (Rozerem)

B. Zolpidem (Ambien)

C. Doxepin (Silenor)

D. Temazepam (Restoril)

E. A and C

F. B and D

G. None of the above

Patient evaluation on intake

• 70-year-old female with a chief complaint of “being sad”

• Feels she had been doing well until her hearing began to diminish in

both ears

– Candidate for cochlear implants in the future, but this is a long way off

– Despite the promise of improved hearing, she often has crying spells

for no clear reason

Psychiatric history

• The patient has been without psychiatric disorder throughout her life

• Has felt increasingly sad over the last year and these feelings were not

triggered by an acute stressor

• Lives alone with the help of a home aide

– Her spouse died many years ago due to CAD

– Despite her aide and her son who visits often, she is having a

harder time coping with both instrumental and basic activities of

daily living

• She admits to full MDD symptoms

– She is sad, has lost interest in things she used to enjoy, and is

fatigued with poor focus and concentration

– Denies feelings of guilt, worthlessness, or any suicidal thoughts

– Appears mildly psychomotor slowed

– Additionally states that sleep is “awful”

◦ Does not fall asleep easily as her legs “ache and jump”

◦ Takes frequent naps during the day as a result

◦ She admits to snoring frequently

• There is no evidence of cognitive decline or memory problems

• She has a supportive son who accompanies her to all appointments and

helps provide her care

Social and personal history

• Graduated high school, was married, and raised her children

• Denied any academic issues, learning disability, or ADHD symptoms

growing up

• Having and maintaining friendships has been easy and successful over

the years

• At times, she is lonely at home

• Her mobility has declined somewhat, which limits her going out

• Participates in activities at a local elders’ center

• No history of drug or alcohol problems

Medical history

• HTN

• Hypothyroidism

• CAD

• Anemia

• Environmental allergies

• Obesity

Family history

• Reports AUD throughout her extended family

• MDD reportedly suffered by her mother

Medication history

• Never taken psychotropic medications

Psychotherapy history

• Recently, has gone to a few sessions of outpatient supportive

psychotherapy, but her hearing loss makes this modality almost

impossible

– Hearing aids have failed to help

– May be a candidate for cochlear implants

• She has a fax machine at home and states that she and her therapist

often fax notes back and forth, which she finds helpful as receiving them

brightens her mood

– Perhaps this is “supportive facsimile therapy”

PATIENT FILE

Patient evaluation on initial visit

• Gradual onset of geriatric, first-episode MDD symptoms likely as a result

of hearing loss and mobility loss

• This caused interpersonal disconnectedness, loneliness, and onset of

MDD

• Suffers from daily crying spells and seems very tired

• Has good insight into her illness and wants to get better

• There appears to be no suicidal or safety concerns clinically

• The fatigue and possible infirmities of strength and balance may be

problematic if side effects compound these symptoms

Current medications

• Furosemide (Lasix) 40 mg/d

• Lisinopril (Zestril) 40 mg/d

• Levothyroxine (Synthroid) 100 mcg/d

• Enteric-coated aspirin 325 mg/d

• Fexofenadine (Allegra) 180 mg/d

• Ferrous sulfate 1000 mg/d

Question

Interpersonal approaches to psychotherapy would suggest that social

disconnection and loss of role function causes depression, and treating this

patient by changing the way she thinks, feels, and acts in problematic

relationships may help. Does this make sense for this particular patient?

• Yes, this approach is evidence based in terms of providing IPT

• Yes, this approach clinically fits this patient’s precipitating events prior to

developing MDD

• Yes, for the reasons noted. However, her inability to hear well might

render IPT difficult to apply and outcomes difficult to achieve

Attending physician’s mental notes: initial evaluation

• Patient has her first MDE now

• It appears chronic in nature, but essentially, has been untreated

• It seems more than an adjustment disorder as it is pervasive, lasting over

time, and clearly disabling at this point

• As this is an initial MDE and an initial foray into treatment with good

family support, her prognosis is good

• However, her older age of onset, loss of hearing, mobility, and marked

medical comorbidity are concerning

• Psychotherapy, especially IPT-based, would be clearly indicated but

difficult to deliver adequately

PATIENT FILE

Question

Which of the following would be your next step?

• Start an SSRI such as citalopram (Celexa)

• Start an SNRI such as duloxetine (Cymbalta)

• Start an NDRI such as buporpion-XL (Wellbutrin-XL)

• Start an NaSSA such as mirtazapine (Remeron)

• Start a SPARI such as vilazodone (Viibryd)

• Start a SARI such as trazodone-ER (Oleptro)

• Start a multimodal serotonin receptor modulating antidepressant

with geriatric depression/cognition data, such as vortioxetine

(Brintellix)

Attending physician’s mental notes: initial evaluation (continued)

• This case seems easy in that she is untreated up to this point; therefore,

any antidepressant has a chance of working

• However, there is concern regarding her obesity and lethargy; thus,

avoiding medications with high weight-gain side-effect burden is

warranted

• Sleep is also very disrupted

– By initial insomnia, which may be caused by her depression

– Perhaps by restless legs syndrome (RLS)

– It is unclear if she snores and has OSA

• Hearing loss and inability to communicate well is also problematic in

providing her with good psychotherapy

– Even delineating symptoms in the medication management session

is a difficult task

– Likely need to pressure and advocate for the cochlear

implants acting as an antidepressant in order to advance this

process

Further investigation

Is there anything else you would especially like to know about this patient?

• She has marked fatigue; have medical causes been ruled out?

– She is euthyroid and her anemia is stable with a normal hematocrit

– Her cardiac function is stable and without compromise

– If she has RLS, this could account for her fatigue and should be

investigated

– If she has OSA, this could account for her fatigue and should be

investigated

PATIENT FILE

Case outcome: first interim follow-up visit four weeks later

• Citalopram (Celexa), an SSRI, was started at 10 mg/d and titrated to

20 mg/d

• She appears less weepy and is in a partial response

• Still is not sleeping well

• Denies any typical side effects

Question

Would you increase her current SSRI medication?

• Yes

• Yes, only if it appears that she is partially better and her response has

reached a plateau in this partial response range

• No, she is a partial responder with only four weeks of treatment. Longer

treatment may allow for remission

• No, addition of a sleeping pill may treat insomnia and result in improved

energy and concentration, thus facilitating a better overall response via

polypharmacy

• No, citalopram carries cardiac warnings, especially in geriatric MDD

patients

Attending physician’s mental notes: second interim follow-up visit

at two months

• Despite being a little better, the patient is still suffering

• She is crying less but there is now more of a need to improve her sleep

and daytime fatigue issues

• She has clinical risks for OSA (HTN, obesity, large neck size), and if this

is a positive finding, CPAP treatment may be an excellent choice for her

apnea and her depression residual symptoms

• Her access to a sleep laboratory is limited and it may take months to

have the study completed

Case outcome: second interim follow-up visit at two months

• Citalopram (Celexa) is increased gradually, given her age, to 30 mg/d

– Historically, the QTc prolongation warning did not exist when this

patient was prescribed this medication

– Currently, use above 20 mg/d is discouraged in the elderly

◦ If a higher dose is needed clinically, it would make sense to obtain

plasma levels and an EKG in the current era

• Sleep electrophysiology is ordered to rule out OSA, RLS

• She is placed on off-label tiagabine (Gabitril) as a hypnotic in order to

avoid more respiratory suppressing, psychomotor impairing, sedativehypnotic

BZ or BZRA agents

PATIENT FILE

– This agent has human sleep laboratory data suggesting it increases

slow wave, restorative deep sleep

– Its theoretical mechanism of action is GABA reuptake inhibition,

selectively at the GAT1 transporter, making it an SGRI

– She is allowed to titrate to 6 mg/d at bedtime

– This agent, interestingly, is approved to treat epilepsy but came out

with a warning, well after this patient utilized this “drug” therapy that

tiagabine might actually induce seizures in non-epileptic patients

• The patient subsequently shows moderate improvement in her affect

• Experiences slightly less RLS

• Is not initiating sleep any better

• She is felt to be 20%–30% better globally, but is plagued by daytime

fatigue as a chief complaint

– This may actually be occurring due to the adverse effect profile of

tiagabine (Gabitril)

Question

What would you do next?

• Continue escalating her SSRI to a higher dose

• Switch or augment with a more stimulating antidepressant

• Augment with a formal stimulant

• Add a formal hypnotic agent to better improve sleep

Attending physician’s mental notes: second interim follow-up visit

at two months (continued)

• Cannot wait months for a sleep study

• Her SSRI is at a reasonable, moderate dose, and has effectively treated

the target symptom of sadness and dysphoria

– Switching from this may cause a relapse

• Adding a noradrenergic or dopaminergic agent may target her fatigue

symptoms a little better

• Adding a hypnotic may improve her sleep, and secondarily, her next day

wakefulness, but need to watch for respiratory suppression and

psychomotor impairment, especially if she has severe undiagnosed OSA

Case outcome: interim follow-up visits through four months

• The NDRI bupropion-XL(Wellbutrin-XL) is added to her SSRI and titrated

to 300 mg/d

– There is moderate improvement in her vegetative MDD symptoms

and her drive and motivation improves slightly

• Zaleplon (Sonata) 5 mg at bedtime is started in place of tiagabine

(Gabitril) with improved sleep onset overall, but she still reports RLS

PATIENT FILE

– Zaleplon is chosen as the shortest half-life (1 h) BZRA, and in theory,

should have least impact on psychomotor impairment or respiratory

suppression in this class of sleep-inducing agents

• Further workup suggests she meets criteria for RLS. Sleep study is still

pending

• Cochlear implants are approved and surgery scheduled

Question

What would you do next?

• Increase the bupropion-XL (Wellbutrin-XL) to the approved maximum

450 mg/d

• Increase the citalopram (Celexa) further above the geriatric approved

maximum dose

• Increase zaleplon (Sonata) toward the approved maximum of 20 mg/d

(10 mg/d in the elderly)

• As she is a partial responder, make no changes until her cochlear

implants are in place and her sleep study is performed

Attending physician’s mental notes: interim follow-up visits

through four months

• Fairly good resolution of dysphoria is reported but insomnia and fatigue

are still a major problem

• It will still be a while for her to obtain a sleep study and she likely

has OSA clinically, thus markedly increasing a sedative at night is

worrisome

• RLS is now more concerning to the patient, and she admits she likes to

stay up watching late-night TV

– The initial insomnia may be more of a circadian rhythm sleep

disorder (CRSD) in that she is choosing to stay up late and then has

to get up early when her home health aide arrives

– She is inappropriately awake in the early morning hours and

inappropriately tired during the daytime. A circadian delayed phase

shift has occurred

• Perhaps a “win–win” situation exists where her RLS and initial insomnia

could be treated with one medication

– This was attempted with tiagabine (Gabitril)

◦ This helped the RLS

◦ Did not improve her sleep onset

◦ Left her more fatigued in the morning

◦ Could consider using another off-label antiepileptic medication,

given her partial RLS response to tiagabine and hope for less

daytime fatigue

PATIENT FILE

• A literature search suggests that gabapentin (Neurontin) does have a

limited evidence base showing effectiveness in RLS

– Otherwise, an option would be to choose a formal RLS-approved

dopaminergic medication such as pramipexole (Mirapex) or

ropinirole (Requip)

– These D2 receptor agonists have some data suggesting they may

provide antidepressant response but fatigue is a key side effect

– It might help fatigue at night, but the daytime fatigue may be a

problem

Case outcome: interim follow-up visits through nine months

• Gabapentin (Neurontin) is titrated to 300 mg twice a day as patient also

has RLS symptoms intermittently through the day as well

• Zaleplon (Sonata) 5 mg at bedtime is still allowed, but only as needed for

severe insomnia

• SSRI (citalopram [Celexa]) and NDRI (bupropion-XL [Wellbutrin-XL]) are

continued at the same doses, 30 mg/d and 300 mg/d, respectively

• There is remission of MDD symptoms

• RLS resolves and she sleeps better with minimal morning fatigue

• However, she still seems to go to bed after midnight due to watching TV

– Patient and family educated about sleep hygiene and behavioral

management of sleep initiation

– It is not possible to ask the home health aide to arrive later due to her

schedule, so the patient cannot sleep late to allow for an adequate

number of hours of sleep

• Her sleep study shows moderate OSA

– She is fitted for a CPAP mask, which causes discomfort and

claustrophobia and she declines to wear it

• Medications with known sedation side effects are moved to afternoon or

dinner-time to avoid iatrogenic sedation in the morning

Attending physician’s mental notes: interim follow-up visits

through 12 months

• Patient has been doing very well on moderate dose of two

antidepressants and a hypnotic agent used as needed

• RLS is well treated with a low-dose antiepileptic

• Cochlear implants are implanted and work very well. She is able to hear

and converse, which has helped lower her social isolation and likely has

helped her depression

• There are minimal to no side effects and she agrees to maintain these

medications

• Compliance and family support are excellent

234

PATIENT FILE

Case outcome: interim follow-up visits through 18 months

• There is a resurgence of insomnia and daytime fatigue

• Zaleplon (Sonata) is increased to a 10 mg dose at bedtime, which is

used more routinely, but is ineffective

– This is discontinued and she is allowed to take the next

longest half-life BZRA hypnotic, zolpidem (Ambien) up to 10 mg at

bedtime

• Sleep improves some, but sometimes she still chooses to watch TV and

go to bed late

– One morning she falls asleep at the breakfast table in front of her

home health aide

– She later falls and fractures her arm and requires inpatient physical

rehabilitation

– While there, develops panic attacks and is treated by the inpatient

physician successfully with the BZ anxiolytic, alprazolam (Xanax), in

low doses (0.25 mg as needed)

• Upon returning home, she discontinues the alprazolam anxiolytic

– Is not depressed but her insomnia and fatigue continue

– Still refuses CPAP treatment and behavioral modification measures

fail to help

– It becomes clear that at night, her sleep patterns and use of her

zolpidem (Ambien) are erratic

• Instead of trying to induce sleep to improve daytime fatigue, which is

likely due to OSA, the patient and son agree to approach her case with

regard to providing more daytime wakefulness with a stimulant

medication

– Starts modafinil (Provigil) as it is approved for OSA fatigue and likely

has fewer cardiac and blood pressure adverse effects than true

stimulant-class medications

• Given her fall on full-dose zolpidem (Ambien) and her OSA, it is agreed to

remove sedative-type medications

• However, providing better sleep initiation is still needed

– Ramelteon (Rozerem), an MT1/MT2 receptor agonist hypnotic

agent, is started

◦ This should provide for better sleep onset without the risk of

much respiratory suppression or falls

◦ This combination should allow better daytime alertness with a

relative absence of morning fatigue side effects and likely less

risk for developing ataxia, psychomotor impairment, and fall

potential

PATIENT FILE

Case debrief

• Over the next several months, the patient ultimately is maintained in an

MDD-free state, RLS-free state, and the OSA fatigue is reduced by at

least 50% by use of modafinil (Provigil), which clearly improves her

quality of life

• Her current regimen includes:

– Citalopram (Celexa) 20 mg/d

– Bupropion-XL (Wellbutrin-XL) 300 mg/d

– Gabapentin (Neurontin) 600 mg/d

– Modafinil (Provigil) 400 mg/d

– Ramelteon (Rozerem) 16 mg/d

• Modafinil had to be escalated to its full dose to allow for its sustained

response (400 mg/d)

• Ramelteon had to be doubled over the approved 8 mg dose for better

effectiveness (16 mg at bedtime)

• Citalopram was reduced to 20 mg/d as it was felt to be contributing to

fatigue

• Finally, after a physical rehabilitation stay, her need or desire to stay up

late for TV watching diminished and her home health aide adjusted her

schedule to arrive a bit later in the morning

– These behavioral modifications seemed to improve her CRSD

symptoms and improved her quality of life because her delayed

phase shift was allowed to continue instead of being resisted

◦ Essentially, as her health aide could come later, the patient was

allowed to sleep in and obtain more consecutive hours of sleep

Take-home points

• Geriatric depression is complicated given the psychosocial issues that

must be navigated, medical comorbidities that are present, and the

possibility of more pronounced side-effect burden in this age group

• Sometimes treating the depression is simple, but treating the

comorbidities require more effort or collaboration with other providers to

optimize treatment

– In this case, collaboration with otolaryngology, pulmonology–sleep

medicine, primary care, physical medicine and rehabilitation, home

healthcare, and the family often occurred

Performance in practice: confessions of a psychopharmacologist

• What could have been done better here?

– Unlike other cases in this book, this patient was not escalated to the

maximum higher dose monotherapy before combination therapy

was started

PATIENT FILE

◦ Polypharmacy ultimately helped this patient and worked to lower

her symptoms

◦ It is possible that her medications could have been further

streamlined by removing her SSRI and leaving her NDRI

in place

– Given her OSA and tendency toward falls, BZ and BZRA sleepinducing

agents likely should have been avoided

– Interestingly, well after this patient was treated with citalopram and

tiagabine, FDA warnings were given about QTc prolongation and

seizure induction, respectively

◦ As such, these may be poor treatment options currently

• Possible action items for improvement in practice

– Research information on CPAP equipment. It is possible that newer

generations of equipment might be less cumbersome and

claustrophobia inducing

◦ This information could be used in a motivational format to improve

CPAP compliance and avoid excess medication use to treat residual

fatigue

◦ Dental appliances that fit like mouth guards may be utilized

instead of CPAP to keep her airways open more at night

– Become aware of available hypnotic agents that are not addictive and

for those that have less psychomotor impairment and respiratory

suppression, e.g., ramelteon (Rozerem), doxepin (Silenor),

doxylamine (Unisom), suvorexant (Belsomra)

– These agents are Non-BZ and Non-BZRA

Tips and pearls

• Shorter half-life hypnotic agents have a shorter span of clinical

effectiveness and often provide somnolence for four to six hours, e.g.,

zaleplon (Sonata) and zolpidem (Ambien Intermezzo)

• Shorter half-life hypnotic agents often are fully metabolized after four to

eight hours of sleep and should have less impact with regard to causing

morning sedation or impairment

– Despite this, the FDA recently suggested that lower doses of

the BZRA agents be utilized to avoid psychomotor daytime

impairment

• Intermediate and longer-acting hypnotic agents provide for longer

durations of sleep maintenance but may also allow for more side effects

upon awakening, e.g., zolpidem-CR (Ambien-CR) and eszopiclone

(Lunesta)

PATIENT FILE

Mechanism of action moment

Does melatonin facilitation induce sleep or remove wakefulness?

• Endogenous melatonin is secreted by the pineal gland during darkness

and acts mainly in the SCN to regulate circadian rhythms

• There are three types of receptors for melatonin: MT1 and MT2,

which are both involved in sleep, and MT3, which is the enzyme NRH:

quinone oxidoreductase-2, and not thought to be involved in sleep

physiology

– Specifically, MT1 receptor agonism, by way of endogenous

melatonin at nighttime or by direct agonism through ramelteon use,

may allow for inhibition of neurons in the SCN that are responsible for

promoting wakefulness

◦ With this mechanism, MT1 receptor activation removes

wakefulness at the level of the circadian “clock” or

“pacemaker”

◦ The SCN’s alerting signals, dampened by melatonin, likely do not

stimulate the reticular activating system (RAS)

◦ Monoamine transmission (DA, NE) from the brainstem is

attenuated secondarily

◦ This mechanism removes the brain’s ability to create an aroused,

wakeful state, thus allowing sleepiness to occur

– Phase shifting (being routinely awake or somnolent at the wrong

hours of the day/night) and circadian rhythm effects of the normal

sleep/wake cycle are thought to be primarily mediated by MT2

receptors, which entrain these signals in the SCN

– This is important for the following reasons

◦ Worsening sleep, by way of phase-delayed circadian rhythms

(similar to this patient), tends to worsen MDD symptoms

◦ Brain neurogenesis, learning, and memory may also be impacted

negatively

◦ Deep sleep may increase neurotrophic factors and growth

factors

◦ Interestingly, SSRIs, TCAs, ECT, and possibly psychotherapy

may also increase neurotropic factors in the CNS

• There are several different agents that act at melatonin receptors, as

shown in Figure 16.1

PATIENT FILE

MT2

MT3

MT1 MT1 MT2

Ramelteon

and Tasimelteon

Melatonin

Figure 16.1. Melatonergic agents.

• Endogenous melatonin, or over-the-counter preparations, act at MT1

and MT2 receptors as well as at the MT3 site

• Ramelteon (Rozerem) is an MT1 and MT2 receptor agonist hypnotic

agent available by prescription for sleep initiation

• Tasimelteon (Hetlioz) is also an MT1 and MT2 receptor agonist

specifically approved for “non-24” patients. These patients are blind, do

not respond to typical day/night cues, and develop persistent CRSD

– By increasing brain derived neurotrophic factor (BDNF) and

improving neurogenesis

– By antagonizing 5-HT2C receptors, which facilitates NE and DA

neurotransmission to the frontal cortex

Two-minute tutorial

Restless legs syndrome: what should psychiatrists know?

Diagnosis

• Patients develop an urge to move their legs, often accompanied by

or felt to be caused by uncomfortable and unpleasant sensations

in the legs

• The urge to move and unpleasant sensations begin, or worsen, during

periods of rest or inactivity, such as lying down or sitting

• These sensations are often relieved by movement, such as walking or

stretching, at least as long as the activity continues

• These symptoms occur or are worse in the evening or night compared to

the day

Etiology

• 60% of RLS patients report a positive family history for RLS

• Genetic association studies have now identified five genes and 10

different risk alleles for RLS

PATIENT FILE

• One of the allelic variations associated with increased risk of RLS is also

associated with decreased serum ferritin, indicating relative reduction in

body iron stores

• Theoretically, brain iron deficiency may produce dopaminergic

pathology producing RLS symptoms. This iron–DA hypothesis may best

explain the pathology of RLS

• Initial cerebrospinal fluid (CSF), autopsy, and brain imaging studies

showed expected brain iron deficiency particularly affecting the

DA-producing cells in the substantia nigra

• Animal and cellular iron deficiency studies have suggested that

tyrosine hydroxylase activity in the substantia nigra, decreased

D2 receptors in the striatum, decreased DAT functioning, and

increased extracellular DA, with larger increases in the amplitude of the

circadian variation of extracellular DA exist in RLS models

• These same findings have largely been replicated in RLS patients,

revealing the iron–DA link

• Specifically, brain iron deficiency affects dopaminergic function

• First, by increasing tyrosine hydroxylase, which then increases

extracellular DA

• This results in a decrease in DAT (reuptake pumps) on the cell surface

(DAT downregulation)

• In extreme cases, it also causes a decrease in the number of D2

receptors on neuronal surfaces (receptor downregulation)

• In these cases, RLS is a hyperdopaminergic condition with an apparent

postsynaptic dopaminergic desensitization that overcompensates

during the circadian low point of dopaminergic activity in the evening and

night

• Counterintuitively, this leads to the RLS symptoms that can be easily

corrected by adding D2 receptor agonist medications at night

• Essentially, more DA activity is added to overcome the desensitization

• This D2 receptor agonist prescription-induced excess activity is very

effective at calming RLS symptoms

• However, this sometimes leads to RLS augmentation where RLS may

actually worsen in a select few patients over longer-term treatment

because this creates a further imbalance of greater DA activity in the face

of even more downregulation of receptors

• RLS may also be related to cortical sensorimotor

dysfunction

• This would be consistent with the disruptions in the adenosine and

dopaminergic systems regulating sensorimotor responses that have

been reported for iron deficiencies noted here

• RLS often is comorbid with MDD, which is also known to have DLPFC

hypoactivity

PATIENT FILE

• In this manner, MDD and RLS may share overlapping dysfunctional

frontocortical DA neurocircuits

RLS and comorbidity

• Health-related quality of life is substantially reduced in RLS patients and

is comparable to other chronic neurological disorders such as

Parkinson’s disease and stroke

• Severity of RLS plus MDD symptoms have the most significant negative

impact on quality of life

• RLS is also common in those who are pregnant, suffer from renal

disease, or rheumatoid arthritis

RLS treatment

• Dopaminergic drugs are the first-line treatment and have been shown to

relieve symptoms in 70%–90% of patients

• Ropinirole (Requip) and pramipexole (Mirapex) are approved agents that

are D2 receptor agonists

• Adverse effects include induction of compulsive behaviors, nausea,

asthenia, sedation, somnolence, syncope, hallucinations, or dyskinesias

• Oral iron treatment may significantly reduce RLS severity

• Opioids may be considered for patients presenting with neuropathy or

painful dysthesias

• Alpha-2-delta calcium channel blocking anticonvulsants (gabapentin

[Neurontin] or pregabalin [Lyrica]) have also been studied, showing RLS

symptom reduction

Posttest self-assessment question and answer

Which of the following hypnotic agents is less likely to be addictive, impair

psychomotor function, or cause respiratory suppression?

A. Ramelteon (Rozerem)

B. Zolpidem (Ambien)

C. Doxepin (Silenor)

D. Temazepam (Restoril)

E. A and C

F. B and D

G. None of the above

Answer: E

Ramelteon and doxepin are not GABA-A receptor positive allosteric

modulators (PAMs), are therefore not related to the true BZ or BZRA class of

hypnotics, are not associated with addiction, and appear to have little to no

respiratory suppression or psychomotor impairment, comparatively speaking.

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