Depresion, mental status testing, addiction and skin and bone

infectrions

10/07/11

Which of the following is the most common comorbidity

associated with nonresponse to antidepressants?

 A) Diabetes B) Posttraumatic stress disorder

(PTSD) C) Hypothyroidism D) Substance abuse

Answer

•  D) Substance abuse

Understanding antidepressant nonresponse• since physicians diagnose depression on basis of symptoms and

history, many patients with other illnesses meet diagnostic criteria

• (must rule out, eg, thyroid disease, unrecognized diabetes, malignancies)

• medication selection—important

• since predicting responses not possible, iterative trials required

• adherence—one-third of patients choose not to refill prescriptions

• in Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, each treatment failure resulted in loss of 10% to 20% of patients

According to data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, two-thirds of patients who responded to their treatments reported benefits

after: A) 12 wk B) 8 wk C) 6 wk D) 3 wk

Answer

•  C) 6 wk

• Focus on improved methods of engaging, preparing, and ensuring follow-through with patients requiring continued treatment;duration—guidelines recommend 8-wk trial, but speaker argues that likelihood of response low if not seen after first 2 wk

• disability, complexity, and comorbidities—patients with poor natural history or prognosis often have poor responses (10%-20% efficacy in some groups) and may require different framework of expectations or time course

• focus on establishing unit of symptom benefit (not remission

Common causes of nonresponse• Nonadherence• Unrecognized bipolarity—antidepressants show poor efficacy in patients with bipolar disorder

(BD) or bipolar spectrum features• unrecognized psychosis — late-life depression may present with delusions and hallucinations• psychotic depression often accompanies severe recurrent illness in patients 60 to 70 yr of age, but

may occur earlier in life• psychosis plus depression in younger patients may indicate bipolarity• since patients may• mask delusions or hallucinations, watch for near-psychotic signs (eg, perplexity, slippage,

blocking, nonsequiters, confusing logic or reasoning)• dosages of antipsychotics used to augment antidepressants do not adequately treat psychosis• unrecognized comorbidities—in studies, 5% to 10% of patients presenting with apparently

uncomplicated depression found to have 1 significant systemic medical illness capable of affecting diagnosis or treatment outcomes

• substance abuse most common comorbidity responsible for antidepressant failures (often masked)• reassess for abuse at every stage of treatment

Adequate treatment trials• 4- to 6-wk trials at full or maximum therapeutic dosage recommended

• however, may discontinue in patients with significant side effects and no benefits at minimum dose

• always document rationale for early discontinuation

• speaker attempts trials with nutriceuticals, increased emphasis on psychotherapy, or transcranial magnetic stimulation in patients with history of intolerance to many (6-8) antidepressants

• patients with extremely poor tolerability to one medication typically have similar responses to all agents in same class;

• remission vs response — although remission may be ideal, patients showing significant improvement should continue current treatment

• attempt augmentation strategies to induce remission in patients with partial response

• STAR*D data — two-thirds of responsive patients showed results by 6 wk

• speaker discourages 12-wk trails (without steady trend of improvement with acceptable tolerability

In STAR*D, patients who failed one adequate trial of an antidepressant showed:

 A) Superior response rates when switched to a multiple-action agent (eg, buproprion,

venlafaxine) B) Superior response rates when switched to

a second selective serotonin reuptake inhibitor (SSRI)

 C) Comparable response rates when switched to either multiple-action medications or SSRIs

Answer

• C) Comparable response rates when switched to either multiple-action medications or SSRIs

Strategies for stage I resistance

• switch within same class

• switch across classes

• adjunctive strategies

• combining selected antidepressants

• switching vs augmentation

• Switching may be preferable (prevents costs of second treatment and allows targeted remediation of side effects

STAR*D data on medication switch outcomes

• no statistically significant differences found among patient groups switched from citalopram to sertraline, bupropion, or venlafaxine

• authors found same-class switching viable option (nearly as effective as switch to multiple-action agents)

• nortriptyline and mirtazapine showed comparable efficacy

• however, mirtazapine shows superior safety profile and tolerability (no cardiography or blood tests required for patients >40 yr of age

Benefits of augmentation strategies

• response more rapid

• No washout period needed

• easier implementation (eg, no issues with cross-titration

Lithium has superior benefits as an augmentative agent when used

with: A) Tricyclic antidepressants 

 B) SSRIs C) Serotonin and norepinephrine

reuptake inhibitors D) Anxiolytics

Answer

•  A) Tricyclic antidepressants 

Best evidence-supported adjunctive therapies• lithium — long history of use in enhancement of tricyclic antidepressants (TCAs)• requires blood level monitoring• significant side ef fects• less effective with modern antidepressants• has proven therapeutic efficacy• typically effective at 600 mg to 1200 mg daily (high blood levels not required)• thyroid augmentation — T3 hormone preferred (25-50 µg daily), since T4 not used for brain

activity• showed comparable efficacy to lithium augmentation in STAR*D, but with easier

implementation• One study linked efficacy to genetic polymorphisms affecting conversion of T4 to T3• (possible explanation for inconsistent results);• buspirone — nonhabit-forming anxiolytic (via partial agonism of serotonin receptor 1A)• appears to enhance or modify effects of selective serotonin reuptake inhibitors (SSRI)• potentially difficult to use (due to wide dosage range [5 mg bid to 20 mg tid] and side effect

burden); relieves anxiety and reverses sexual side effects when used with SSRI

 _______ is recommended for use in thyroid augmentation of

depression treatments, due to its activity in the brain.

 A) Monoiodothyronine B) Diiodothyronine

 C) T3 hormone  D) T4 hormone

Answer

•  C) T3 hormone 

According to STAR*D, augmentation of an

antidepressant with _______ has superior benefits in patients with

more severe anxiety. A) Buspirone B) Bupropion

 C) Lithium D) Lamotrigine

Answer

•  B) Bupropion

Antidepressant combinations• many agents have complementary effects

• no washout required

• efficacy remains understudied

• citalopram augmented by bupropion vs buspirone (STAR*D)

• combinations showed comparable efficacy

• bupropion showed superiority in patients with greater anxiety and buspirone showed superiority in patients with milder anxiety

Other options• adjunctive benzodiazepines —show benefits only with continuous use (ie,

palliative but not curative)

• use caution when initiating for chronic complicating anxiety due to high risk for long-term dependency

• monoamine oxidase inhibitors (MAOIs) —classically effective agents with unique mechanisms of action

• particularly effective in early-onset chronic depression with reversed vegetative features

• in STAR*D level 4, many physicians failed to prescribe adequate dosages of MAOIs

• mirtazapine plus venlafaxine found more effective than tranylcypromine (possibly due to relative ease of use

• DR Stahl calls it California rocket full

Responses to sequential treatment in STAR*D

• after 4 failed medication trials, only 10% of patients eventually achieve remission

• increasing treatment resistance also increases risk for relapse after response (close follow-up and monitoring required

Atypical antipsychotics show proven efficacy in _______ of

patients with depression. A) 55% B) 35% C) 20% D) 10%

Answer

•  C) 20%

Augmentation with atypical antipsychotics (AAP)

• Proven effective (compared to placebo), but only in 20% of patients and in trials of 6 to 8 wk

• guidelines for use undetermined

• long-term use gradually increases risk for metabolic side effects and tardive dyskinesia (in 1 yr follow-up of patients using adjunctive aripiprazole, several cases of reversible acute onset dyskinesia occurred [<1% of patients])

• Approved combinations — olanzapine plus fluoxetine

• aripiprazole plus many antidepressants

• quetiapine plus many antidepressants

• risks —studies found olanzapine plus fluoxetine increased weight by average of 5.5 kg over 8 wk

• speaker’s conclusions — use only when justified by severity or urgency

• keep baseline of weight and metabolic activity

• record abnormal involuntary movement scores in patients undergoing long-term treatmen

Augmentation with other mood stabilizers

• lamotrigine most widely used

• shows “quelching” effect in patients with history of posttraumatic stress disorder (PTSD)

• covers subtle bipolar syndromes

• speaker prefers AAPs due to superior clinical evidence

Modafinil and armodafinil augmentation

• reduce symptoms of drowsiness and fatigue, but do not improve mood, optimism, or hedonic capacity

• costly and often not covered by insurance

• recommended only in patients reporting persistent difficulties with sleepiness, hypersomnolence, and fatigue

Dopaminergic options

• pramipexole — nonhabit-forming selective dopamine agonist

• shows antidepressant effects in small studies of treatment-resistant depression and BD

• may cause drowsiness, lightheadedness, and inappropriate alertness at night (20% of patients discontinue

Conclusions

• outcome measuring, following adherence, working through sequential treatment hierarchies, retrials, and confident use of TCAs, MAOIs, and electroconvulsive therapy

• (and appropriate combinations of therapies),

• depression can be successfully resolved within 1 yr in 90% of patients

_______ is shown to be the most accurate psychologic screening tool, but

it requires more time than competing forms of testing.

 A) Mini-Mental State Examination B) Mini-Cog Assessment

 C) St. Louis University Mental Status Examination

 D) Montreal Cognitive Assessment

Answer

• D) Montreal Cognitive Assessment

NT vs Mini-Mental State Examination (MMSE)

• does not replace thorough cognitive assessment

• outdated; has high falsepositive rate in patients >60 yr of age; fails to account for baseline performance in patients with above- or below-average level of education

Mini-Cog Assessment

• recommended for assessing dementia

• requires only 2 to 3 min

• public domain

• patients required to retain memory of 3 words while drawing picture of clock set to specific time

• can be performed by any caregiver

Alternatives to MMSE• St. Louis University Mental Status

• Examination— public domain

• more difficult than MMSE

• has higher expectations for healthy aging of brain

• Brevity similar to that of MMSE, but yields far more accurate results

• Montreal Cognitive Assessment—most accurate cognitive screening tool, but has slightly longer administration time

• public domain

• translated into >20 languages

• easily score

Serial evaluation with NT should ideally be spaced _______ apart.

 A) 6 to 12 wk B) 3 to 6 mo

 C) 9 to 12 mo D) 1 to 2 yr

Answer

• C) 9 to 12 mo

Nearly all forms of pleasure are associated with dopamine release

in the: A) Nucleus accumbens

 B) Anterior insula C) Cingulate gyrus

 D) Brainstem

Answer

• A) Nucleus accumbens

Disulfram causes a toxic reaction to alcohol by inhibiting the

metabolism of: A) Ethyl glucuronide

 B) Acetaldehyde C) Acetic acid

 D) Phosphatidyl ethanol

Answer

•  B) Acetaldehyde

_______ is most effective in patients with a strong family history of alcoholism and an

early age of onset. A) Disulfram B) Naltrexone

 C) Acamprosate D) Baclofen

Answer

• B) Naltrexone

_______ has been shown to prolong the time until relapse in

patients with stimulant dependence.

 A) Bupropion B) Topiramate C) Modafinil

 D) Naltrexone

Answer

• A) Bupropion

Background on addiction• brain disease characterized by compulsive behavior, continued

substance use despite consequences, and persistent changes in brain structure and functioning

• pathophysiology — all commonly abused substances act at synaptic level

• synaptic effects cause cascade of intracellular changes that affect long-term reactivity, gene expression, and connectivity to other neurons

• reward pathways — nearly all forms of pleasure coincide with dopamine release in nucleus accumbens (NAcc), serotonin release in brainstem, and activation of opioid receptors by endogenous opiate peptides in NAc

Management of alcohol dependence• Disulfiram: patients typically discontinue usage before relapsing;

causes toxic reaction to alcohol by inhibiting metabolism of acetaldehyde (secondary stage of ethanol metabolism)

• patient sensitivity varies (some report side effects when ingesting vinegar)

• potential for severe hepatotoxicity (monitoring of liver function tests [LFTs] required)

• has no effect on alcohol cravings• recommended for patients with high motivation to maintain

sobriety, awareness of upcoming triggers, and supportive individuals who can witness patient's self-administratio

Naltrexone• blocks rewarding effects of alcohol at opioid receptors• dosing —50 to 100 mg daily; LFTs required• Poor compliance causes poor outcomes• depot preparation— monthly intramuscular injection slowly releases

naltrexone into bloodstream at fixed rate• circumvents compliance issues efficacy— limited reduction in cravings• blunts response to alcohol if relapse occurs• most effective in patients with strong family history and early onset of

alcoholism (possibly due to transcription variations in µ-opioid receptors)

• blockading opioid receptors on GABA neurons inhibits dopamine release in NAc

Acamprosate• chemically similar to GABA• reduces glutamate transmission; mechanism of action— since alcohol acts

as• substitute for GABA, endogenous production of GABA decreases with

repeated intoxication• suppressed GABA results in compensatory increase of glutamate (causing

anxiety, tremors, and potential seizures if patient withdraws from alcohol)• acamprosate helps restore GABA-glutamate balance• characteristics — few side effects; reduces cravings; may cause

gastrointestinal irritation (rarely affects adherence)• requires large dose taken 3 times daily• Excreted through kidneys; efficacy—speaker reports lackluster results in

United States (possibly due to different phenotypes of alcoholism

Topiramate: Gabapentin: • Topiramate 25 to 300 mg daily shown to improve overall well-being,

reduce some cravings, reduce harmful drinking consequences;

• well-tolerated low-risk intervention (despite reports of cognitive disturbances and “numbness”)

• suppresses appetite in some patients

• Gabapentin GABA analogue

• can reduce cravings and anxiety and delay relapse; shown to improve sleep initiation and maintenance in alcoholics during first 6 mo of recovery

• appears to increase endogenous GABA production; may be

• started at high doses (eg, 600 mg before bed, 300 mg in morning), since sedation not typically seen in patients with history of alcoholism

Others

• Baclofen: 30 mg daily shows impressive rates of abstinence vs placebo in randomized controlled trials (RCTs)

• Ondansetron: shows trend toward positive results in patients biologically predisposed to alcoholis

Management of opiate dependence• Background: increasing in prevalence due to abuse of synthetic

medical opioids (eg, oxycodone); • Symptomatic detoxification— performed from office (outpatient);

clonidine tapered over 3 to 6 days (speaker recommends starting at 0.1 mg); always provide treatment for diarrhea, stomach

• cramping, piloerection, and rhinorrhea (over-the-counterremedies typically suffice)

• trazodone or gabapentin may• help sleep and anxiety issues• causes of continued• addiction —fear of withdrawal symptoms (often severe)• long-term craving

Buprenorphine• partial agonist of opioid receptors• Unlike full agonists, effects plateau at 32 mg daily (prevents respiratory depression and euphoric

effects)• Abolishes most withdrawal symptoms and blunts cravings (after acute detoxification);• oral buprenorphine plus naloxone• (Suboxone) — patients must be clean of opiates for 24 hr• before starting therapy (prevents abrupt withdrawal symptoms); typically induced at 2 to 4 mg daily• most patients show lasting effects at 12 to 16 mg daily• regulations — physicians must become federally registered prescribers• conclusions from study — buprenorphine has superiorsafety and lower abuse potential than

methadone but does not appear to reverse physical dependence• Preventing diversion — patients should consent to opiate contracts• and receive continuous education; treatment during• pregnancy — form without naloxone (Subutex) shown superior to methadone in preventing

neonatal abstinence syndrome Naltrexone• not effective as outpatient treatment; depot formulation (Vivitrol) recently approve

Management of stimulant dependence• Medications: no approved adjunct treatment• several high quality open-label trials and small RCTs have assessed bupropion,

topiramate, modafinil, disulfiram (inhibits metabolism of dopamine), and naltrexone

• Cocaine vaccine: currently under development• primes body to remove cocaine from bloodstream before reaching brain• Depression and anxiety• speaker recommends low threshold for use of selective serotonin reuptake

inhibitors (SSRIs; eg, citalopram, fluoxetine) for patients with poor compliance; maximize usage of nonhabit-forming anxiolytics (eg,

• hydroxyzine, buspirone, propranolol, quetiapine [for racing thoughts and avoidance of sleep])

• mindfulness meditation shows efficacy• bupropion found to stave off relapse

Management of stress• addictive substances induce intense

• acute stress states; hyperactive states induced by substances

• make patients more attuned to cues associated with cravings

• or relapse; treating heightened stress responses (with, eg, SSRIs, beta-blockers) can greatly improve quality of life in substance-dependent patient

Which of the following is most useful in the diagnosis of septic

arthritis?A) Serum white blood cell

(WBC) countB) Synovial fluid WBC countC) Erythrocyte sedimentation

rateD) C-reactive protein level

Answer

• B) Synovial fluid WBC count

Septic joint• most commonly affects hip, knee, and ankle joints• multiple joints affected in 5% to 10% of cases (usually

asymmetric); microbiology—similar in children (except neonates) and adults

• nearly 50% of infections due to Staphylococcus aureus• other causes include streptococci, gram-negative bacilli,

and Neisseria• presentation —joint pain• history of joint swelling in 80% of patients; fever in 60%

of patient

Serum LaboratoryValues• white blood cell (WBC) count nonspecific and not helpful• erythrocyte sedimentation rate (ESR) <30 mm/hr helpful• C-reactive protein (CRP) >100 mg/L slightly helpful• synovial fluid studies —septic arthritis highly likely in

patients with WBC count >100,000/µL (cut-off, 25,000-50,000/µL [ie, >25,000/µL highly suggestive of septic arthritis])

• polymorphonuclear leukocytes (PMNs) >90% (strong predictor)

• consider differential diagnosis

Management• drainage of joint by arthrocentesis, arthroscopy, or open

drainage; duration of antimicrobial therapy not welldefined, but 2 to 4 wk typical (gonococcal infection can be treated for 7-10 days)

• for suspected gram-positive infection,• use vancomycin (15-20 mg/kg every 8-12 hr; empiric coverage

in case of methicillin-resistant S aureus [MRSA] Adjust as needed)

• Fluoroquinolones• antipseudomonal Beta-lactams;• carbapenems; for gram-negative infection, cover for S aureus

Although not well defined, typical duration of antimicrobial therapy for treatment of septic

arthritis is _______.A) 5 daysB) 1 wk

C) 2 to 4 wkD) 4 to 6 wk

Answer

• C) 2 to 4 wk

Choose the correct statement about 3-phase technetium bone scanning in the

diagnosis of osteomyelitis.A) Shows uptake in phases 1 and 2, with focal intense uptake in delayed images

B) Exposes patient to high-dose radiationC) Not useful if multiple sites suspected

D) Sensitivity and specificity 90%

Answer

• A) Shows uptake in phases 1 and 2, with focal intense uptake in delayed images

Conventional radiology• sensitivity low

• abnormal in 45% to 70% of cases

• normal in 25% of cases

• normal until 10 to21 days after infection (not reliable in setting of acute disease)

• lytic changes not seen until >50% of bone matrix destroyed; specificity low (25%); early clues include soft tissue swelling, periosteal thickening or elevation, or osteo penia reflecting bony destruction; previous abnormality (eg, fracture) major limitation

Magnetic resonance imaging (MRI)

• highly sensitive

• High resolution of periosteal bone, cortical destruction, and joint damage

• sensitivity varies (60%-100%)

• specificity “quite good” in patients with no previous bone destruction

• excellent anatomic resolution (of, eg, associated abscess

Studies consistently show intravenous (IV) metronidazole

more effective in the treatment of osteomyelitis than oral

metronidazole.A) TrueB) False

Answer

• B) False

TreatmentIV antibiotics serum concentrations of Beta-lactams

(eg, nafcillin, cefazolin) 50 to 150 µg/mL (in bone, 5-15 µg/mL; minimum inhibitory concentration [MIC] <2 µg/mL)

bone penetration of daptomycin not as high due to high protein binding, but MIC lower; oral antibiotics —difficult to achieve high bone levels with traditional beta-lactams; adequate serum concentrations can be achieved with fluoroquinolones

metronidazole effective (IV or orally)

serum concentration of linezolid 10 to 20 µg/mL

good ratio with linezolid and trimethoprim-sulfamethoxazole (TMP-SMZ)

good penetration with clindamycin and rifampin

Long courses of _______ are associated with bone marrow and

nerve toxicity.A) Trimethoprim-

sulfamethoxazole (TMP-SMZ)B) Metronidazole

C) LinezolidD) Rifampin

Answer

• C) Linezolid

Outpatient studies show that IV vancomycin alone for treatment

of Staphylococcus aureus infection leads to significantly

better outcomes than other drugs.A) TrueB) False

Answer

• B) False

According to guidelines from the Infectious Diseases Society of America, what is the primary

treatment of abscesses?A) Incision and drainage (I&D)

B) I&D plus clindamycinC) Rifampin

D) Combination of rifampin and another antibiotic

Answer

• A) Incision and drainage (I&D)

Abscesses• Abscesses: Infectious Diseases Society of America guidelines incision

and drainage (I&D) primary treatment• benefit of addition of antibiotics unclear• high (85%-90%) cure rates with or without active antibiotic suggest

I&D alone may be sufficient in most cases• consider antibiotic therapy for patients who present with severe or

extensive disease, signs or symptoms of systemic• illness, associated comorbidities, immunosuppression, extremes of age,

abscess on area difficult to drain completely (eg, hand, face, genitalia), or failure of previous I&D

• study of patients with purulent infections, abscesses, and cellulitis found most infections due to MRSA, suggesting MRSA coverage indicate

Which of the following antibiotics provides coverage of methicillin-resistant S aureus,

methicillin-susceptible S aureus, and group A streptococci?

A) TMP-SMZB) DoxycyclineC) MinocyclineD) Clindamycin

Answer

• D) Clindamycin

Oral antimicrobial options for CA-MRSA• TMP-SMZ, doxycycline, and minocycline associated with low rates of resistance, but

unreliable for group A streptococci (GAS)

• clindamycin— covers MRSA, MSSA, and GAS

• excellent tissue and abscess penetration

• associated with risk for C difficile infection

• linezolid—indicated for complicated skin and soft tissue infections; expensive; may lead to adverse events (primarily with long-term use)

• inducible clindamycin resistance —clindamycin therapy associated with potential for selecting for resistance detected by specialized testing (D-test)

• consider when laboratory report shows MRSA isolate resistant to erythromycin and susceptible to clindamycin

• rates vary; unclear whether it leads to treatment failure; in some cases (eg, mild or improving infection), may be reasonable to continue clindamycin if patient

• does not respond to therapy or if patient has moderate to severe infection, change antibiotics

Choose the correct statement about decolonization regimens for recurrent skin

and soft tissue infections.A) Mupirocin shown to prevent first-time skin

and soft tissue infectionB) Chlorhexidine appears to have transient effect on colonization, but does not reduce

skin and soft tissue infection ratesC) Oral antimicrobial regimens routinely

recommendedD) Long-term use of rifampin-based regimens

recommended

Answer

• B) Chlorhexidine appears to have transient effect on colonization, but does not reduce skin and soft tissue infection rates

Decolonization regimens• no clinical data suggest effectiveness in preventing recurrences

• mupirocin—in recent study, application to nose twice daily for 5 to 10 days resulted in reduced colonization, but did not prevent first-time skin and soft tissue infection

• mupirocin plus topical skin antiseptic (eg, chlorhexidine, dilute bleach)—chlorhexidine alone appears to have transient effect on colonization, but does not reduce skin and soft tissue infection rates

• combination recently shown to reduce surgical site infection rates

• oral antimicrobial regimens—not routinely recommended

• may consider in combination with rifampin

• Cochrane Review showed no benefit of systemic antibiotics for eradication of hospital-acquired MRSA or reduction in infection rates

• other systemic review found short-term reduction in S aureus colonization with rifampin-based combination regimens, but no effect on infection rates

• concerns include rifampin resistance and potential side effects

• rifampin-based regimens recommended for short courses only

• “if all else fails”—combination of TMP-SMZ and rifampin for 5 days, then repeat every 6 wk for 8 cycles

• add chlorhexidine and counsel about personal hygiene

• vitamin C possibly beneficial (data limited)

Which of the following is the most common cause of

monomicrobial necrotizing fasciitis?

A) S aureus B) Clostridia

C) β-hemolytic streptococciD) Group A streptococci

Answer

• D) Group A streptococci