Mood Enhancement

Motivation: Recently, one of my friends in psychiatry commented that the blog almost never touches upon psychiatry.  And, that is unfortunately true despite the amount of psychiatric diseases in the medical wards.  So, today, I wanted to examine the question of what happens when the SSRI just does not work after a good six weeks.  Often, I have seen psychiatrists "augment" the treatment with a variety of anti-psychotics.  Is there data behind the practice, and which anti-psychotic is the best one?

Paper: Nelson, J.C. and Papakostas, G.I.  "Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of Placebo-Controlled Randomized Trials" Am. J. Psychiatry (2009) 166: 980-991.

Methods: Meta-analysis of double blind randomized trials comparing addition of atypical anti-psychotic versus placebo in patients with non-responsive major depression.  Response was defined as >50% improvement in baseline scores of a depression rating scale (Montgomery-Asberg Depression Scale or Hamilton Depression Scale).

Results:
Trials: In total, 16 trials were analyzed with trial duration ranging from 4-12 weeks (9 trials lasted 8 weeks, 5 lasted 6 weeks, 1 lasted 12 weeks, and 1 lasted 4 weeks).  The agents tested were olanzapine, risperidone, quetiapine, and aripiprazole.  These anti-psychotics were added to anti-depressants which were typically a SSRI or SNRI.

Olanzapine: Overall, meta-analysis of 586 in treatment arm and 414 in control group.  Odds ratio as listed below (higher OR with favorable treatment):
- Response: 1.39 (95% CI: 1.05-1.84), Remission: 1.83 (1.30-2.56)
- Adverse Effect: 3.85 (2.03-7.29)

Risperidone: Analyzed 211 in treatment arm and 175 in control group.  Odds ratios as below:
- Response: 1.83 (1.18-2.82), Remission: 2.63 (1.51-4.57)
- Adverse Effect: 2.84 (0.91-8.91)

Quetiapine:Analyzed 677 in treatment arm and 352 in control group. Odds ratios as below:
- Response: 1.60 (1.24-2.08), Remission: 1.89 (1.41-2.54)
- Adverse Effect: 5.52 (2.71-11.24)

Aripiprazole: Analyzed 540 in treatment arm and 525 in control group. Odds ratios as below:
- Response: 2.07 (1.58-2.72), Remission: 2.09 (1.55-2.81)
- Adverse Effect: 2.68 (1.23-5.81)

Duration of Trial: No effect seen in response to drug based on duration ranging from 4 to 12 weeks.

Discussion:  This meta-analysis both demonstrates the utility of anti-psychotics in treatment resistant depression and the equivalence for the four examined anti-psychotics (despite aripiprazole being the only FDA approved augmentation anti-psychotic).  Interestingly, addition of anti-psychotics also resulted in increased adverse effects pretty uniformly.  The meta-analysis did not describe the most common adverse effects (such as mild or severe or suicidal).  Another limitation of this analysis is that only the acute phase of treatment (4-12 weeks) was examined.  No data about maintenance phase was available although treatment is often extended to the maintenance phase as well.  In summary, when faced with a depressed patient unresponsive to usual first line SSRI/SNRI agents, addition of an accessible anti-psychotic (whether risperidone or aripiprazole) is reasonable though patients should be monitored closely for severity of adverse effects.

Is this MDS?

Motivation: In the past few months, I have come across multiple patients with chronic unexplained macrocytosis.  I am often tempted to diagnose MDS and request a bone marrow biopsy.  But, is there a better non-invasive scoring system to triage the likelihood of MDS?  Recently, while searching this topic, I came across this paper that estimates a pre-test likelihood of MDS.

Paper: Rauw, J., Wells, R.A., Chesney, A., et. al.  Validation of a scoring system to establish the probability of myelodysplastic syndrome in patients with unexplained cytopenias or macrocytosis.  Leukemia Research (2011) 35: 1335-38.

Methods: Retrospective review of bone marrow biopsies (2006-2008) at an academic hospital in Toronto, Canada.  Inclusion criteria were anemia (hemoglobin <12 g/dL), thrombocytopenia (platelet < 150), leukopenia (WBC < 4), neutropenia, or macrocytosis (MCV > 96).  Patients with known or suspected hemato-lymphoid diseases (such as lymphoma or widespread lymphadenopathy) were excluded.  BM biopsies were classified as MDS, suspected MDS (met most but not all pathological criteria), or not MDS.

Results:
Scoring System: The authors designed a scoring system with four parameters: (1) age >= 65, (2) RDW > 14.5%, (3) MCV > 96, and (4) LDH  > 250.

Bone Marrow Diagnoses: Of the 313 biopsies reviewed, 100 had MDS, 27 had suspected MDS, and 186 did not have MDS.  Among those not having MDS, 34% were normal, 10% had AML, and the rest had other diagnoses.

Sensitivity and Specificity of Confirmed/Suspected MDS Based on Risk Factors:
Risk Factors              Sensitivity              Specificity
>=1 factor                  95%                       18%
>=2 factors                74%                        46%
>=3 factors                39%                        79%
    4 factors                6%                          96%

Discussion: I liked this paper because it provided a risk assessment of MDS based on parameters that are easily and routinely measured.  Having multiple risk factors should lower the threshold for referral to hematology and having a bone marrow biopsy.  As in other retrospective reviews from tertiary medical centers, the numbers in this paper are affected significantly by referral bias.  In the patients with anemia and macrocytosis getting BM biopsy, probably all had B12 and folate checked and had MCV measured when abstaining alcohol.  In the regular inpatient setting, alcoholism as well as B12 deficiency probably accounts for a significant portion of macrocytosis.  For patients without these other more straightforward explanations, stratifying patients for MDS by these risk factors is a quick clinical tool.

G-CSF for Acute Liver Injury

Motivation: When patients do not respond to steroids for acute alcoholic hepatitis, there is little else you can do - besides watching them wither away.  While observing another such tragedy, I wondered if there is anything else to do.  Most patients with acute alcohol use do not qualify for a liver transplant.  I came across this paper published recently evaluating the remarkable potency of G-CSF for acute on chronic liver injury.

For background, the theory is that G-CSF mobilizes bone marrow derived stem cells (CD 34+), and one hopes that with more stem cells floating around, some will engraft in the liver and lead to regeneration.

Paper: Garg, V., Garg, H., Khan, A. et. al. "Granulocyte Colony-Stimulating Factor Mobilizes CD34+ Cells and Improves Survival of Patients with Acute-on-Chronic Liver Failure" Gastroenterology (2012); 142: 505-512.

Methods: Blinded randomized trial in a hospital in New Delhi, India.   Between December 2008 and August 2010, consecutive patients with acute on chronic liver failure (defined as acute rise in bilirubin, INR, ascites, or encephalopathy in patients with known liver disease) were randomized to placebo or 5 ug/kg G-CSF (12 doses over month).  Exclusion criteria included hepatocellular carcinoma, portal vein thrombosis, multi-organ failure, sepsis, or grade 3 or 4 encephalopathy.  Primary end point was survival at day 60.

Results:
Cohort: In total, 47 patients were randomized with 23 patients to G-CSF and 24 patients to placebo.  Majority of patients were male in each group (3 females in each group).  Mean age was 40 in either arm.  Both groups were balanced in terms of MELD score, grade of varices, CTP score, liver enzyme levels, and encephalopathy.  Most patients had acute alcoholic hepatitis.  The placebo group had more HBV reactivation liver injury.

CD 34 Cells: To verify whether G-CSF actually led to stem cell engrafment, authors compared CD34 cells in liver at baseline and at day 30.  Compared to baseline value of 27.5% CD34 cells in sinusoids (based on cell counting in immunohistochemistry), G-CSF treatment resulted in 45% CD34 cells in sinusoids.  No increase was seen in the placebo group (CD34 cells decreased from 30% to 20%).

Survival: The actuarial probability of survival was 66% with G-CSF versus 26% with placebo (p=0.001).  In total, 7 patients died in G-CSF group versus 17 deaths in placebo arm (majority from progressive multi-organ failure, mostly HRS)

MELD Scores: .Median change in MELD score at days 7, 30, and 60 was -7.4%, -18.23%, and -15.34% in G-CSF group versus +3.33%, +6.25%, and +11.76% in placebo group.

Adverse Effects: G-CSF treatment resulted in three adverse events - one had transient rash, one had herpes zoster, and one had high fevers.  Other patients completed therapy without reported adverse effects.

Discussion: This small randomized trial suggests that G-CSF has significant mortality benefit in acute on chronic liver failure!  In the two month trial period, there were 10 fewer deaths in the G-CSF group suggesting an amazingly large benefit.  There are, of course, a few caveats to this trial.  With the number of recruited patients numbering in the 20s in each group, there is no guarantee that the groups were actually well-balanced.  Also, with two month follow-up, it is unclear whether the effects of G-CSF are persistent or transient.  Clearly, this smaller trial calls for a larger, better designed randomized trial.  In the meantime, if someone with acute on chronic liver failure is perishing on standard therapy, I would strongly consider G-CSF therapy.