PNIPs, SNPs, and Phenotypes

How can we get even better at customizing treatment for our patients and thereby achieve improved outcomes? How do we avoid becoming relegated to mere brokers of psychopharmacologic commodities? A few thoughts in this brief communication.

[Editor's note: Dr Scheiderer will be speaking at this year's PsychCongress in a presentation titled "Psychoneuroimmunology: Clinical Application of an Emerging Field in Psychiatry with a Special Emphasis on Atypical Depression."


The more exciting the message about launches of new antidepressants with novel modes and mechanisms, the louder the punishing drumbeat of that old assertion: the clinical efficacy of antidepressants-both between and within different classes-is comparable. While this assertion may be true from a strictly statistical standpoint, it is clinically useless, maybe even harmful. It fosters the practice of differentiating treatments by cost alone. After all, if antidepressants are similarly efficacious, why not pick the cheapest, most widely available ones?

Such a one-size-fits-all approach, however, stands directly opposed to a core tenet of psychiatric practice: personalize the treatment to fit the patient. It is also likely a major cause of the poor antidepressant treatment response rates so often reported. For example, despite advances of psychopharmacologic treatment, more than one-third of patients do not respond to the first drug tried. Moreover, results of the well-known STAR*D study found that 2/3 of patients remained symptomatic following antidepressant treatment.

The numbers are irrefutable. At the same time, these same antidepressants perform better in the hands of savvy clinicians. That is because clinicians, whether or not we can precisely articulate the rationale, attempt to match medication and other treatments to specific attributes of our patients. For example, we are unlikely to prescribe paroxetine monotherapy for the same type of depression that we would treat first line with bupropion.

Melancholic vs Atypical Depression: Clinical Features

Level of arousalHyperarousedHypoarosed, apathetic
Anxiety levelAnxiousGenerally not anxious
Reactivity to environmentRelatively unreactiveReactive to environment
Emotional memoryBroods over painful pastEmotionally detached
CognitionReduced concentration; perseverationPoor focus
BehaviorRegressionUnmotivated, inactive
Strong link to bipolarNoYes
SleepDecreased, poor qualityIncreased, poor quality
AppetiteDecreased, weight lossIncreased, weight loss
EnergyVariable"Leaden paralysis"
Diurnal variationWorse in morningWorse in evening

How, however, can we get even better at customizing treatment for our patients and thereby achieve improved outcomes? How do we avoid being hoisted with our own statistical petard, becoming relegated to mere brokers of psychopharmacologic commodities? Wouldn’t it be nice to stratify our depressed patients in such a way that we could more deliberately select from among various medications? Which of our depressed patients, for example, will best be served by a generic SSRI or SNRI? Who, on the other hand is the Brintellix or Fetzima or Viibryd patient? Where does bupropion fit in, who needs adjunctive therapy with a second medication, and who is most likely to respond to the addition of Deplin?

These are among the questions I will attempt to address at the upcoming 2014 US Psych Congress in my lecture entitled -  Psychoneuroimmunology: Clinical Application of an Emerging Field in Psychiatry with a Special Emphasis on Atypical Depression.

The usual disclaimers will apply. I don’t intend to talk off label. This will be a discussion of people who suffer from depression. And, as depression is the most common psychiatric illness in the world; is a leading contributor to disability globally; is degenerative and systemic; and is associated with premature aging and death, that’s plenty to talk about.


Melancholic vs Atypical Depression: Biological Features

HPA axisCentrally activatedCentrally-mediated hypoactivity
Cortisol/CRF outputHigh/highLow/low
DSTLow suppressionHigh suppression
Response to prednisone     --Yes
Sympathetic activityIncreasedDecreased
Lean body massDecreased (sarcopenia)Normal
Immune functionImmunosuppressed, increased infectionsImmunoenhanced increase inflammation  
Heart diseasePrenature CHDPremature CHD
Bone densityPremature osteoporosisNormal bone

(Juruena MF, Cleare AJ. Rev Bras Psiquiatr. 2007 May;29 Suppl 1:S19-26.)

The remainder of this brief communication highlights some of the main points I hope to make.

  • Depression is not a single entity but rather a description of several distinct, overlapping medical conditions, each with its own unique symptoms and biological correlates.1,2 Highlighting the heterogeneity of depression, the DSM-V identifies two distinct clinical variations that seem to be the reverse of each other: melancholic and atypical depression.
  • Different subtypes of depression reflect different pathophysiological processes (psycho-neuro-immunological perturbations: PNIPs). “The heterogeneity of the depression concept seems to play a differentiating role: metabolic syndrome and inflammation up-regulations appear more specific to the atypical depression subtype, whereas hypercortisolemia appears more specific for melancholic depression.”3
  • Different symptom clusters respond selectively to different treatments. “It has therefore become essential to determine parameters (or predictors) that would rationalize the therapeutic choice, taking into account not only the clinical features, but also the ‘biological state,’ which is a major determinant in the antidepressant response.”4 Profiling symptom patterns and corresponding biological correlates is potentially useful as a first step in developing tailored intervention and treatment programs.
  • The approach offered in this lecture to rationalize and tailor treatment interventions, and thereby improve outcomes, focuses on 5 areas:
  • The patient’s phenotypic profile - Melancholic versus Atypical symptom clusters;
  • Biological correlates (psycho-neuro-immunological perturbations – PNIPs);
  • Internal comorbidities;
  • Genetic (SNPs) and epigenetic (ELA) variables; and
  • Patient preference.

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1. Gili M, Roca M, Armengol S, et al. Clinical patterns and treatment outcome in patients with melancholic, atypical and non-melancholic depressions. PLoS One. 2012;7(10):e48200.
2. Lamers F, Vogelzangs N, Merikangas KR, et al. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry. 2013;18:692-699.
3. Penninx BW, Milaneschi Y, Lamers F, Vogelzangs N. Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. BMC Med. 2013;15:129.
4. Duval F, Mokrani MC, Ortiz JA, et al. Neuroendocrine predictors of the evolution of depression. Dialogues Clin Neurosci. 2005;7:273-282.