“But what we call our despair is often only the painful eagerness of unfed hope.”

—George Eliot (1819 - 1880)

My last column (Damage Control, May 2006) reviewed the somewhat demoralizing findings that mood disorders cause damage at multiple correlated levels: molecular, clinical, social, and spiritual. I invited readers to join me for this column in which I would discuss new neurobiologic discoveries that bear the promise not just of controlling but of reversing these protean levels of damage.

The trigger for the initial column had been a passage describing the ability of a midbrain infusion of brain-derived neurotrophic factor (BDNF) to reduce the behavioral despair of a rat. This same animal was subjected to the infamous forced swim test—a proxy for human depression—repeatedly, resulting in decreased levels of BDNF messenger RNA in its stressed hippocampus.1 I will argue that what seems a modestly interesting basic science experiment may actually herald and exemplify an amazing breakthrough in the treatment of serious mental illness.

The felicitous sounding “brain-derived new growth factor” is an intimation of the new hope neurobiology is bringing to clinical psychiatry. BDNF does exactly as it promises: it literally grows, sustains, and nourishes new neurons. As we saw with our rat friend, stress and depression seem to switch off the gene for BDNF, leading to the atrophy and even apoptosis of neurons, particularly in the sensitive hippocampus, which plays such a leading role in learning and emotion.2 The shrinkage, impairment, and death of these crucial neurons shown in neuroimaging studies are convincingly hypothesized to contribute to depressive episodes that are more frequent, deep, persistent, and resistant to treatment.3

While it may sound as if I am back to announcing my themes of neurobiologic doom and gloom, I am actually setting the stage for the good psychopharmacologic news that BDNF can increase the strength of synapses and the survival and growth of neurons through activation of a transmembrane receptor with intrinsic tyrosine kinase activity (TrkB). Even more pragmatically exciting, electroconvulsive therapy (ECT) and antidepressant therapy up-regulate the gene for BDNF and TrkB.4 Perhaps most incredibly, the old medication workhorse lithium and the much maligned ECT can actually stimulate growth of new neurons in the adult brain.


Neurogenesis as a philosophical concept seems more akin to science fiction than to our practice of writing antidepressant prescriptions in the office for outpatients who are struggling to keep some semblance of a life together. However, a robust body of research demonstrates that ECT, antidepressants, and even lithium all reverse the learned helplessness of human beings, whom nurture and nature have forced to swim against the tide of depression.4

BDNF is only the most well established of a host of newly discovered second-messenger chemicals and cascades that likely have the miraculous properties of neurogenesis. The most hopeful quality of these proteins is neuroplasticity, or cellular resiliency, which holds the molecular keys to liberation from the grip of depression and a renewal of psychological flexibility.5

As discussed in my earlier column, research has increasingly moved the source of pathology in the major psychiatric disorders from neurochemistry to neuroanatomy. Reports over the last decade have demonstrated reduction in brain volumes and abnormalities in brain structures in nearly every area implicated in psychiatric disorders.6 Scientists are now exploring whether mood stabilizers sold in the local pharmacy, such as valproate and lithium, can promote neuronal plasticity. Glycogen synthase kinase-3β negatively affects neuronal viability, development, and functioning. Laboratory studies have shown that therapeutic doses of lithium powerfully inhibit glycogen synthase kinase-3β-- as does valproate--and, it is theorized, thus enhance neuroplasticity.7

These space-age discoveries are fascinating to the researchers we all admire, but are they relevant and useful for the clinicians most of us are? I would not be writing a column about BDNF and its cousins unless I thought they could relieve the suffering and improve the well-being of our patients with mood disorders. The rest of this column will outline what I see as the humanistic, professional, and even spiritual implications of the newly recognized potential of neurotrophic agents.8

From remission to restoration

Recently, considerable and timely attention has been given to the idea that remission is not good enough for patients and that psychiatry must strive to achieve recovery. The 3 Rs--response, remission, and recovery--are often misused, and hence misunderstood, but clarification of the terms is crucial to appreciating the fourth R--restoration. Definitions of the 3 Rs in the context of depression are more consistent and consensual than in bipolar or other mood disorders and so we will adapt those delineations as shown in the Table.9

It is now accepted that partial response and residual symptoms (ie, failure to achieve remission) lead to recurrence, relapse, continued psychosocial problems, poorer physical and mental health, and greater health care utilization—all stemming from unvanquished and still enervating affective symptoms.10 Viewed against the background of BDNF, we now know that these persistent symptoms are the phenotype of underlying secondmessenger system malfunction and that neurons will suffer, wither, and die until we aggressively and definitively treat each episode of depression. Our goal—and the molecular miracles of neurogenesis make it a real possibility, not just a fantasy—is to travel beyond recovery to restoration. Restoration is a global idea of healing and, while only heuristic, we can envision it as a flowchart showing augmentation of human actualization, as sketched in the Figure.

The 4Rs of psychiatric treatment
  Term Definition Level/perspective
Response 50% or greater reduction in diagnostic symptoms on assessment scales Clinical care: syndromic
Remission Absense of diagnostic symptoms to the degree found in mentally healthy persons Unemployment, educational underachievement
Recovery Return to premorbid state of functioning Personal and social: operational
Restoration Holistic integration of illness Global: spiritual


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