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A discussion of new neurobiologic discoveries that bear the promise not just of controlling but of reversing protean levels of damage.
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
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.
|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|
Rather than try to explicate the concept of restoration, it may be more useful to illustrate it with several examples from my clinical work with mood disorder patients. I have a score of men in whom bipolar illness was diagnosed in their 20s; who were hospitalized repeatedly; and who had multiple suicide attempts, legal troubles, and failed marriages stemming from inadequate treatment and nonadherence. Once these patients were able to work through the obstacles of finding competent care and their own internal barriers to accepting the diagnosis of a chronic disorder and consequent need for lifelong medication, their lives gradually but steadily transformed.
Most of these men are now not only symptom-free but disorder-free. Many of them work full- or part-time, and those who are retired or on a pension are volunteering, traveling, and raising children and grandchildren. They are phenomenally stable on modest but therapeutic levels of lithium, valproate, and perhaps small doses of adjunctive benzodiazepinesand atypical antipsychotics. I see them 2 or 3 times a year for checkups and I can seldom find even mild swings of the mood pendulum.
Most of these patients have painful memories of their active illness, yet other than having to take pills with the prosaic daily rituals of breakfast and sleep, their Axis I diagnosis has little effect on their lives, self-images, plans, or dreams. They will all readily admit that they may be in a different place socially and economically than they would have been had they not had bipolar disorder; but most are at peace with their genetic legacy and enjoy their quality of life.
To a patient, they attribute their stability and fulfillment (restoration, if you will) to their mood stabilizers. The only intense emotional reactions I have seen from these patients is when they are afraid that their trusted medication regimens might be altered. As one patient told me at his initial visit, I always am anxious about seeing a new doctor because I am afraid they will feel they have to change my medicines to prove themselves. I know what has kept me out of the hospital and I don't want to fix what is not broken.
At this point, many readers may be rightly wondering if I am a biological reductionist. Far from it: the benefits of neurogenesis are only possible if patients commit to the messages in the bottle, and only psychosocial therapies can foster and sustain such a commitment. It is psychotherapy that enables patients to integrate their illness into their identity and reconcile the losses and traumas it has wrought. It is psychoeducation and case management that teach patients and families early on about the signs of relapse and the triggers of episodes and how to manage side effects; it is supportive employment and consumer groups that help patients develop lifestyles and relationships that enable them to integrate into the community, overcome stigma, and follow the path to recovery.
This coalition of interventions is what Noordsy and colleagues,11 in a pioneering paper on redefining the goals of antipsychotic treatment, call recovery-oriented psychopharmacology. Rather than widening the mind/brain split, restoration offers a synthesizing consilience of Luhrmans' dialectic characterizing a profession divided and divisive over the use of psychopharmacology and psychotherapy.12 This synthesis is a spiritual one, not in a theological sense, but in a transcendent sense. Restoration is more than the sum of any parts of symptom remission or return to functioning or even recovery of original homeostasis. Restoration is a process of growth and healing from neuron to mind to soul or spirit that is holistic in nature and iterative in process and that encompasses the healing of damage from cell to self.
For years, psychiatrists have had a fortress mentality, and have been on the defensive against substance use, noncompliance, and the recurrent nature of affective illness. Our victories of Hamilton Depression Rating Scale response and remission with residual symptoms often seemed Pyrrhic and transient until the next relapse. We watched in frustration and shame while too many patients spiraled into disability payments, group homes, and revolving- door admissions; too few achieved mere remission.
The reality of recovery and the realistic hope of restoration transform psychiatry into what Kupfer,13 in a different context, deemed the mission of therapeutics. This mission involves a vigorous dedication to early diagnosis and intervention of serious mental illness; aggressive treatment with all the neurogenic therapeutic modalities, including psychotherapy, of every patient with an affective disorder; and the professional commitment to an ethic that we will accept nothing less than recovery and ultimately restoration for each patient.
These are the strengths of the mission. Are there limitations? Of course, as with any vision it is a long translational road from bench to examining room; there are enormous economic and policy problems to resolve if we are to have adequate funding for such an ambitious project; psychiatric education will need to undergo a minor revolution if medical students and residents are to embrace the new activist and activated face of psychiatry; and ethical questions regarding the place of pharmaceutical companies, primary prevention, and outpatient commitment must be resolved. We really have no choice, though, except to go forward--because once we found that BDNF could reverse the effects of forced swimming, and treatments already in our possession could generate new neurons, morally, everything has changed.
Dr Geppert is chief of consultation-liaison psychiatry and chief ethics consultant at New Mexico Veterans Affairs Health Care System in Albuquerque. She is also assistant professor in the department of psychiatry and associate director of religious studies at the University of New Mexico in Albuquerque.
Young LT, Bakish D, Beaulieu S. The neurobiology of treatment response to antidepressants and mood stabilizing medications. J Psychiatry Neurosci. 2002;27:260-265.
Stahl SM. Blue genes and the monoamine hypothesis of depression. J Clin Psychiatry. 2000;61: 77-78.
Soares JC, Mann JJ. The anatomy of mood disorders- review of structural neuroimaging studies. Biol Psychiatry. 1997;41:86-106.
Coyle JT, Duman RS. Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron. 2003;38:157-160.
Duman RS, Malberg J, Nakagawa S, D’Sa C. Neuronal plasticity and survival in mood disorders. Biol Psychiatry. 2000;48:732-739.
Soares JC, Mann JJ. The functional neuroanatomy of mood disorders. J Psychiatr Res. 1997;31: 393-432.
Bowes M. Are today’s mood stabilizers tomorrow’s neurotrophic agents? Neuropsychiatry Reviews. 2(4); May 2001. Available at
http://www. neuropsychiatryreviews.com/may01/npr_may01_ mood.html
. Accessed June 2, 2006.
Manji HK, Moore GJ, Chen G. Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness. Biol Psychiatry. 2000;48:740-754.
Mann JJ. The medical management of depression. N Engl J Med. 2005;353:1819-1834.
Thase ME. Evaluating antidepressant therapies: remission as the optimal outcome. J Clin Psychiatry. 2003;64(suppl 13):18-25.
Noordsy DL, Torrey WC, Mead S, et al. Recoveryoriented psychopharmacology: redefining the goals of antipsychotic treatment. J Clin Psychiatry. 2000;61 (suppl 3):22-29.
Luhrmann TM. Of 2 Minds: The Growing Disorder in American Psychiatry. New York: Knopf; 2000.
Kupfer DJ. The mission of therapeutics. Neuropsychopharmacology. 1993;9:169-180.