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Biology 202
2001 Third Web Report
On Serendip

The trail of evidence from treatment to causes of depression

Andréa Miller

When a person is depressed, the primary characteristic is a subjective awareness of mood change: the person has an ongoing feeling of sadness or emptiness. This feeling is often accompanied by eating disturbances, feelings of hopelessness, inability to concentrate, indecisiveness, sleep disturbances, lost interest in enjoyable activities, psychomotor retardation, fatigue, sluggishness or lethargy, and is often co-morbid with other disorders, especially anxiety.

This constellation of feelings and observable behaviors give rise the term depression. In cases where the depression is not severe or recurrent, psychotherapy alone may be sufficient. However, in many cases, antidepressants in conjunction with psychotherapy are indicated. And in some proportion of cases, where the depression is especially severe, persistent, debilitating and resistant to antidepressants, therapies involving electrical stimulation to the brain are sometimes used.

In psychology, theories surrounding the etiology of depression vary widely, from neurobiological to cognitive to behavioral, socioenvironmental and psychodyanmic. Biosocial models acknowledge that both biological predisposition and environmental factors play an interactive role in the creation and maintenance of depression.

The nervous system is always changing. It changes as a result of its own activity, which itself is a reflection of responses to a variety of sources: external input, the system's own cyclical fluctuations, and its modification due to past experiences. Moreover, the nervous system's changes occur in varying degrees, from extremely temporary (action potentials transiently change the nervous system) to lasting (synaptic modification, network modification, production of new pathways through neuron growth, as well as pruning).

While it is true that the state of the nervous system at any moment is a complex interplay of both input from the external world and the system's own internal biases and states, so that the "internal/external" dichotomy is perhaps an oversimplification -- I think that patients who respond favorably to psychotherapy alone (and don't experience later relapses) may represent a qualitatively different underlying etiology than those who experience recurrent, persistent and debilitating depression. Put differently, if the nervous system is constantly changing, and we recognize that some of the changes are more temporary while others reflect more lasting modifications, the patients for whom psychotherapy alone is effective perhaps reflect more transient underlying nervous system changes.

In terms of a biosocial stress-diathesis model (diathesis refers to biological predisposition and stress to environmental contribution), these psychotherapy-receptive patients may have a low diathesis, and whatever environmental stressors have occurred to induce depression, have not done so to the extent that they have altered the biological system in a pervasive and lasting way. Therefore, the scope of this paper will not further address this group of depression sufferers, concentrating instead on those who experience persistent, severe and/or recurrent depression, whose manifestations and course suggest stable changes to the nervous system in a variety of ways, that whatever the original cause (biological predisposition or change as a result of experience), will necessarily require more invasive intervention.

It is, of course, cause that concerns me greatly: underlying the mental and physical manifestations, can we discover neurobiological correlates, causes?.And here, I define "cause" as "mechanism." What biological factors, or set of factors, give rise to depression? The discussion that follows will highlight observations that have suggested the involvement of neurotransmitters, hormones and maladaptive electrical activity patterns in the brain.

The neurotransmitters seratonin and norepinepherine have increasingly become a focus of interest in the study of depression. The brain is an electro-chemical system. Information is carried within the neuron electrically (via action potentials and passive current) and between neurons chemically. Specifically, each neuron has its own set of neurotransmitters that are released from its axon terminal into the synapse, a small space between neurons. When these free-floating neurotransmitters attach to the dendrite of a nearby postsynaptic neuron, this in turn causes permeability changes in that neuron, and ultimately set off electrical changes, firing down the axon to repeat the process again as they induce neurotransmitters to be released into the synapse.

Theoretically, the chemical (neurtransmitter) end of the system can malfunction in two ways: if the postsynaptic neuron is insensitive and doesn't allow enough of the neurotransmitters to attach, or if the presynaptic neuron doesn't release enough neurotransmitter into the synapse. (1) fMRI studies and cereberospinal fluid studies have suggested that the problem has to do with underrepresentation of seratonin and norepinepherine in the synapse rather than insensitivity in the postsynaptic neuron. (2)

As further evidence, the therapeutic effect of tricyclics, selective seratonin reuptake inhibitors (SSRI's) and a new drug, reboxetine (a norepinepherine reuptake inhibitor) (3) all relieve depression by blocking neurotransmitter reuptake, thereby increasing the level of these neurotransmitters in the synapse. However, the causal link is far from established: although low levels of these neurotransmitters in the synapse are associated with depression and increased levels in the synapse often alleviates it, we still cannot conclude that increase of neurotransmitter in the synapse is treating a primary mechanism of depression or merely a symptom.

Another theory about the primary cause of depression implicates hormones. Specifically, overactivation of the HPA axis (hypothalamic-pituitary-adrenal axis) which regulates the release of stress related hormones is thought to play a role: it increases the output of CRF in the hypothalamus, activating overproduction of ACTH in the pituitary, and ultimately increases levels of cortisol. (1) Increased levels of cortisol have been associated with depression, and though the causal link is unknown, overproduction of cortisol is also known to kill cells in the hippocampus, a center of emotion and memory, and the chronically depressed have been shown to have less hippocampal tissue. (1)

Nemeroff proposes a stress-diathesis model for depression: genetic factors create a biological weakness for depression (diathesis) in either the neurotransmitter system or the HPA circuit. However, he says, that in itself is not generally sufficient to cause depression. Early abuse or neglect stress the biologically compromised system, initiating permanent changes that make the system over-sensitive to stressors in the HPA axis. (1) In other words, early experience acts on biological vulnerabilities to enact permanent changes on the nervous system's (HPA's) sensitivity to stress. Interestingly, he notes that somehow (it is not known how), SSRI's return CRF levels to normal, and reduce symptoms of depression. But this does not establish a direct causal explanation about how, if at all, the HPA hormone circuit and neurotransmitters are related to each other in the establishment or maintenance of major depression.

Some depression sufferers who are not responsive to antidepressant therapies do respond to anticonvulsants. (3) Anticonvulsants are generally prescribed to control seizures in patients with epilepsy, though the mechanism is not well understood. For example, the Physician's Desk Reference says that although the anticonvulsant gabapentin is "structurally related to the neurotransmitter GABA, it does not interact with GABA receptors, nor is it converted metabolically into GABA or a GABA agonist, and is not an inhibitor of GABA reuptake or degradation." (4) In other words, gabaprentin's link to the neurotransmitter GABA is suspected but is presently not established or understood, and therefore, how gabapentin actually works is also unknown.

Interestingly, other therapies have been used to alleviate both epileptic seizures and major depression. For example, electroconvulsive therapy (ECT), an early treatment of epilepsy, has also been used to relieve patients of their depressive symptoms. In ECT, electricity is passed through scalp to the temporal regions of the cortex, inducing a grand-mal seizure in the patient, which was thought to reset the brains activity back to baseline. For depression, the procedure is repeated for several sessions. This method of therapy has come under attack, though, because it may exert its effect on depression primarily through causing retrograde amnesia, (so that patient's symptom alleviation has more to do with confusion or loss memory of the events leading to depression rather than acting on primary neurological causes of the same). Moreover the complications can be severe, including permanent memory loss, cognitive deficits and even death. (5)

In response to reservations about severe complication risk surrounding ECT, researchers have begun to develop other, safer electrically based therapies for epilepsy, including a safer version of ECT: transcranial magnetic stimulation (TMS) as well as vagal nerve stimulation (VNS). (3) (7) (8) Just like the medical therapies for epilepsy, these new electrical therapies have also made their way into the treatment of depression.

TMS works much like ECT, except that instead of direct current, magnetic fields produce small amounts of current that pulse in fractions of a second intervals through the temporal lobes. It has been shown to reduce both rates of epileptic seizures and symptoms of depression using objective measures for up to 3 months. (7) Again, the mechanism behind its efficacy is not well understood.

In VNS, a small pacemaker is implanted under the left breastbone. Wires tunnel up to the left vagus nerve and coil around it. When the pacemaker is turned on, it sends small electrical bursts to the vagus nerve for 30 seconds in 5-minute intervals. VNS was approved for use with epilepsy in 1997, and shortly after its inception, researchers began to notice improvement in affect among some of the epileptic patients, leading them to investigate its efficacy on depressed subjects. (3) (10) In the first pilot study of 30 patients, 40% of the major depressive disorder (MDD) patients who had been resistant to drug and ECT therapies for an average of 10 years, showed 50% improvement in affect, after 10 weeks of therapy. This is a striking results. Some patients were so improved that they were willing to return to a "normal" life after years of incapacitation. (8) (9) Though VNS and ECT are both electrically based treatments, VNS does not induce seizure like ECT does. Instead it sends a small current to the vagus nerve, where some tracts go to the limbic system, a center of emotion, memory, sleep and temperature regulation. (10) Researchers hypothesize that the mechanism behind both mood elevation and reduction in seizure activity has to do with its effect on neurotransmitter activity in those areas: the stimulation activates seratonin, releasing more of the substance into the synapse. (10) (11) Theories regarding how increased seratonin in the synapse reduces seizures were not described.

Jobe and his colleagues suggest that pharmacological and electrical evidence establish a link between epilepsy and depression. In the first place, both epilepsy and depression are somehow related to norenepherine and seratonin deficits. And anticonvulsants improve mood while antidepressants reduce epileptic seizures in some patients. Electrical stimulation elevates mood and decreases seizure rate. So far, the evidence seems to point to a common origin for both epilepsy and depression. Moreover, Jobe and his colleagues make a surprising observation. They contend that seizures, "whether spontaneously occurring or therapeutically induced, protect against depression." (11)

What sense can be made of this observation -- if both epilepsy and depression are hypothesized to stem from a similar deficiency, and are sensitive to some of the same therapies, how can one act as cure to the other? How is it possible that seizures, spontaneous or induced (ie, via epilepsy or ECT), protect against depression?

Moreover, does the converse hold true as well? Does the presence of depression increase the likelihood of later epilepsy? There is some evidence that it does. In elderly patients, the presence of depression makes the likelihood of seizure increase 6 fold. (3) These two pieces of evidence raise questions about the nature of the link between epilepsy and depression.

All of the therapies discussed thus far make explain the mechanism of depression (and epilepsy) either directly or indirectly in terms of deficiencies in seratonin and norepinepherine in the synapse. The implication here is that it is the absence of these neurotransmitters is the primary deficit, and whatever else is involved (hormones, abnormal electrical patterns) is artifact or precursor or result of the primary deficit.

But remembering that the brain's function is an interdependent cycle of electrical and chemical action, it may be useful to conceptualize depression with a theory that takes both electrical and chemical action into account, and integrates evidence about the efficacy of seizure on depression. In this light, it is even possible to propose that the primary deficit (if there is one) has more to do with an overall pattern of electrical activity, rather than observed changes in neurotransmitter levels.

For example, an argument could be made based on the evidence that the seizures reduce depression symptomology, and that with depression seizure is more likely -- that seizures may be akin to the nervous system's own 'reset button.' In other words, perhaps the entire brain becomes trapped in electrical cycles that are maladaptive. These electrical cycles affect neurotransmitter release into the synapse, which in tern affects the electrical activity of the postsynaptic neuron. Perhaps such interactive development is something like a 'positive feedback loop' feature, making the cycle more severe and stable. In that case, if the system had a threshold, a point at which the system would trip, and electrically reset itself back to a "normal state" of function, such a mechanism would be adaptive.

In fact, using epileptic evidence we could look at it just that way. In William Calvin's "Conversations with Neil's brain" we get a neurologist's eye view of the epileptic brain's action. Epileptics like Neil, in normally functioning states, sometimes show temporal lobe spikes on electrocephalogram. These spikes indicate abnormal electrical cycles in part of the brain. EEG is an instrument that summarizes electrical neuron activity, rather than recording the activity of a single neuron. Calvin describes how prior to a seizure, these spikes, or brainwave patterns characteristic of epilepsy, increase on EEG. If too many of the spikes occur together, there's a good chance that a seizure will ensue. (6)

The way I understand it, grand mal seizures are set off by increased levels of abnormal activity in one area sparking activity all over the brain through the brain's widely distributed connections. He uses a "lawn sprinkler" metaphor to explain how input (like water) enters one part of the system and then spreads diffusely all over (the lawn). After it spreads through the brain, a grand mal seizure spontaneously terminates. It seems as though somehow whatever electrical pattern ran riot, it is self-limiting. After the seizure, the pattern of activity looks like normal resting state again, not like the spikey pattern that precipitated the seizure.

But how does this knowledge inform theories of depression? How can we account for the efficacy of electrical seizure in alleviating depression? What I think is that somehow, depression might have something to do with a generalized state of electrical activity, that produces local disturbances in levels of neurotransmitters in the synapse, that these electrical-chemical cycles reinforce and intensify each other, and that therapies designed to intervene at the neurotransmitter level help but may not be able to affect permanent changes in the nervous system. They can't bring it back to a state of "normal" electrical activity. For that, some sort of electrical intervention may be needed. In this way, seizures (spontaneous and induced) somehow accomplish this -- by causing a "short circuit" which essentially resets the brain's electrical activity to normal levels. Additionally, the new VNS evidence suggests that low-level, ongoing electrical stimulation may affect the same qualitative long-term changes in the brain, but without the potential hazards of massive electrical insult to the brain.

This model tries to incorporate both the chemical and electrical therapy evidence into account in its theory of the mechanisms of major depression. However, it should be noted that in practice, there is a problem: if these lines of evidence are all interconnected, if they all tap into a generalized model of depression, why do some therapies work for some people and not for others? And for any individual, one therapy may work, while another is ineffective. For example, antidepressants alone work for 20% of severely depressed patients, anticonvulsants alone work for 20% and a combination works for up to 60% (electrical therapies were not cited in this source). Moreover, 40% of the individuals who received 10 weeks of VNS therapy showed significant improvement, which is encouraging. However, such evidence, even if encouraging, does not support the theory that everyone's underlying mechanism can be explained in the same terms.

In short, if there is a generalized mechanism for depression, why is there no single therapy that works for all people? Perhaps the answer lies in the "stress-diathesis" model. Perhaps the complex interplay between differing levels of hereditary and environmental influence combine to make no one treatment a "one size fits all." Just to take a stab at this: perhaps if a person has a low diathesis but a lot of ongoing environmental influence, life experience continually affects the nervous system with a kind of insult that acts in repeated singular events. These multiple, ongoing, disconnected, transient episodes may in the long run have the same effect as a biological predisposition (which acts in somewhat more stable and continuous ways, though with variation) on the nervous system. However, because they are atomistic, ie, happen one at a time perhaps in these cases, drug therapy may work relatively well in some cases, if treated early enough.

However, as mentioned earlier, over the long run, even these temporary nervous system changes can enact permanent effects on the nervous system. In other words, they may come to be as imbedded as biological dispositions, which may be less responsive to drug treatment, and may require a more systemic approach such as electrical stimulation to reset the whole system.

To me the two most compelling observations for the centrality of electrical component in depression are the Vagus Nerve Stimulation evidence, and the observation that spontaneous epileptic seizures decrease depressive symptomology and the presence of depression increases the likelihood that a seizure will occur. These seem to suggest to me that not only does the generalized state of the nervous system have something to do with depression, but that the system itself may have embedded in it, a self corrective mechanism that can help us better understand depression and its complex causality.

WWW Sources

1) The neurobiology of depression , by Charles Nemeroff

2)Contributions from imaging, also by Charles Nemeroff

3) The antidepressant waiting game: future of depression treatments

4) Physician's Desk Reference, 55th ed. 2001

5) Shock treatment, brain damage and memory loss: a neurological perspective , by John Friedberg

6) Conversations with Neil's Brain , by William Calvin and George Ojemann


8) New technique looks promising for treatment resistant depression

9) Vagus nerve stimulation for treatment-resistant depressions: a multi-center study. led by John Rush

10) VNS: high tech hope for those with major depression , by Sandra Gordon 11) A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders by P C Jobe et al

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