Neurobiology of depression

 

I.                    Depression

II.                 Neuropathology

a.       General

b.      Prefrontal cortex

c.       Amygdala

d.      Hippocampus

III.               Treatments

a.       MAO inhibitors

b.      Tricyclic antidepressants

Where are these monoaminergic systems?

c.       SSRIs

d.      NRIs

e.       SNRIs

f.        NDRIs

IV.              Theories of Depression

a.       Monoamine Hypothesis

                                                               i.      Evidence

                                                             ii.      Problems with simplified monoamine hypotheses

b.      Monoamine Receptor Hypothesis

c.       Altered intracellular signaling and gene expression

d.      Neurogenesis Hypothesis

e.       Neurokinin Hypothesis

f.        Where does the monoamine hypothesis stand?

 

Hippocrates was probably the first to suggest that depression is due to physiological dysfunction.  He believed that depression was due to an imbalance in the four humors, with an excess of melancholia, or black bile.

 

Mike provided a description of the symptoms of depression and prevalence rates. Depression is characterized by dysphoria, anhedonia, and a generalized loss of interest in the world.  In addition, some of the following symptoms may be present: disturbed sleep, diminished appetite, loss of energy, decreased sex drive, restlessness, feelings of worthlessness, thoughts of dying and suicide.  It is important to note that there is a great deal of heterogeneity both in depression-related behaviors and neuropathology.  This is evidenced by the variety of antecedents to depressive syndromes (genetic, medical, psychosocial), the diversity of responses to therapies, and the variable presence of neuroendocrine, neurochemical and circadian rhythm disturbances in depressive samples.

 

Neuropathology

 

Abnormalities have been reported in the prefrontal cortex, basal ganglia, hippocampus, thalamus, cerebellum, and the temporal lobe.  In individuals suffering from unipolar depression, the most reliable findings are in the prefrontal cortex, basal ganglia, hippocampus and cerebellum. We have already discussed the possibility of a relationship between hippocampal volumetric reductions, the HPA axis and depression. 

 

Because there are several types of depression, one must recognize that the pathology associated with one type may not be present in all cases.  For example, late onset depression that is not related to familial ties is likely associated with pathology in the frontal lobes and basal ganglia, indicative of cerebrovascular accidents. 

 

Prefrontal cortex

 

Familial cases of unipolar and bipolar depression show an abnormality in the prefrontal cortex.  Some studies have found altered volumetric measures in the prefrontal cortex.  For example, Elkis et al (1996) found a reduction in the amount of tissue in the prefrontal cortex of young unipolar depressed patients.  Similarly, Drevets et al (1997) found a reduction in the size of a particular region of the medial prefrontal cortex in patients with unipolar depression. Postmortem studies have also found a reduction in the number of glial cells in this region.  This finding is important, because this is a region of the prefrontal cortex that is important for regulation of mood states (remember our emotion systems).  It has extensive connections with the amygdala, nucleus accumbens, hypothalamus, and the NE, 5HT and DA systems of the brain stem.

 

Functional imaging studies have also reported abnormalities in function.  Increased activity may occur in some areas of the prefrontal cortex (posterior orbital), amygdala and anterior cingulate cortex (Drevets et al, 1992; Abercrombie et al., 1998).   This is consistent with a literature that suggests that sadness and anxiety in normal subjects increases activity in these areas of prefrontal cortex (think now of Ulla’s talk on OCD). The increases in the ventral, orbital and cingulate cortices may be related to emotions and/or obsessive ruminations.

 

But not all regions of the prefrontal cortex show increases in activity.  For example, during the depressive phase, activity in a very specific area of the prefrontal cortex (ventral to the genu in the corpus callosum) is reduced.  This may be accounted for by a reduction in the volume of the gray matter of this part of the prefrontal cortex.  A reduction in the dorsal prefrontal cortex may be related to the neuropsychological impairments.

The following is from Drevets, et al. 2000.  Although the color will not translate when you print it out, it illustrates increased activity in the medial orbital frontal cortex, as well as the amygdala in depressed individuals.

 

 

 

 

 

So, there appears to be prefrontal lobe dysfunction, with reductions in volume and activity in some regions, but increases in activity in other regions. 

In sum:

 

Amygdala

 

In addition, one of the most consistent functional changes positively correlated with depression severity is increased amygdala metabolism (Abercrombie, et al, 1996; Drevets et al., 1992; 2000, see above).  Interestingly, this overactivity also correlates positively with plasma cortisol levels, which fits with Karin’s discussion on stress and depression. In fact, glucocorticoids enhance NE release into the amygdala (Ferry et al., 1999).  This increase in activity may be related to anxiety.  Moreover, this activity is normalized with successful antidepressant treatment.

 

 

There are also structural changes in the amygdala.  The following is from Bowley et al, 2002 (from Drevets’ group).  As you can see, there are the controls, individuals with major depression disorder (MDD), and individuals with bipolar disorder (BD).  There is a reduction in glia/neuron ratio.  Interestingly, the arrows depict individuals who were not on lithium or valproic acid treatment (drug treatments for bipolar disorder), which suggests that a similar alteration may be present in bipolar patients who are not treated pharmacologically.

 

 

 

 

Hippocampus

 

There is also evidence of reduced hippocampal volumes, which we’ve already discussed in the stress section.  This might contribute to the cognitive impairments, as well as the inappropriate context-based regulation of emotion.

 

In summary, there appear to be structural and functional changes in the prefrontal cortex, amygdala, and hippocampus, areas that are important for emotions and learning.  Again, keep in mind that there is great biological heterogeneity in these populations, which is probably why the picture appears so complicated.  With a more sophisticated division of depression subtypes, one may be able to identify the relationship between specific neurobiological pathology and depression. 

 

TREATMENTS:

 

Pharmacotherapy:

 

Mike provided a nice overview of drug treatments that are used for depression and how these relate to the theories of depression.  Mike also provided a good view of how our conceptualization of the underlying neuropathology has evolved. 

 

MAO Inhibitors

Prior to the 1950s no effective antidepressants existed.  Mike discussed how isoniazid was discovered serendipitously.  It was originally developed as a treatment for tuberculosis.  It was noted during clinical trials that some patients who had depression experienced an elevation in mood when treated.  Isoniazid and iproniazid are monoamine oxidase inhibitors (MAOIs).  MAOIs increase monoaminergic activity by reducing monoaminergic breakdown.  Remember that the monoamines include dopamine, norepinephrine, epinephrine, and serotonin.  The first MAOIs were irreversible enzyme inhibitors.  One of the problems with the first MAOIs was the cheese effect.  MAO is found not only in the CNS, but also in the bloodstream where it breaks down pressor amines (which are similarly to catecholamines) from foods like cheese, yogurt, yeast breads, chocolate and wine.  Normally, these pressor amines are deactivated by MAO.  But when MAOIs are taken, the MAO breakdown in the blood is also blocked, which can lead to overactivation of the sympathetic nervous system and consequent high blood pressure and heart rate.  This can be severe enough to produce intracranial bleeding or cardiovascular collapse!  Today, they have developed more specific MAOIs that are reversible inhibitors (reversible inhibitors of MAO (RIMAs)) and are, therefore, safer.

 

            ***incidentally, as Mike mentioned, there are two subtypes of MAO, A and B.  MAO A inhibition is linked more to the antidepressant effects.  MAO B inhibition is linked to prevention of neurodegenerative processes, like Parkinson’s and Alzheimer’s diseases.  The B form is thought to convert some amine substrates, called protoxins, into toxins that may cause damage to neurons.

 


Tricyclic Antidepressants

 

Another category of antidepressants are the tricyclic antidepressants. The tricyclic antidepressants block the reuptake of NE and 5HT and, to some extent, DA.  By retarding reuptake, the drugs keep the neurotransmitter in contact with the postsynaptic receptors, thus prolonging the postsynaptic effects.  Unfortunately, as with all pharmacologic agents, they act at other receptor sites as well as the desired sites, which may lead to the side effects of dry mouth, blurred vision, constipation, sedation, and weight gain.  Mike provided a list of these side effects and also mentions that various drugs may have different sensitivities for the various neurotransmitter systems.

Mike also mentioned that the tricyclics have been used to treat OCD and panic attacks and that these are still popular in other countries.  There is a list of tricylics in his handout.

 

Before going on, where are these monoaminergic systems?

 

As Mike pointed out, the major serotonergic pathways have their origin in the raphe n. in the brain stem and project to hundreds of targets cells in a large-diffuse distribution.  There are at least seven different 5-HT receptor types.  The NE pathways originate in the locus coeruleus.  The axons of some locus coeruleus neurons innervate the hypothalamus, cortex, and hippocampus.  Others descend to the spinal cord.  Like the serotonergic cells, NE neurons innervate broad areas and act on a number of receptor types.  Certain components of the NE system appear to be involved with arousal and fear, while others are thought to be involved (together with the mesolimbic components of the DA system) in positive motivation and pleasure.  The pervasive anxiety and loss of pleasure characteristic of depression may be related to dysregulation of these two components of the NE system.

 

Mike’s handout provides pictures

 

Mike also mentioned how these systems interact.  Their interactions are complex: NE and 5-HT can excite or inhibit one another, depending on the location and receptors subtypes at various neuronal regions. He mentioned that NE from the locus coeruleus to the cells of the raphe nuclei occupy alpha-2 serotonin receptors, antagonizing serotonin release.  In contrast, in the frontal cortex, NE occupies alpha-1 receptors, which increase 5-HT release.

 

Now, back to drugs…

 

Following the development of tricyclics, more specific drugs were developed:

 

Specific serotonin Reuptake Inhibitors (SSRIs)

 

As their name suggests, these drugs act more specifically on the serotonergic system.  Thus, they can be effective without all of the side effects associated with the tricyclics.  Mike mentioned that the therapeutic effects of SSRIs are thought to be mediated by serotonin’s action on the frontal cortex.  Keep in mind there are many subtypes of serotonin receptors!

 


Noradrenergic Reuptake Inhibitors (NRIs)

 

As the name suggests, these drugs act more specifically on the noradrenergic systems.  Mike mentions that their site of action may be on the Beta 1 receptors in the frontal cortex and pathways in the limbic cortex.

 

Serotonin Noradrenergic Reuptake Inhibitors (SNRIs)

 

These drugs have a dual action, blocking the reuptake of both serotonin and noradrenaline, but because they are more specific, they do not produce the side effects associated with tricyclics.  The synergistic effects of blocking reuptake of both serotonin and NE may lead to higher rates of remission.

 

Noradrenaline Dopamine Reuptake Inhibitors (NDRIs)

 

Again, the action is obvious.  As Mike mentioned, there is a hesitancy to market these DA agonists because of the known role of dopamine in addiction.

 

What about dopamine?

 

Mike then asked about dopamine, another monoamine. We discussed the role of DA in the mesolimbic pathway and how this is related activated in response to rewarding stimuli.  As mentioned by Mike, the depression literature has really focused on 5-HT and NE systems, although some of the newer antidepressants (NDRIs discussed above and Wellbutrin) have an stronger affinity for DA systems.

 

Other treatments:

 

In addition to pharmacologic treatments, there is psychotherapy, electroconvulsive shock therapy, transcranial magnetic stimulation therapy, and sleep therapy that may effectively reduce depression.

 

MONOAMINE HYPOTHESIS OF DEPRESSION

 

The fact that effective antidepressants increase 5-HT and NE activity led to the development of the monoamine hypothesis: that depression is caused by too little monoaminergic activity.  Consistent with this hypothesis, reserpine (which blocks the storage of monoamines in the synaptic vesicles) can produce depressive symptoms in some individuals.  Together, it makes sense that depression may be due to a pathological reduction in monoaminergic activity.  Mike mentioned how many aspects of depression are consistent with 5-HT and NE dysfunction.   Depression is related to changes in sleep and fatigue, eating alterations, etc.—behaviors that are regulated by NE and 5-HT.

 

 

 

 

Evidence of altered monoamine levels:

 

Several studies have found that suicidal depression in related to decreased CSF levels of serotonin metabolite, 5-HIAA.  A decreased level of 5-HIAA implies that less 5-HT is being produced and released in the brain.  However, not all subjects show this effect.  In fact, it may be related to those who killed themselves violently, and it is possible that the low levels are more closely related to poor impulse control and aggression (remember Dina’s talk?).  Sedvall et al (1980) analyzed the CSF of healthy, nondepressed volunteers.  The families of subjects with unusually low levels of 5-HIAA were more likely to include people with depression.  So, although there is some evidence among suicidal patients, the data are far from clear.

 

Delgado et al (1990; 2000) used a different approach to study the role of serotonin in depression—the tryptophan depletion procedures.  Keep in mind that tryptophan is a 5-HT precursor.  To determine whether effective antidepressant medication was mediated by alterations in 5-HT, they gave the patients a low-tryptophan diet on the first day, followed by tryptophan-deplete amino acid cocktail on the second day.  Amino acids compete with one another for the transporters across the blood-brain barrier.  Competing amino acids further eliminate or minimize the amount of tryptophan that gets into the brain.  Delgado found that tryptophan depletion caused most of the patients to relapse back into depression.  Then when they began eating a normal diet again, they recovered.  These results strongly suggest that the therapeutic effect of some antidepressant drugs depends on the availability of serotonin in the brain.  By the way (and very interestingly), the tryptophan depletion has little or no effect on the mood of healthy subjects, but does lower the mood of individuals with a family history of affective disorders.  It also has no effect on individuals who are successfully treated with norepinephrine reuptake inhibitors.

 

Two PET studies attempted to determine the brain regions involved in the relapse of depression caused by tryptophan depletion (Bremner et al., 1997; Smith et al., 1999).  They examined patient’s regional metabolic rate before and after the cocktail or placebo.  Both found a decrease in brain metabolism in the prefrontal cortex associated with the return of depression.

 

What evidence is there of reductions in NE activity?

 

This literature is even more confusing.  There is a mixed bag of results.  Obviously, some depressed patients are successfully treated with specific NE reuptake inhibitors.  But increased, decreased, and unchanged urinary NE metabolites have been reported.  Those with low urinary NE metabolite levels appear to be responsive to treatment with tricyclics than those with high levels of NE (see Anand & Charney, 2000 for possible changes in adrenergic receptors)

 

So, the data examining monoaminergic levels does not provide a clear picture.

 


Problems with the monoamine hypothesis.

 

1- First, why does it take so long for the antidepressants to work?

 

This area is the subject of intense research interest and debate.  One primary hypothesis is that, initially, the increase in serotonin activates both postsynaptic receptors AND autoreceptors.  One type of autoreceptor is actually found on the soma and dendrites of the serotonergic neuron (5HT1A receptor), so activation leads to a slowing of neuronal impulse flow through the serotonin neuron, reducing 5-HT release.  Over time, the autoreceptors become desensitized and

then serotonin release is increased.  If this is true, then a drug that blocks the autoreceptors should permit the antidepressant drugs to act sooner.  Pindolol blocks 5-HT1A autoreceptors in the dorsal raphe.  Several studies have examined if this drug speeds up the action of SSRIs, but at this time, the data are equivocal. 

 

Also, it may be related to the number or sensitivity of postsynaptic 5-HT receptors.  It is noted that initially, in response to depressed serotonergic activity, there may be an up-regulation of 5-HT receptors (see receptor hypothesis below).  Interestingly, during antidepressant treatment, there is a down-regulation of 5-HT2 receptors.  The time course of this down-regulation is consistent with the time course of therapeutic action.  Similarly, there is evidence of a down-regulation of B-1 adrenoreceptors (activated by NE).  Most of this evidence is from preclinical studies, but evidence is accruing that it occurs in humans as well.

 

2- Why doesn’t the tryptophan depletion technique induce depression in normal subjects?

 

If depression was caused simply by a reduction in monoamines, or more specifically serotonin, then reducing tryptophan should lead to increased depression in controls, but it does not.  Interestingly, it can induce depression in individuals with a familial link to depression.  Obviously, the process must be complicated.

 

3- Finally, in some patients with depression, the onset of the illness is associated not with a decrease but with an increase in the level of NE in spinal fluid and treatment leads to a reduction back to a normal level.  It is possible that this variation, as noted above, is due to heterogeneity in the type of depression. (see the work of Charles Nemeroff for more discussion).

 

A simple monoaminergic hypothesis, then, is not completely sufficient to explain depression.  Many have begun to investigate actions downstream from the monoaminergic levels.  Perhaps the dysfunction is not related to altered monoamine levels, but alterations in monoamine receptors (as discussed under problem #1) or receptor-related intracellular signaling.

 

MONOAMINE RECEPTOR HYPOTHESIS

 

It was suggested that, perhaps, the dysfunction is not at the level of neurotransmitter release, but is related to altered receptor number and action.  Remember earlier in the class, when we talked about adaptation in the nervous system?  We talked about down-regulation and upregulation of receptors.  It has been suggested that depression may be related to an upregulation of monoaminergic receptors.  When an individual takes an antidepressant that increases availability of monoamines, it takes time for the receptors to re-adapt and down regulate to a normal level of functioning.  After that neuroadaption, the benefits of the antidepressant are obvious. 

Several investigators have also reported an increase in the density of postysnaptic 5-HT 2 receptor binding site in the frontal cortices of depressed suicide victims and unmedicated depressed patients (Stanley, 1983; Yate, 1990), presumably related to up-regulation following low serotonin levels (Owens, 1994). 

 

Intracellular signaling

Perhaps the physiopathology related to depression is not even at the receptor level, but related to signals beyond the receptors.  Alterations in second messenger systems and other intracellular events, including gene expression, are also being examined as the sites of dysfunction.  For example, lithium, which is used for bipolar disorder, works by blocking certain second messengers, dampening excessive neural activity in mania.

 

Neurogenesis Hypothesis

 

Another hypothesis, that we’ve discussed briefly several times throughout this course, is the neurogenesis hypothesis. Depression may be related, in part, to reductions in hippocampal plasticity and neurogenesis.  Robert Duman (1999) suggests that antidepressant actions are related to neuronal plasticity, neurotrophic factors, and neurogenesis.  Depression and stress are related to a reduction in brain-derived neurotrophic factor (BDNF), which may lead to hippocampal atrophy and inhibited neurogenesis.  In contrast, serotonin enhances BDNF and neurogenesis in the hippocampus (Jacobs, et al, 2000).  Perhaps the delay in the effectiveness of antidepressants is due to the time it takes for new neurons to be produced and incorporated into hippocampal circuitry.

 

Neurokinin Hypothesis

 

Substance P is a peptide in the class of neurokinins.  Substance P plays a known role in the pain pathways.  Studies examining the possibility that antagonists to substance P could reduce pain in individuals suffering from pain discovered that mood improved in the subjects, even if the pain did not.  In fact, as Mike illustrated, neurokinens are found in the areas of the brain important for emotion.  They are now investigating the possibility that neurokinin antagonists may act as effective antidepressants.

 

So where does the monoamine hypothesis stand?

 

There have been several modifications of the hypothesis and there is probably not a simple relationship between biogenic amines and depression.  Why?  The subtypes of major depression are most likely not single disorders, but a group of disorders with several underlying pathologies.  Second, disturbances in one of several transmitter systems can lead to depression.  Finally, the various modulatory systems of the brain do not function independently of each other but

rather interact at several levels.  For example, 5HT and NE may coexist on the same neurons.  But investigators are looking beyond direct dysfunction of these systems.  Many suggest that although it is clear that monoamine systems are the mechanism of action of antidepressants, that the underlying mechanism of damage may be related to pathology of other factors that are modulated by the monoamines, including intracellular transduction factors and neurotrophic

factors.  Thus, 5-HT and NE may modulate or be modulated by other neurobiologic

systems.

 

So, again, we have a lot to learn.  Generally speaking, there appears to be dysfunction in the frontal cortex and limbic structures associated with depression.  AND, manipulation of serotonergic and noradrenergic systems can alter depressive symptoms.  However, the exact site of dysfunction is still not known.  By the way, other neurochemicals, including neuropeptide Y (NPY), are being investigated as playing a role in depression.

 

Finally, do not forget the role of stress!  We also already discussed the neuroendocrine dysfunction and the role of stress in depression. 

 

One can imagine that when we have a better understanding of the underlying causes and physiopathology related to depression, as well as a better understanding of subtypes, we will develop more effective antidepressant treatments.

 

 

References, suggested readings:

 

Abercrombie, H.C. et al. 1998. Metabolic rate in the right amygdala predict

negative affect in depressed patients, Neuroreport, 9, 3301-3307.

 

Anand, A., & Charney, D.S. 2000. Norepinephrine dysfunction in depression.

Journal of Clinical Psychiatry, 61, 16-24.

 

Bowley, M.P., Drevets, W.C., Ongur, D., & Price, J.L. Low glial numbers in the amygdala in major depressive disorder. Biological Psychiatry. 5, 404-12.

 

Bremnar, J.D. et al. 1997. Positron emission tomomgrpahy measurement of cerebral

metabolic correlates of tryptophan depletion-induced depressive relapse. Archives

of General Psychiatry, 54, 364-374.

 

Delgado, P.L. 1990. et al. 1990. Serotonin function and the mechanisms of antidepressant action: Reversal of antidepressant induced remission by rapid depletion of plasma tryptophan.  Archives of General Psychiatry, 47, 411-418.

 

Delgado, P.L. 2000. Depression: the case for a monoamine deficiency, Journal of Clincial Psychiatry, 61 Suppl.6, 7-10

 

Drevets, W.C. 1999. Prefrontal cortical-amygdalar metabolism in major depression. Annals of the New York Academy of Sciences. 877, 614-37.

 

Drevets, WC. 2001. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Current Opinion in Neurobiology. 11, 240-249.

 

Drevets, W.C., Bogers, W., Raichle, M.E. 2002. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. European Neuropsychopharmacology. 12, 527-44.

 

Drevets,  W.C., Price, J.L., Simpson, J.R., Todd, R.D., Reich, T., Vanneir, M., Raichle, M.E. 1997. Subgenual prefrontal cortex abnormalities in mood disorders. Nature, 386, 824-827.

 

Drevets, W.C., Videen, T.O., Price, J.L., Preskorn, S.H., Carmichael, S.T., Raichle, M.E. 1992. A functional anatomical study of unipolar depression.  Journal of Neuroscience, 12, 3628-3641.

 

Duman RS. Malberg J. Thome J. 1999. Neural plasticity to stress and antidepressant treatment. Biological Psychiatry, 46, 1181-91.

 

Elkis, et al. 1996. Increased prefrontal sulcal prominence in relatively young patients with unipolar major depression.  Psychiatry Research: Neuroimaging, 67, 123-134.

 

Ferry, B., Roozendaal, B., McGaugh, J.L. 1999. Role of norepinephrine in mediating stress hormone regulation of long-term memory storage: a critical involvement of the amygdala. Biological Psychiatry. 46, 1140-52.

 

Jacobs BL. Praag H. Gage FH. 2000. Adult brain neurogenesis and psychiatry: a novel theory of depression. Molecular Psychiatry, 5, 262-269.

 

Manji, H., Drevets, W.C., & Charney, D. 2001. The cellular neurobiology of depression. Nature Medicine, 7, 541-547.

 

Mayberg, H.S., Brannan, S.K., Tekell, J.L., Silva, J.A., Mahurin, R.K., McGinnis, S., Jerabek, P.A. 2000. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biological Psychiatry. 48, 830-843.

 

Owens, M.J., Nemeroff, C.B. 1994. Role of serotonin in the pathophysiology of depression: focus on the serotonin receptor. Clinical Chemistry, 40, 1288-2295.

 

Sevall, et al 1980. Relationship in healthy volunteers between concentrations of monoamine metabolites in CSF and family history of psychiatric comorbidity. British Journal of Psychiatry, 136, 366-374.

 

Smith, K.A. et al. 1999. Brain mechanisms associated with depressive relapse and associated cognitive impairment following acute tryptophan depletion.  British Journal of Psychiatry, 174, 525-529.

 

Stahl, S.M. 2000.  Essential Psychopharmacology, 2nd edition. Cambridge, Cambridge University Press.

 

Stanley, M., Mann, J.J. 1983. Increased serotonin-2 binding site in frontal cortex of suicide victims.  Lancet, 1 214-216.

 

Yates, M et al. 1990. 5-HT2 receptor changes in major depression. Biological Psychiatry, 27, 489-496.