The norepinephrine depletion theory was originally based on the observation that reserpine,

which depleted catecholamine stores in the central nervous system (CNS), was capable of
causing depression.17,18 This theory evolved into the permissive hypothesis, which
emphasized a greater role for serotonin in promoting or “permitting” a decline in
norepinephrine function. Specifically, this hypothesis suggests that lowconcentrations of
serotonin or norepinephrine in theCNSprecipitated depressive symptoms,whereas lowlevels of
serotonin and increased activity of norepinephrine resulted in manic symptoms.
Antidepressants were believed to relieve depression by inhibiting the reuptake of
norepinephrine and/or serotonin from the synapse up into the neuron, and effectively increasing
neurotransmitter concentrations in the synaptic cleft.

First, antidepressants were capable of blocking the reuptake of neurotransmitters almost

immediately after administration, yet several weeks lapsed before therapeuticn effects were
evident (i.e., delayed onset).20 Second, synaptic concentrations of biogenic amines are not
always decreased in depressed individuals and can actually be higher than those seen in normal
controls.21 Lastly, antidepressants in development can work via mechanisms that do not
involve relative increases

in synaptic neurotransmitter concentrations. Such mechanisms includeblockade of

substanceP,andantagonism of corticotropin 22 Releasing factor or corticosteroid receptors.
The dysregulation hypothesis has evolved more recently and suggests that depression, as well
as other psychiatric disorders, is the result of a dysregulated neurotransmitter system. Such
dysregulation may include (a) an impairment in the regulatory or homeostatic mechanisms, (b)
an erratic basal output of neurotransmitters, (c) a disruption in normal periodicities (circadian
rhythm), (d) a less selective response to environmental stimuli, (e) perturbation of the system
resulting in a delayed return to baseline, and (f ) restoration to efficient regulation through the
use of pharmacologic agents.25

Depression has been associated with changes in presynaptic and postsynaptic receptor densities
(or sensitivities) that have been described as being downregulated or desensitized.26 Changes
include a decrease in postsynaptic alpha-adrenergic receptor sensitivity, along with alterations
in the sensitivities of the alpha-adrenergic, dopaminergic (D2) and serotonin receptor subtypes
(5-HT1A and 5HT2A). For example, selective serotonin reuptake inhibitors (SSRIs) can
increase the efficiency of serotonergic neurotransmission acutely (through reuptake blockade),
but their therapeutic effects are linked temporally with increased release of serotonin through
downregulation of presynaptic autoreceptors (5-HT1A).27

For instance, appetite, sleep, libido, motor function, anxiety, and aggression all appear to be strongly influenced
by serotonin transmission. Research evidence for serotonergic influence has demonstrated that the concentration
of serotonin’s primary metabolite (5-hydroxyindoleacetic acid [5-HIAA]) is decreased in the cerebrospinal fluid
of depressed patients.27 Low 5-HIAA concentrations have also been found in the cerebrospinal fluid of patients
attempting suicide and may have a role in triggering other violent activities.28 Dietary depletion of l-tryptophan,
a serotonin precursor, has induced relapse in depressed patients previously responsive to SSRIs, and symptoms
such as irritability and disrupted sleep/appetite appear to return preferentially.29
Alternatively, deficiencies in norepinephrine (and dopamine to some extent) are believed to mediate depressive
symptoms such as anhedonia, decreased energy, memory impairments, and executive dysfunction. 30
Administration of α-methyl paratyrosine (which inhibits the synthesis of norepinephrine) has resulted in the
return of these depressive symptoms among patients previously treated successfully with noradrenergic
antidepressants.31 The role of dopamine in mediating this constellation of symptoms has been implied through
postmortem studies, neuroimaging results, and the demonstrated effectiveness of pure dopamine agonists (e.g.,
amantadine, pramipexole) in relieving depression.32 Ultimately, it is still believed that a common circuitry is
influenced by these various neurotransmitters, \resulting in the clinical manifestation of depression. 31
Neuroendocrine Findings
Along with dysregulated neurotransmitter systems, neuroendocrine abnormalities may contribute to the
development of depression. Depressed patients often have abnormal thyroid function tests (including low
triiodothyronine [T3] and/or thyroxine [T 4] levels).33 They also may exhibit an abnormal response to challenge
with thyroid-releasing hormone, consisting of a blunted or exaggerated thyroid-stimulating hormone
response.34 Clinical hypothyroidism can also induce depressive symptoms, and thyroid supplementation can
reverse this pathology, suggesting an indirect association between mood disorders and thyroid homeostasis.35
The hypothalamic-pituitary-adrenal (HPA) axis may also influence the manifestation of depression, with a
relative hyperactivity of this system commonly reported in depressed individuals. Pituitary and adrenal glands
are often enlarged in depressed patients, and concentrations of corticotropin-releasing
factor are often elevated during depressive episodes and decline with the administration of antidepressant
medications or electroconvulsive therapy (ECT).24,36 Exogenous administration of corticotropin-releasing factor
has elicited classic symptoms of depression in laboratory animals (including decreased appetite,
anxiety, insomnia, and decreased libido).37 In humans, medications that block postsynaptic corticosteroid
receptors have also displayed antidepressant properties, as demonstrated with ketoconazole and
mifepristone.38,39 Interestingly, serotonin has been recognized as a strong influence on the HPA axis (and vice
versa). Activation of the postsynaptic serotonin receptors(5-HT2) along the hypothalamic paraventricular
nucleus can stimulate corticotropin-releasing hormone–secreting neurons. Loss of hippocampal
volume in major depression leads to increased levels of circulating glucocorticoids, which leads to neuronal
apoptosis.40 Hypercortisolemia due to chronic stimulation of the HPA axis has been implicated in potentially
reducing gray matter loss in humans. It should be noted that the relationship between hippocampal
volume and depression is not consistently observed
and that various factors may affect these findings.41 Corticosteroids
can also modulate serotonin synthesis, metabolism, and
reuptake.24
Not all of the evidence, however, supports a causative role of
HPA overactivity in the manifestation of depression. The acute
administration of high-dose corticosteroids, for instance, is more
commonly associated with mood elevation (e.g., euphoria or
hypomania), leading some to suggest that the exaggerated HPA
response seen with depression is actually the body’s attempt
to overcome this mood disorder. Furthermore, HPA overactivity
has not been observed in certain populations of depressed
patients, such as adolescents and young adults. Given the strong
association of depression with chronic inflammatory conditions,
further exploration of the relationship of the HPA axis to depressive
symptoms is imperative.
Genetic Studies
Over the last few years, significant scientific advances have been
made in genetics and pharmacogenomics. Several genes have
beenimplicated in predictive response or adverse effects to antidepressants.
Pharmacodynamic targets have focused on serotonin
transporters (5-HTTLPR), tryptophan hydroxylase enzymes 1
and 2 (TPH1 and TPH2), serotonin 1A (5-HT1A) and 2A
(5-HT2A) receptors, brain-derived neurotrophic factor (BDNF),
G-protein beta-3 subunit (GNB3), monoamine oxidase enzymes
and p-glycoprotein; pharmacokinetic targets have been focused
on polymorphic variations in CYP1A2, CYP2C19, CYP2D6, and
CYP3A4 enzymes.42–44 Variations in the serotonin transporter
SLC6A4 gene have been associated with remission and response
rate in a meta-analysis of 1,435 patients.43 Researchers found that
patients with the ss genotype are less likely to reach remission
during SSRI treatment and take longer to achieve 50% symptom
improvement compared to those with the ll genotype. Asian
patients had the most significant heterogeneity in response,
although the association was also seen among white patients.
The cytochrome P-450 (CYP) system has been extensively studied
for predicting drug response and toxicity with CYP2D6 being
the most studied isoenzyme. Patients with a variable number
of copies of the functional CYP2D6 alleles can display different
abilities to metabolize CYP2D6 substrates, including antidepressants.
Patientsmay be classified as ultra-rapid metabolizers, rapid
metabolizers, intermediate metabolizers, and poor metabolizers,
depending on the number of copies of the variant allele.
In one study, the highest percentage of patients who were considered
poor metabolizers experienced modest or marked side
effects compared to those subjects who were rapid metabolizers
or ultra-rapid metabolizers.45 Additional discussion on the
impact of CYP on antidepressant metabolism is provided in the
Drug Interactions section (Case 83-1, Questions 14, 15). A major
challenge with pharmacogenomic studies lies in the difficulty
of defining unambiguous drug response phenotypes in complex
diseases, such as depression. Most likely there aremultiple genes
that are involved in disease phenotype, drug response, and toxicity.
Gene–environment interactions undoubtedly also play a role
in the determination of these phenotypes. Although the concept
of personalized medicine or the ability to predict response
or toxicity to medications for an individual patient has proven
to be a reality for some disease states, there is still insufficient
evidence to recommend routine pharmacogenomic testing in
patients treated with SSRIs for non-psychotic depression according
to the Evaluation of Genomic Applications in Practice and
PreventionWorking Group.46
Imaging Studies
Imaging studies (including computed tomography, magnetic
resonance imaging, positron emission tomography, and singlephoton
emission computed tomography) suggest that patients
with depression have regional brain dysfunction, most often
affecting the limbic structures and prefrontal cortex. Alterations
in cerebral blood flowand/or metabolism in the frontal-temporal
cortex and caudate nucleus are associated with common depressive
symptoms such as dysphoria, anhedonia, hopelessness, and
flat affect.47 Increased firing of the amygdala in the left hemisphere
has been linked in positron emission tomography studies
with the future development of depression.48 Because subtypes
of depression have been linked to different regional dysfunctions,
a network hypothesis has begun to emerge thatmay lead to
improvements in depression diagnosis and targeted treatments. 49