T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 358;1 www.nejm.org january 3, 2008 55 review article Mechanisms of Disease Major Depressive Disorder R.H. Belmaker, M.D., and Galila Agam, Ph.D. From Ben Gurion University of the Negev, Beersheba, Israel. Address reprint requests to Dr. Belmaker at Beersheba Mental Health Center, P.O. Box 4600, Beersheba, Israel, or at [email protected] N Engl J Med 2008;358:55-68. Copyright © 2008 Massachusetts Medical Society. Depression is related to the normal emotions of sadness and bereavement, but it does not remit when the external cause of these emo-tions dissipates, and it is disproportionate to their cause. Classic severe states of depression often have no external precipitating cause. It is difficult, however, to draw clear distinctions between depressions with and those without psychosocial precipitating events.1 The diagnosis of major depressive disorder requires a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sex- ual desire; constipation; loss of the ability to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. These chang- es must last a minimum of 2 weeks and interfere considerably with work and fam- ily relations. On the basis of this broad definition, the lifetime incidence of depres- sion in the United States is more than 12% in men and 20% in women.2 Some have advocated a much narrower definition of severe depression, which they call melan- cholia or vital depression.3 A small percentage of patients with major depression have had or will have manic episodes consisting of hyperactivity, euphoria, and an increase in pleasure seeking. Although some pathogenetic mechanisms in these cases and in cases of major depres- sive disorder overlap, a history of mania defines a distinct illness termed bipolar dis- order.4 Depression is a heterogeneous disorder with a highly variable course, an inconsis- tent response to treatment, and no established mechanism. This review presents the major current approaches to understanding the biologic mechanisms of major de- pression. G e n e t i c s Studies comparing concordance rates for major depression between monozygotic and dizygotic twins suggest a heritability of about 37%,5 which is much lower than the heritability of bipolar disorder or schizophrenia. Some aspects of the normal person- ality, such as avoidance of harm, anxiousness, and pessimism, are also partly heritable.6 Kendler et al.7 showed that although depression is due in part to heritable depression- prone personality traits, it is also the result of heritable factors that are independent of personality. Early-onset, severe, and recurrent depression may have a higher heri- tability than other forms of depression.8 It is clear from studies of families that majo.

1. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
n engl j med 358;1 www.nejm.org january 3, 2008 55
review article
Mechanisms of Disease
Major Depressive Disorder
R.H. Belmaker, M.D., and Galila Agam, Ph.D.
From Ben Gurion University of the Negev,
Beersheba, Israel. Address reprint requests
to Dr. Belmaker at Beersheba Mental
Health Center, P.O. Box 4600, Beersheba,
Israel, or at [email protected]
N Engl J Med 2008;358:55-68.
Copyright © 2008 Massachusetts Medical Society.
Depression is related to the normal emotions of sadness and
bereavement, but it does not remit when the external cause of
these emo-tions dissipates, and it is disproportionate to their
cause. Classic severe states
of depression often have no external precipitating cause. It is
difficult, however, to
draw clear distinctions between depressions with and those
without psychosocial
precipitating events.1 The diagnosis of major depressive
disorder requires a distinct
change of mood, characterized by sadness or irritability and
accompanied by at least
several psychophysiological changes, such as disturbances in

2. sleep, appetite, or sex-
ual desire; constipation; loss of the ability to experience
pleasure in work or with
friends; crying; suicidal thoughts; and slowing of speech and
action. These chang-
es must last a minimum of 2 weeks and interfere considerably
with work and fam-
ily relations. On the basis of this broad definition, the lifetime
incidence of depres-
sion in the United States is more than 12% in men and 20% in
women.2 Some have
advocated a much narrower definition of severe depression,
which they call melan-
cholia or vital depression.3
A small percentage of patients with major depression have had
or will have manic
episodes consisting of hyperactivity, euphoria, and an increase
in pleasure seeking.
Although some pathogenetic mechanisms in these cases and in
cases of major depres-
sive disorder overlap, a history of mania defines a distinct
illness termed bipolar dis-
order.4
Depression is a heterogeneous disorder with a highly variable
course, an inconsis-
tent response to treatment, and no established mechanism. This
review presents the
major current approaches to understanding the biologic
mechanisms of major de-
pression.
G e n e t i c s
Studies comparing concordance rates for major depression

3. between monozygotic and
dizygotic twins suggest a heritability of about 37%,5 which is
much lower than the
heritability of bipolar disorder or schizophrenia. Some aspects
of the normal person-
ality, such as avoidance of harm, anxiousness, and pessimism,
are also partly heritable.6
Kendler et al.7 showed that although depression is due in part to
heritable depression-
prone personality traits, it is also the result of heritable factors
that are independent
of personality. Early-onset, severe, and recurrent depression
may have a higher heri-
tability than other forms of depression.8 It is clear from studies
of families that major
depression is not caused by any single gene but is a disease with
complex genetic fea-
tures. Studies of pedigrees with multiple cases of major
depression have identified
chromosomal regions with linkage to the disorder, and some of
these loci have been
replicated in more than one study, although no single
chromosomal region has been
replicated in every family study of genetic linkage in
depression. Holmans et al.9 found
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
n engl j med 358;1 www.nejm.org january 3, 200856
evidence of linkage of recurrent, early-onset de-
pression to chromosome 15q25-q26, but the pop-
ulation attributable risk was small.

4. No specific molecular risk factor has been reli-
ably identified. One common polymorphic variant
of the serotonin-transporter–linked polymorphic
region (5-HTTLPR), which affects the promoter of
the serotonin-transporter gene, causes reduced
uptake of the neurotransmitter serotonin into the
presynaptic cells in the brain.10 Some studies have
shown that this polymorphism confers a predis-
position to depression,11 but it also confers a pre-
disposition to an anxious and pessimistic person-
ality.10 Brain imaging reveals functional differences
in emotion-related areas of the brain among car-
riers of the different common polymorphisms of
5-HTTLPR,12 although a direct relation to depres-
sion is unclear. In a large, prospective epidemio-
logic study, Caspi et al.13 found that 5-HTTLPR
predicted depression only in association with de-
fined life stresses. Some environmental factors
could confer a predisposition to depression by af-
fecting the genome epigenetically — for example,
increased maternal care in rodents causes an epi-
genetic change in the promoter region of the glu-
cocorticoid-receptor gene.14
T h e M o n o a m i n e - D e f i c i e n c y
H y p o t h e s i s
The noradrenergic and serotonergic systems orig-
inate deep in the brain and fan out over almost
the entire brain, suggesting a system capable of
modulating many areas of feeling, thinking, and
behaving. The early antidepressants blocked the
reuptake of norepinephrine and serotonin by the
presynaptic neuron. The immediate effects of this
pharmacologic action are to increase the availabil-
ity of norepinephrine and serotonin in the synapse

5. and to increase stimulation of the postsynaptic
neuron. Inhibitors of the enzyme monoamine oxi-
dase were also discovered to have antidepressant
properties. This enzyme catabolizes norepineph-
rine and serotonin in their respective presynaptic
neurons, and such inhibition could be expected to
increase the availability of neurotransmitters. These
discoveries led to a major theory of depression
known as the monoamine-deficiency hypothesis.
Numerous studies of norepinephrine and serotonin
metabolites in plasma, urine, and cerebrospinal
fluid, as well as postmortem studies of the brains
of patients with depression, have yet to identify the
purported deficiency reliably. However, a newly dis-
covered form of the enzyme tryptophan hydroxy-
lase, designated TPH-2, is specific to the brain15
and could explain why previous postmortem stud-
ies of total enzyme activity did not show differ-
ences in tryptophan hydroxylase activity between
patients with depression and controls.16 A recent
positron-emission tomographic study using a li-
gand for brain monoamine oxidase showed a 30%
increase of the enzyme in a subgroup of patients
with depression.17 A study measuring differences
in monoamine metabolites between the internal
jugular vein and the brachial artery showed lower
production by the brain of norepinephrine metabo-
lites in patients with depression than in controls.18
The monoamine-deficiency hypothesis continues
to stimulate research whenever a new technical
window into the brain is opened.
Serotonin and norepinephrine can be depleted
experimentally in humans by oral treatments.19
A drink containing all amino acids except trypto-

6. phan stimulates the liver to synthesize proteins
and rapidly depletes the plasma (and therefore the
brain) of tryptophan. Tryptophan is rate-limiting
for serotonin synthesis in the brain. Such oral
tryptophan depletion does not induce depression
in healthy subjects but will cause a relapse of de-
pression in patients who have been successfully
treated with a serotonin-reuptake inhibitor.19 Sim-
ilarly, α-methyl paratyrosine inhibits tyrosine hy-
droxylase, the rate-limiting step in catecholamine
synthesis. Treatment with α-methyl paratyrosine
does not induce depression in normal subjects but
will induce a relapse in patients who have been
treated successfully with a norepinephrine-reup-
take inhibitor.19 These findings suggest that nor-
epinephrine and serotonin have critical roles in the
mechanisms of these treatments of depression but
that additional neurochemical factors are neces-
sary to cause depression.
Because direct measurements of monoamine
neurotransmission did not yield definitive findings
in relation to depression, the downstream effects
of monoamine neurotransmission were explored
(Fig. 1). The serotonin-1B receptor is located pre-
synaptically and regulates the release of serotonin
by feedback inhibition. Postmortem studies show
that the levels of p11, a protein that enhances the
efficiency of serotonin-1B receptor signaling, are
decreased in the brains of patients with depres-
sion.20 The serotonin-1A receptor is located both
presynaptically and postsynaptically to regulate
mech a nisms of dise a se

7. n engl j med 358;1 www.nejm.org january 3, 2008 57
serotonin function (Fig. 1). The receptor can be
evaluated in patients with depression by injecting
specific agonists and measuring specific neuro-
endocrine responses, such as elevation of the pro-
lactin level.21 Results suggest that the sensitivity
of this receptor is reduced in patients with depres-
sion.21 The α2-noradrenergic receptor, which is
usually presynaptic, modulates norepinephrine re-
lease by feedback inhibition (Fig. 1). Heightened
receptor sensitivity has been described in patients
with depression,22 which is consistent with re-
duced norepinephrine release.
It is conceivable that the second-messenger sys-
tems for serotonergic and noradrenergic neuro-
transmission malfunction in depression, and for
this reason the phosphatidylinositol and cyclic
AMP second-messenger systems have been exten-
sively evaluated. Reduced inositol levels have been
found in postmortem studies of the brains of per-
sons who have died by suicide23 and in magnetic
resonance spectroscopic studies of the frontal cor-
tex in patients with depression.24 A blunted cyclic
AMP response to stimulation was found in post-
mortem studies of the brains of patients with de-
pression.25 These reductions in second-messenger
function may impair neurotransmitter function
even without changes in monoamine levels or re-
ceptor numbers. These data indirectly support
elaborations of the original monoamine-deficiency
hypothesis of depression (Fig. 1).
G proteins that mediate signaling between re-

8. ceptors and second-messenger systems have also
been investigated in patients with depression, both
in postmortem studies of the brain26 and in stud-
ies of peripheral-blood cells.27 Although these
systems are clearly affected, no consistent picture
has emerged because there are numerous forms
of G proteins that vary in different areas of the
brain. The cyclic AMP response element–binding
protein (CREB) is a transcription factor affected by
cyclic AMP in the cell. In an animal model of de-
pression, rats with overexpression of CREB in the
dentate gyrus behaved similarly to rats treated
with antidepressants, but the opposite effect was
found when CREB was overexpressed in the nu-
cleus accumbens.26,28 Thus, the role of CREB in
depression is specific to the region of the brain.
Most but not all studies show that long-term treat-
ment with antidepressants stimulates CREB func-
tion, possibly depending on the type of drug and
the dosage.28 Levels of CREB and phospho-CREB
were reduced in postmortem studies of the cor-
texes of patients who had a major depressive
disorder and had not taken antidepressants, as
compared with controls.26,28 Many studies of sec-
ond-messenger systems and transcription factors
in depression were inspired by the belief that it
takes several weeks before antidepressant treat-
ment has an effect; consequently, the studies were
designed to detect time-dependent biochemical
changes in the cell. New meta-analyses suggest
that antidepressant effects begin rapidly, howev-
er,29 thereby supporting the classic monoamine-
deficiency hypothesis.
A strong point of the monoamine theory has

9. been its predictive power. Almost every compound
that has been synthesized for the purpose of in-
hibiting norepinephrine or serotonin reuptake has
been proved to be a clinically effective antidepres-
sant. A behavioral model of depression has been
developed in which a rodent is placed in a glass
cylinder filled with water, the sheer wall offering
no chance of escape. The animal struggles for a
while and then floats passively (the forced swim
test). A single prior injection of antidepressant in-
creases the struggling time; results in this model
have excellent predictive validity for new antide-
pressants. Other animal models have been devel-
oped by selective breeding of rats for depression-
like behavior, and these genetically susceptible
rodents also have a response to antidepressants.30
Still other models that can be studied biochemi-
cally induce depression with the use of long-term
mild stress or learned helplessness. However, no
animal model of depression captures the periodic
change of behavior into and out of depression that
is seen in patients with depression.
Molecular techniques such as gene knockout
partially support the monoamine theory of depres-
sion. The serotonin-reuptake–transporter knock-
out mouse is excessively anxious and characterized
by increased immobility in the forced swim test.31
This effect is similar to that of the low-activity
polymorphic variant of the serotonin receptor on
human personality10 but is the opposite of the ex-
pected effects of serotonin-reuptake–inhibitor an-
tidepressants. However, this inconsistency could
be explained by the difference between a chron-
ic monoamine abnormality during brain develop-
ment31 and the hypothesized acute monoamine

10. depletion in an adult with depression. Table 1
shows the effects in mice of knocking out genes
related to monoamine neurotransmitters.
The effects of stimulants on mood indirectly
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
n engl j med 358;1 www.nejm.org january 3, 200858
support the monoamine-deficiency hypothesis of
depression and show that mood can be altered
rapidly. Cocaine and amphetamines are powerful
releasers of monoamines into the synapse as well
as inhibitors of reuptake. Their mood-elevating
effects are immediate, but in patients with severe
depression they have often been reported to cause
agitation rather than relief of depression. This
finding could reflect the ability of these stimulants
to deplete the presynapse of monoamines and thus
cause a “crash” into depression. Recent studies
support the theory that an acute response to a
single dose of amphetamine predicts a patient’s
longer-term response to monoamine-reuptake in-
hibitors.46
The role of dopamine deficiency in depression
is suggested by the frequency of depression in pa-
tients with Parkinson’s disease and the effect of
reserpine, which depletes serotonin, norepineph-
rine, and dopamine, causing a hypoactive state in
animals. The antidepressant agent buproprion in-
hibits the reuptake of dopamine. Some direct do-
pamine-receptor agonists, such as pramipexole,

11. have been reported to be efficacious in the treat-
ment of depression, even though they were devel-
oped for Parkinson’s disease.47
A major liability of the monoamine-deficiency
hypothesis is its derivation from the mechanism
of currently available antidepressants. Approxi-
mately two thirds of patients have a clinical re-
sponse to these agents, whereas one third have a
response to placebo.48 Perhaps the mechanism of
depression is not related to monoamines in two
of three cases.
S t r e s s , t h e H y p o t h a l a m i c –
P i t u i t a r y – A d r e n a l A x i s ,
a n d G r o w t h F a c t o r s
Stress49 is perceived by the cortex of the brain and
transmitted to the hypothalamus, where cortico-
tropin-releasing hormone (CRH) is released onto
pituitary receptors. This stimulus results in the se-
cretion of corticotropin into plasma, stimulation
of corticotropin receptors in the adrenal cortex,
and release of cortisol into the blood. Hypothalam-
ic cortisol receptors respond by decreasing CRH
production to maintain homeostasis (Fig. 2).
There is considerable evidence that cortisol and
its central releasing factor, CRH, are involved in
depression.50,51 Patients with depression may have
elevated cortisol levels in plasma,38 elevated
CRH levels in cerebrospinal fluid,50 and increased
levels of CRH messenger RNA and protein in
limbic brain regions.50 In studies using dexa-

12. methasone to evaluate the sensitivity of the hypo-
thalamus to feedback signals for the shutdown of
CRH release, the normal cortisol-suppression re-
sponse is absent in about half of the most se-
Figure 1 (facing page). The Monoamine-Deficiency
Hypothesis Extended.
The monoamine hypothesis of depression postulates
a deficiency in serotonin or norepinephrine neurotrans-
mission in the brain. Monoaminergic neurotransmis-
sion is mediated by serotonin (5-hydroxytryptamine
1A [5-HT1A] and 5-hydroxytryptamine 1B [5-HT1B]) or
norepinephrine (noradrenaline) released from presyn-
aptic neurons (serotonergic neuron, shown on the left
side, and noradrenergic neuron, shown on the right
side [condensed virtually]). Serotonin is synthesized
from tryptophan, with the first step in the synthetic
pathway catalyzed by tryptophan hydroxylase; norepi-
nephrine is synthesized from tyrosine, with the first
step catalyzed by tyrosine hydroxylase. Both mono-
amine transmitters are stored in vesicles in the presyn-
aptic neuron and released into the synaptic cleft, there-
by affecting both presynaptic and postsynaptic
neurons. Cessation of the synaptic action of the neu-
rotransmitters occurs by means of both reuptake
through the specific serotonin and norepinephrine
transporters and feedback control of release through
the presynaptic 5-HT1A and 5-HT1B regulatory autore-
ceptors for serotonin and the α2-noradrenergic autore-
ceptors for norepinephrine. Monoamine oxidase A
(MAO-A) catabolizes monoamines presynaptically and
thereby indirectly regulates vesicular content. The pro-
tein p11, which interacts with 5-HT1B receptors, in-
creases their function. Postsynaptically, both serotonin
and norepinephrine bind two kinds of guanine nucleo-

13. tide triphosphate–binding protein (G protein)–coupled
receptors: cyclic AMP (cAMP)–coupled receptors,
which activate adenylate cyclase (AC) to generate
cAMP, and phosphatidylinositol (PI)–coupled recep-
tors, which activate phospholipase C (PLC). PLC gener-
ates inositol triphosphate (IP3) and diacylglycerol
(DAG); cAMP activates protein kinase A (PKA), and IP3
and DAG activate protein kinase C (PKC). The two pro-
tein kinases affect the cAMP response element–bind-
ing protein (CREB). Findings in patients with depres-
sion that support the monoamine-deficiency
hypothesis include a relapse of depression with inhibi-
tion of tyrosine hydroxylase or depletion of dietary
tryptophan, an increased frequency of a mutation af-
fecting the brain-specific form of tryptophan hydroxy-
lase (TPH-2), increased specific ligand binding to
MAO-A, subsensitive 5-HT1A receptors, malfunction-
ing 5-HT1B receptors, decreased levels of p11, poly-
morphisms of the serotonin-reuptake transporter asso-
ciated with depression, an inadequate response of G
proteins to neurotransmitter signals, and reduced lev-
els of cAMP, inositol, and CREB in postmortem brains.
mech a nisms of dise a se
n engl j med 358;1 www.nejm.org january 3, 2008 59
verely depressed patients.52 Antidepressant-induced
clinical remission is accompanied by reversal of
some of these abnormalities.52
Adults with a history of physical or sexual
abuse as children have increased levels of CRH in
cerebrospinal fluid.53 Adult rodents that were sepa-

14. rated from their mothers or abused as pups show
increased immobility in the forced swim test,
which is reversed by antidepressant treatment.54
Mice with region-specific knockout of the gluco-
corticoid receptor at an adult age have increased
activity of the hypothalamic–pituitary–adrenal axis
and increased immobility in the forced swim test,
both of which are reversed by antidepressants.55
Increased levels of monoamines in the synapse
affect the hypothalamic–pituitary–adrenal axis56
and reverse some of the long-term effects of
stress.56 It is possible that antidepressants relieve
depression by reducing the secondary stress caused
by a painfully dispirited mood rather than by di-
rectly elevating mood. An antistress mechanism
could explain the general usefulness of antidepres-
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
n engl j med 358;1 www.nejm.org january 3, 200860
Table 1. Monoamine-Related Gene Knockouts That Affect
Depression-Related Behavior in Mice.*
Gene or Protein Function Depression-Related Changes
Corroboration
of Monoamine-
Deficiency
Hypothesis
Other Behavior Elicited by

15. Knockout of Gene
sert Serotonin transporter Increased depressive behavior,
reduced se-
rotonin level, desensitized postsynaptic
5-HT1AR, and reduced presynaptic
5-HT1AR function32
No Excessive anxiety32
net Norepinephrine transporter Reduced depressive behavior,
prolonged
norepinephrine clearance, elevated ex-
tracellular norepinephrine levels33
Yes Increased locomotion response
to amphetamines and co-
caine33
5-ht1ar Serotonergic 1A receptor
(presynaptic autorecep-
tor and postsynaptic)
Reduced depressive behavior, normal sero-
tonin level and release, impaired SSRI-
induced neurogenesis32
No Excessive anxiety,
impaired hippocampal learn-
ing32
5-ht1br Serotonergic 1B receptor
(presynaptic autorecep-
tor and postsynaptic)

16. Reduced response to SSRI in forced swim
test, reduced serotonin level and in-
creased serotonin release, increased
SSRI-induced serotonin release, de-
creased serotonin-transporter expres-
sion32
Yes Increased aggressiveness, re-
duced anxiety, increased ex-
ploration, increased use of
cocaine32
p11 (protein) Interacts with and enhanc-
es signaling efficiency
of 5-HT1BR
Increased depressive behavior, increased
serotonin turnover20
No Not reported20
5-ht2ar Serotonergic 2A receptor No change34 No Reduced
inhibition in conflict-
anxiety paradigms34
5-ht7 Serotonergic 7 receptor
(possibly presynaptic
autoreceptor and post-
synaptic)
Reduced depressive behavior and REM
sleep duration35
No Normal locomotion35
α2aar α2A-Adrenergic receptors

17. (presynaptic autorecep-
tor)
Reduced norepinephrine levels, presynaptic
inhibition of release,36 increased depres-
sive behavior37
No Altered sympathetic regula-
tion,36 impaired motor coor-
dination
α2car α2c-Adrenergic receptors
(presynaptic autorecep-
tor restricted to central
nervous system)
Reduced depressive behavior38 Yes Increased
aggressiveness,32
increased locomotion re-
sponse to amphetamines36
mao-a Monoamine oxidase A Increased brain serotonin and
epinephrine
levels39
No Increased aggressiveness and
response to stress,30 de-
creased exploration32
ac VII (hetero-
zygotes)
Adenylyl cyclase type 7 Reduced depressive behavior40 No
Unchanged anxiety40
impa1 Inositol monophos-

18. phatase 1
Reduced depressive behavior, unaltered
brain inositol levels41
Yes Increased hyperactivity and
sensitivity to pilocarpine-
induced seizures41
smit1 Sodium-myo-inositol trans-
porter 1
Reduced depressive behavior and brain ino-
sitol levels42
Yes Increased sensitivity to pilocar-
pine-induced seizures42
creb Cyclic AMP–response ele-
ment–binding protein
Reduced depressive behavior, normal anti-
depressant-induced behavior43
No No increase in BDNF after long-
term use of antidepres-
sants43
bdnf
Male mice Brain-derived neurotrophic
factor
No depressive behavior44 No Increased aggressiveness, hy-
perphagia,45 hyperactivity44

19. Female mice Brain-derived neurotrophic
factor
Increased depressive behavior44 Yes Increased aggressiveness,
hy-
perphagia45
* BDNF denotes brain-derived neurotrophic factor, 5-HT1AR 5-
hydroxytryptamine 1A receptor, 5-HT1BR 5-hydroxytryptamine
1B receptor,
REM rapid eye movement, and SSRI selective serotonin-
reuptake inhibitor.
mech a nisms of dise a se
n engl j med 358;1 www.nejm.org january 3, 2008 61
sants for a wide variety of psychiatric conditions,
including panic disorder, post-traumatic stress
disorder, bulimia, premenstrual syndrome, and
obsessive–compulsive disorder. CRH-receptor an-
tagonists show antidepressant activity in animal
models,57 but the results of large clinical trials
have been disappointing. A compound that blocks
the glucocorticoid receptor has been reported to
be efficacious in depression, but only the most
severe and psychotic type.58
A single test for the cortisol level in blood does
not contribute to the diagnosis of depression, since
levels of cortisol vary markedly in a circadian
rhythm38 and because the overlap between values
in patients and those in controls is considerable.

20. Mild stress induced in the laboratory, such as
Figure 2. The Hypothalamic–Pituitary–Cortisol System in
Depression.
The hypothalamic–pituitary–cortisol hypothesis of depression
postulates that abnormalities in the cortisol response
to stress may underlie depression. The black arrows show that
in response to stress, which is perceived by the brain
cortex and the amygdala and transmitted to the hypothalamus,
corticotropin-releasing hormone (CRH) is released,
inducing the anterior pituitary gland to secrete corticotropin
into the bloodstream. Corticotropin stimulates the ad-
renal cortexes to secrete the glucocorticoid hormone cortisol.
The red lines show that cortisol, in turn, induces feed-
back inhibition in the hypothalamus and the pituitary,
suppressing the production of CRH and corticotropin, respec-
tively. Findings in patients with depression that support the
hypothalamic–pituitary–cortisol hypothesis include the
following: cortisol levels are sometimes increased in severe
depression, the size of the anterior pituitary and adrenal
cortex is increased, and CRH levels in the cerebrospinal fluid
and CRH expression in the limbic brain regions are in-
creased. Hippocampal size and the numbers of neurons and glia
are decreased, possibly reflecting reduced neuro-
genesis due to elevated cortisol levels or due to reduced brain-
derived neurotrophic factor.
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
n engl j med 358;1 www.nejm.org january 3, 200862
T
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e
o
cc
ip
it
al
c
o
rt
ex
a
re
in
cr
ea
se
d
92
,9
3
In

28. tr
av
en
o
u
s
ke
ta
m
in
e,
a
n
N
M
D
A
a
n
ta
go
n
is
t,

29. in
d
u
ce
s
ra
p
id
, s
u
st
ai
n
ed
a
n
ti
-
d
ep
re
ss
an
t

30. ef
fe
ct
9
4
K
et
am
in
e
b
in
d
s
to
h
ig
h
-a
ff
in
it
y-
st

31. at
e
D
2
d
o
p
am
in
e
re
ce
p
to
rs
95
C
o
rt
ic
al
m
es
se

32. n
ge
r
R
N
A
le
ve
ls
o
f
gl
u
ta
m
at
e
tr
an
sp
o
rt
er
s

33. an
d
o
f
th
e
en
zy
m
e
th
at
c
o
n
ve
rt
s
gl
u
ta
m
at
e

34. to
g
lu
ta
m
in
e
ar
e
re
d
u
ce
d
96
It
is
n
o
t
cl
ea
r

35. w
h
et
h
er
a
n
ti
d
ep
re
ss
an
ts
a
ff
ec
t
A
M
P
A
r
ec

36. ep
to
rs
in
t
h
e
b
ra
in
97
R
ed
u
ce
d
G
A
B
A
er
gi
c

37. n
eu
ro
tr
an
sm
is
si
o
n
Le
ve
ls
o
f
G
A
B
A
in
p
la
sm

38. a,
c
er
eb
ro
sp
in
al
f
lu
id
, t
h
e
d
o
rs
o
la
te
ra
l p
re
fr

39. o
n
ta
l
co
rt
ex
, a
n
d
t
h
e
o
cc
ip
it
al
c
o
rt
ex
a
re

40. r
ed
u
ce
d
91
-9
3
G
A
B
A
o
cc
u
rs
in
m
o
re
t
h
an
3

41. 0%
o
f
b
ra
in
s
yn
ap
se
s,
s
u
gg
es
ti
n
g
n
o
n
sp
ec
if

42. ic
it
y
G
A
B
A
-m
o
d
u
la
ti
n
g
ag
en
ts
h
av
e
ef
fe
ct

43. s
in
a
n
im
al
m
o
d
el
s
o
f
d
ep
re
ss
io
n
98
T
h
er
e

44. is
a
la
ck
o
f
d
if
fe
re
n
ce
in
p
re
fr
o
n
ta
l c
o
rt
ex
G

45. A
B
A
le
ve
ls
o
n
M
R
S
in
d
e-
p
re
ss
io
n
99
A
n
ti
d

46. ep
re
ss
an
ts
a
ff
ec
t
G
A
B
A
er
gi
c
fu
n
ct
io
n
98
G

47. A
B
A
n
eu
ro
tr
an
sm
is
si
o
n
m
ay
b
e
re
la
te
d
t
o
s

48. ym
p
to
m
s
o
f
an
xi
et
y
in
d
ep
re
ss
io
n
G
A
B
A
n

49. eu
ro
n
im
m
u
n
o
re
ac
ti
vi
ty
is
r
ed
u
ce
d
in
t
h
e
p

50. re
fr
o
n
ta
l c
o
rt
ex
10
0
A
b
n
o
rm
al
c
ir
ca
d
ia
n

51. rh
yt
h
m
s
S
le
ep
d
ep
ri
va
ti
o
n
a
n
d
li
gh
t
th
er

52. ap
y
h
av
e
an
ti
d
ep
re
ss
an
t
ef
fe
ct
s1
01
,1
02
T
h
e
as

53. so
ci
at
io
n
b
et
w
ee
n
c
lo
ck
-r
el
at
ed
g
en
es
a
n
d
d

54. ep
re
ss
io
n
is
in
co
n
si
s-
te
n
t1
03
S
o
m
e
p
at
ie
n
ts

55. w
it
h
d
ep
re
ss
io
n
h
av
e
ci
rc
ad
ia
n
a
b
n
o
rm
al
it

56. ie
s
o
f
m
o
o
d
, s
le
ep
,
te
m
p
er
at
u
re
, a
n
d
n
eu

57. ro
en
d
o
cr
in
e
se
cr
et
io
n
10
4
R
o
d
en
ts
a
ct
iv
e
d

58. u
ri
n
g
th
e
d
ay
b
ec
o
m
e
d
ep
re
ss
ed
w
h
en
d
ay
lig

59. h
t
is
s
h
o
rt
-
en
ed
10
5
D
ef
ic
ie
n
t
n
eu
ro
st
er
o

60. id
sy
n
th
es
is
C
h
o
le
st
er
o
l l
ev
el
s
ar
e
lo
w
in
p

61. la
sm
a
an
d
t
h
e
b
ra
in
d
u
ri
n
g
d
ep
re
ss
io
n
10
6

62. T
h
e
fi
n
d
in
gs
in
s
ch
iz
o
p
h
re
n
ia
a
re
s
im
ila
r1

63. 07
D
H
E
A
h
as
a
n
ti
d
ep
re
ss
an
t
ef
fe
ct
s
in
p
at
ie

64. n
ts
w
it
h
d
ep
re
ss
io
n
10
8
N
eu
ro
st
er
o
id
s
(n
eu
ro

65. ac
ti
ve
s
te
ro
id
s
in
t
h
e
b
ra
in
t
h
at
m
o
d
u
la
te

66. n
eu
ro
tr
an
s-
m
it
te
r
re
ce
p
to
rs
)
m
o
st
ly
a
ff
ec
t

67. m
em
o
ry
a
n
d
s
le
ep
Im
p
ai
re
d
e
n
d
o
ge
n
o
u
s

68. o
p
i-
o
id
f
u
n
ct
io
n
δ-
O
p
io
id
–r
ec
ep
to
r
ag
o
n

69. is
ts
h
av
e
an
ti
d
ep
re
ss
an
t-
lik
e
ef
fe
ct
s
in
r
o
d
en

70. ts
a
n
d
u
p
-r
eg
u
la
te
le
ve
ls
o
f
B
D
N
F
in
t
h

71. e
b
ra
in
10
9
A
lt
h
o
u
gh
e
ar
ly
r
ep
o
rt
s
su
gg
es
te

72. d
t
h
at
o
p
ia
te
s
m
ay
b
e
ef
fe
ct
iv
e
in
t
re
at
in
g

73. d
e-
p
re
ss
io
n
,1
10
d
at
a
fr
o
m
la
rg
e,
c
o
n
tr
o
lle

74. d
, r
an
d
o
m
iz
ed
t
ri
al
s
ar
e
la
ck
in
g
C
ap
ac
it
y
fo

75. r
co
rt
ic
al
μ
-o
p
io
id
–r
ec
ep
to
r
b
in
d
in
g
is
d
ec
re

76. as
ed
in
r
es
p
o
n
se
t
o
su
st
ai
n
ed
s
ad
n
es
s1
11

77. M
o
n
o
am
in
e–
ac
et
yl
ch
o
lin
e
im
b
al
an
ce
D
ep
re
ss
ed

78. m
o
o
d
c
an
b
e
in
d
u
ce
d
in
h
u
m
an
s
b
y
ad
m
in

79. is
tr
at
io
n
o
f
p
h
ys
o
st
ig
-
m
in
e,
a
n
a
ce
ty
lc
h

80. o
lin
es
te
ra
se
in
h
ib
it
o
r1
12
M
ec
am
yl
am
in
e,
a
n
ic
o

81. ti
n
ic
a
ce
ty
lc
h
o
lin
e
re
ce
p
to
r
an
ta
go
n
is
t,
r
ed

82. u
ce
d
s
ym
p
-
to
m
s
o
f
d
ep
re
ss
io
n
11
3
N
ic
o
ti

83. n
ic
a
ce
ty
lc
h
o
lin
e
re
ce
p
to
r
an
ta
go
n
is
ts
p
o
te

84. n
ti
at
e
an
ti
d
ep
re
ss
an
ts
11
4
M
an
y
an
ti
d
ep
re
ss
an

85. ts
a
re
n
o
t
an
ti
ch
o
lin
er
gi
c
C
yt
o
ki
n
e-
m
ed
ia
te

86. d
c
ro
ss
-
ta
lk
b
et
w
ee
n
t
h
e
im
-
m
u
n
e
sy
st
em

87. a
n
d
t
h
e
b
ra
in
D
ep
re
ss
io
n
is
c
o
m
m
o
n
in
in

88. fe
ct
io
u
s
an
d
a
u
to
im
m
u
n
e
d
is
ea
se
s1
15
M
o
st

89. s
tu
d
ie
s
ar
e
co
rr
el
at
iv
e1
16
E
xp
o
su
re
t
o
c
yt
o

90. ki
n
es
in
d
u
ce
s
d
ep
re
ss
iv
e
sy
m
p
to
m
s,
a
n
d
c

91. yt
o
ki
n
e
se
cr
et
io
n
is
in
cr
ea
se
d
in
m
aj
o
r
d
ep

92. re
ss
io
n
11
5
C
yt
o
ki
n
e-
in
d
u
ce
d
d
ep
re
ss
iv
e
sy

93. m
p
to
m
s
ar
e
te
m
p
o
ra
ry
a
n
d
n
o
t
re
p
lic
at
ed

94. in
al
l s
tu
d
ie
s1
17
A
n
ti
d
ep
re
ss
an
ts
h
av
e
an
ti

95. in
fl
am
m
at
o
ry
e
ff
ec
ts
11
5
S
u
b
st
an
ce
P
a
n
ta
go

96. n
is
ts
a
re
n
o
t
th
er
ap
eu
ti
c
in
d
ep
re
ss
io
n
C
yt
o

97. ki
n
es
a
ff
ec
t
th
e
h
yp
o
th
al
am
ic
–p
it
u
it
ar
y–
ad
re

98. n
al
a
xi
s
an
d
m
o
n
o
-
am
in
es
11
5
mech a nisms of dise a se
n engl j med 358;1 www.nejm.org january 3, 2008 63
stress associated with mental arithmetic calcula-
tions or simulated public speaking, results in
greater changes in plasma cortisol levels than
most reported differences between the values in

99. patients with depression and those in controls.38
It is possible that chronic mild elevations of cor-
tisol, especially at night, when cortisol levels in
normal subjects are very low, have a pathogenic
role in depression. It is also possible that periph-
eral cortisol elevations are only a ref lection of
central disturbances in CRH signaling, which me-
diate the effects of environmental stress on mood.59
A major liability of the hypothalamic–pituitary–
adrenal axis theory of depression is the difficulty
of defining the relationship of stress to depres-
sion. Some patients have a single lifetime depres-
sive episode, whereas a larger proportion have a
recurrent or even chronic course. Various types
of acute stress, early childhood trauma, or long-
term psychosocial problems may be involved and
may lead to different responses of the stress sys-
tem. Stress may be causative in some cases and
secondary to depressed mood in others.
Severe stress in rodents does not necessarily
model the common stresses of childhood. The
association of abuse in childhood with psycho-
pathologic disorders, including depression, in
adulthood could be due to common factors link-
ing family perpetrators of abuse and their victims,
including not only shared genes but also a shared
environment of poverty, poor nutrition, and poor
prenatal care. Depression is not uncommon in
people with no psychosocial risk factors. Most
patients treated for depression have no evidence
of hypothalamic–pituitary–adrenal dysfunction,
just as most such patients have no direct evidence
of brain monoamine deficiency.
The classic teaching is that neurons do not di-

100. vide in the adult mammalian brain, but studies
have shown that neurogenesis occurs in several
areas of the brain, especially the hippocampus.
Neurogenesis is more prominent in rodents than
in primates,60 and some have questioned whether
it occurs in the human cortex.61 Elevated levels of
glucocorticoids can reduce neurogenesis, and this
has been suggested as a mechanism for the de-
creased size of the hippocampus on magnetic
resonance images of the brain in many patients
with depression.62 In postmortem studies of pa-
tients with depression, cell loss in the subgenual
prefrontal cortex, atrophy in the dorsolateral pre-
frontal cortex and the orbitofrontal cortex, and T
h
yr
o
xi
n
e
ab
n
o
rm
al
it
ie
s

101. Le
ve
ls
o
f
tr
an
st
h
yr
et
in
a
re
r
ed
u
ce
d
in
t
h
e
ce

102. re
b
ro
sp
in
al
f
lu
id
in
p
at
ie
n
ts
w
it
h
d
ep
re
ss
io

103. n
11
8
T
h
yr
o
id
h
o
rm
o
n
es
m
o
d
u
la
te
t
h
e
se

104. ro
to
n
er
gi
c
sy
st
em
in
t
h
e
b
ra
in
11
9
T
h
yr
o
xi
n

105. e
m
o
n
o
th
er
ap
y
is
in
ef
fe
ct
iv
e
B
ra
in
n
eu
ro
ge
n

106. es
is
is
d
ec
re
as
ed
a
ft
er
t
h
e
ad
m
in
is
tr
at
io
n
o
f

107. th
yr
o
xi
n
e
in
ad
u
lt
r
at
s
w
it
h
h
yp
o
th
yr
o
id

108. is
m
12
0
H
yp
o
th
yr
o
id
is
m
is
n
o
t
m
an
if
es
te
d
in

109. m
o
st
p
at
ie
n
ts
w
it
h
d
ep
re
ss
io
n
R
at
e
o
f
re

110. sp
o
n
se
t
o
t
ri
io
d
o
th
yr
o
n
in
e
is
in
cr
ea
se
d
d

111. u
ri
n
g
d
ep
re
ss
io
n
12
1
D
ys
fu
n
ct
io
n
o
f
sp
ec
if

112. ic
b
ra
in
s
tr
u
ct
u
re
s
an
d
ci
rc
u
it
s
T
ra
n
sc

113. ra
n
ia
l m
ag
n
et
ic
s
ti
m
u
la
ti
o
n
o
f
th
e
p
re
fr
o

114. n
ta
l c
o
rt
ex
12
2
an
d
d
ee
p
-b
ra
in
st
im
u
la
ti
o
n

115. o
f
th
e
an
te
ri
o
r
ci
n
gu
la
te
a
ff
ec
t
m
o
o
d
12
3

116. Im
p
lic
at
ed
b
ra
in
a
re
as
d
if
fe
r
fr
o
m
s
tu
d
y
to
s

117. tu
d
y
G
lu
co
se
u
se
is
r
ed
u
ce
d
in
t
h
e
p
re
fr
o

118. n
ta
l c
o
rt
ex
12
4
an
d
s
u
b
ge
n
u
al
p
re
fr
o
n
ta
l

119. co
rt
ex
12
5
In
co
n
si
st
en
t
fi
n
d
in
gs
w
it
h
r
es
p
ec

120. t
to
b
lo
o
d
f
lo
w
, v
o
lu
m
et
ri
c,
g
lu
co
se
u
ti
liz
a-

121. ti
o
n
, a
n
d
p
o
st
m
o
rt
em
m
et
h
o
d
o
lo
gi
es
63
,1

122. 24
,1
26
C
ir
cu
it
d
yn
am
ic
s
in
th
e
h
ip
p
o
ca
m
p
u
s

123. ar
e
al
te
re
d
in
a
r
at
m
o
d
el
o
f d
ep
re
ss
io
n
12
7
*

124. A
M
P
A
d
en
o
te
s
al
p
h
a-
am
in
o
-3
-h
yd
ro
xy
-5
-m
et

125. h
yl
-4
-i
so
xa
zo
le
p
ro
p
io
n
ic
a
ci
d
,
B
D
N
F
b
ra

126. in
-d
er
iv
ed
n
eu
ro
tr
o
p
h
ic
f
ac
to
r,
D
H
E
A
d
eh
yd

127. ro
ep
ia
n
d
ro
st
er
o
n
e,
G
A
B
A
γ
-a
m
in
o
b
u
ty
ri

128. c
ac
id
,
M
R
S
m
ag
n
et
ic
r
es
o
n
an
ce
sp
ec
tr
o
sc

129. o
p
y,
a
n
d
N
M
D
A
N
-m
et
h
yl
-d
-a
sp
ar
ti
c
ac
id
.

130. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
n engl j med 358;1 www.nejm.org january 3, 200864
increased numbers of cells in the hypothalamus
and the dorsal raphe nucleus have been reported.63
These effects resemble the atrophic changes in the
brain in patients with Cushing’s disease64 and in
rodents treated with glucocorticoids.65 However,
cortisol elevations in depression are much lower
than in Cushing’s disease.
Restraint in a small container induces stress in
rodents, suppressing neurogenesis, and this effect
is countered by antidepressant treatment.66 An-
tidepressants also enhance neurogenesis in non-
human primates.67 Santarelli et al.68 irradiated the
hippocampus in mice and abolished neurogene-
sis. They found that the radiation also abolished
the ability of the animals to respond behaviorally
to antidepressant treatment in the forced swim
test, but this phenomenon does not occur in every
mouse strain studied.69 Henn and Vollmayr sum-
marized other studies providing evidence that de-
creased neurogenesis is a result of stress and
anxiety but may not be behaviorally relevant.70 The
relevance of animal models of neurogenesis to
clinical studies of depression has been questioned
by analogy with studies of neuroprotection strat-
egies in stroke, for which numerous findings in
animal models have not been replicated in hu-
man studies.71

131. Brain-derived neurotrophic factor (BDNF),
a neurotrophic peptide, is critical for axonal
growth, neuronal survival, and synaptic plastic-
ity,72 and its levels are affected by stress73 and
cortisol.74 A postmortem study of patients with
depression who had committed suicide showed
that BDNF was reduced in the hippocampus.75
Antidepressant drugs and electroconvulsive thera-
py up-regulate BDNF and other neurotrophic and
growth factors75,76; a single bilateral infusion of
BDNF into the dentate gyrus has antidepressant-
like effects.77 One study showed that the hippo-
campus was smaller than normal in patients with
depression who carried a met166 BDNF allele.78
In an animal model of depression, epigenetic his-
tone methylation mediated down-regulation of
BDNF transcripts and antidepressant treatment
reversed this effect.79 These studies suggest that
BDNF is the link among stress, neurogenesis, and
hippocampal atrophy in depression. However,
a genetic association of the BDNF val166met poly-
morphism with depression has not been replicated
in most studies,74 and BDNF may be related not
only to depression but to multiple psychiatric dis-
orders.74 BDNF-knockout mice have behaviors un-
related to depression.45 Reduced BDNF levels in
the peripheral blood of patients with depression
seem to derive almost entirely from blood plate-
lets,80 and many artifacts must therefore be con-
sidered in interpreting these findings. Inflamma-
tion in the brain and some neurotoxins increase
brain BDNF levels, suggesting that the actions of
BDNF are not uniformly therapeutic.81 Castrén82
has proposed that antidepressant treatments may
increase synaptic sprouting and allow the brain

132. to use input from the environment more effec-
tively to recover from depression. This hypothe-
sis highlights the role that cognition may play in
depression and suggests that biochemical mech-
anisms may be nonspecific.
Strong epidemiologic data point to an associa-
tion between major depressive disorder and in-
creased cardiovascular morbidity and mortality.83
In many patients, cardiovascular disorders precede
depression, and in others, depression precedes the
cardiovascular disorder. Both n−3 fatty acid defi-
ciency84 and elevated plasma homocysteine levels85
have been implicated in cardiovascular disease and
in depression. Elevated cortisol levels in depres-
sion could increase the risk of coronary artery
disease, since cortisol increases visceral fat.64,86
Antidepressant treatment increases the survival
rate among patients who become depressed after
coronary occlusion.86 Endothelial-cell signaling
plays a crucial role in brain neurogenesis,87 and
these cells secrete BDNF; thus, both depression
and cardiovascular disease could be examples of
an endothelial disorder. Signs of inf lammatory
processes have been described in major depres-
sion88 and in cardiovascular disease. Some data
suggest that exercise has protective or therapeu-
tic effects in depression.89 Rodent models support
this possibility.90
O t h e r P o s s i b l e M e c h a n i s m s
Table 2 summarizes possible pathophysiological
mechanisms of depression other than those based
on the monoamine-deficiency hypothesis or the
roles of stress, cortisol, and neurogenesis. Many

133. of these other proposed mechanisms have also
been implicated in psychiatric and neurologic dis-
orders other than depression. Since the compo-
nents of the brain are highly interconnected, it is
not difficult to find possible integrative frame-
works between two or more of the various theo-
ries. Testing the theories in a manner that can re-
mech a nisms of dise a se
n engl j med 358;1 www.nejm.org january 3, 2008 65
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reported.
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164. 121.
122.
123.
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127.
128.
129.
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165. Hi Raquel,
for me, the most important thing when it comes to protein
shakes is the flavor. Your idea for offering samples of the
protein shakes is great because even if your product is cost
effective, consumers will not purchase your product if the
flavor doesn’t appease to them. The quality of your product is
your opportunity, then the safety of your product and
production of your product then your low price protein shakes
will surely secure your opportunity.
Hello Jasmin Hottle,
I think it's hard to see your product as different compared to
other products. What are you trying to bring to the marketplace
today? Do you have a target audience in mind that you’re trying
to sell your product to? I think if we are looking at a product
then we need to look at what others are bringing to the market
and what they target and then target audiences that are untapped
resources and haven’t been targeted. This will also give you
more monetary opportunities in today’s fast paced marketplace
where most business don’t last more than a year.
NON-ALCOHOLIC BEVERAGE COMPANY PORTFOLIO
(The NAB Company Portfolio will have lists of things that the
BUS599 students would be able to sort
through to conduct a SWOT Analysis and to apply to
appropriate sections of the NAB Business Plan. )
Note #1:
This is the compilation of Data, Notes, and Information that
have been put together to create a
Business Plan for a start-up company in the non-alcoholic
beverage industry.
The goal of my business plan is twofold:
1. To help identify and outline all the issues I will need to
address in starting this company.

166. 2. To present to funders to help raise money to finance this
company.
NAB Background:
Melinda Cates has been selling her NAB at County Fairs for the
past 7 years for $2 a bottle. She
sells an average of 10 Cardboard cartons each weekend a
County Fair is open. From her
calculations, it takes $.56 to make a bottle of NAB when she
calculates all the NAB ingredients
and the cost of the bottle and cap. Her rich uncle, Bill, just died
and left her a small monetary
inheritance. However, since he so enjoyed her home-made NAB,
he also left her equipment to
start a small NAB business.
Melinda and I have been close, trusted friends for years. She
found out that I just earned my
MBA from Strayer University, and she asked me to help her get
her NAB business up and
running.
I have agreed to put together a NAB Business Plan, and I have
agreed to be the CEO/President of
the company for at least the next five years.
NAB Today:
Parameters for New Company
Here are the parameters in which I must work.
ss is a start-up: We are not yet in operation. We
already have a “recipe” for a
beverage, but we are not yet making sales at any significant
level.
-alcoholic
beverage (NAB). It is up to me
to decide upon what type of non-alcoholic beverage I intend to
make and market. It can
be sold in individual sizes or wholesale.
geographical area within a

167. 100 mile radius from my home address.
ize. I can grow the NAB business to any size in
excess of one million dollars in
revenue by year two. In other words, this cannot be intended to
be a one- or two-person
micro-business.
have already started with
friends and family money. But at some point I will need funds
from outside investors,
either angels or venture capitalists, depending on how much I
project I need to raise or
receive from a group of individual investors on kickstarter.
I intend to have employees and develop my own
organizational hierarchy.
NON-ALCOHOLIC BEVERAGE COMPANY PORTFOLIO
support for the first six months. In
other words, I do not need to take a salary/draw for myself for
six months of projections.
I am assuming I can live off my personal savings.
Note #2:
included
Some of
Owned Eq
Two (2)
This Bev
machine,
system, i
It is suita
advanced
Two Bot
See Auto
Four Veh
Three Co

168. Graphic
Leased E
Labeling
Printers -
Inventor
Glass Bo
Metal cap
Cardboar
NAB-ing
NON
The NAB F
.
the items we
quipment:
NAB Mixer
verage Filling
, imported fr
t can be app
able for norm
d Filling mac
tling machin
o AccuSnap
hicles (used
omputers (Ap
Software - $
Equipment:
g machinery –
- $550/month
ry:
ottles, 16 oz.
ps: 24,000 -
rd Cartons (h
gredients: en
N-ALCOHO
Financial Wo
e currently o

169. rs (mixes up
g machine is
rom Italy. Be
plied to fill h
mal temperat
chine at pres
nery (for filli
Capper, belo
panel vans)
pple Macint
$750 (value i
– $450/mon
h in current
: 24,000 - $3
$300 (value
holds 48 bot
nough to mak
OLIC BEVE
orksheets wi
own:
p to 200 gallo
s combined w
ecause it is e
ot or cold fru
ture filling o
sent .
ing and capp
ow.
– $10,000 e
tosh) - $1,20
in current $)
th in current
$
3,000 (value
e in current $
ttles): 500 -

170. ke 24,000 bo
ERAGE CO
ill have the v
ons each) – $
with rinsing,
equipped wit
uit juice, tea
r hot filling
ping bottles)
ach (value in
00 each (valu
t $
in current $
$)
$500 (value
ottles - $600
OMPANY PO
value of this
$28,500 each
, filling and
th constant t
a and other b
16 oz. bottle
) - $9,600 ea
n current $)
ue in current
$)
e in current $
(value in cu
ORTFOLIO
equipment a
h (value in c
capping 3 in
temperature
beverage into
es. It is one o

171. ach (value in
t $)
$)
urrent $)
O
and inventor
current $)
n 1 monoblo
controlling
o 16 oz bottl
of the most
current $)
ry
oc
les.
lip balm
variety o
Each mac
belt optio
The Auto
automate
SnapCap
Dimensi
Height: 9
Width: 2
Length: 3
Weight
800 lbs. (
Speed
Up to 12
Cap Size
Min: 10m
Electrica
110 VAC
Air Requ
120 PSI @

172. Current V
NON
caps, over c
f other cap a
chine is desi
ons are avail
o AccuCapp
ed delivery d
p007
ons
94” (238 cm)
4” (61 cm)*
32” (91.4 cm
(363 kg)
0 CPM**
e:
mm / Max: 6
al:
C 20 Amp (2
uirements:
@ 2 CFM
Value: $9,60
N-ALCOHO
aps, “top hat
applications
igned to acco
lable to stabi
er feature an
device the Ac
)*
m)*
60mm
220 available
00.00 new
OLIC BEVE
t” seals, twis

173. are all withi
ommodate a
ilize differen
n Accutek ce
ccutek Snap
e)
ERAGE CO
st cap with r
in the capabi
a wide variety
nt types of co
entrifugal bo
Capper can
OMPANY PO
ratcheted rip
ilities of Acc
ty of contain
ontainers.
owl or cap el
n reach speed
ORTFOLIO
NOTES on
Auto AccuS
Accutek Au
are continuo
machines th
tedious wor
pressing and
caps. Accut
prevent cos
removing hu
this process
can also hel
repetitious m
and strains t
force that ca

174. manually pl
Accutek Au
systems are
three differe
Roller, and
to offer solu
variety of sn
Milk jugs, d
seal, bar top
cutek Snap C
ner types. A v
levator orien
ds up to 120
O
n EQUIPME
Snap Capper
uto AccuCap
ous motion
hat replace th
rk of manual
d/or placing
tek Snap Cap
tly spills by
uman error f
s. This mach
lp prevent
motion injur
to your work
an result wh
lacing snap c
uto AccuCap
e available in
ent styles, B
Plunger in o
utions to a
nap cap type

175. dropper inser
p caps, and a
Cappers.
variety of gr
ntator. With a
CPM.
ENT
r.
ppers
he
lly
snap
ppers
from
hine
ries
k
hen
caps.
ppers
n
elt,
order
es.
rts,
a
ripper
an
NON-ALCOHOLIC BEVERAGE COMPANY PORTFOLIO
Note #3
Personnel:
Myself: I have collected $20,000 from friends and relatives who
would like to either have their
seed money returned by the end of this calendar year at no
interest or by the end of the second
year of operation with 5% interest.

176. Stephen Job: Part Time (20 hrs/week) Computer
Expert/Assistant: $10/hr
Melinda Cates: NAB Creator & Master Mixer (owns the patent
on the NAB): has $40,000
inheritance
Other colleagues with specific skills and talents:
Ian Glass: retired PepsiCo plant production line foreman. Ian
recently retired with 35 years of
loyal PepsiCo service in every position from janitor to
production line foreman, and he and his
wife moved into your neighborhood. He is tickled that you have
asked him to help develop a
plan to get the NAB Company’s production line going. He said
he can help organize and sit on
the planning committee as a non-paid member until the NAB
company can hire its own
Production Line Foreman. He hinted that he retired from
PepsiCo with an annual salary of
$55,000, but he says that’s just the starting salary that large
companies pay their foremen who
are in an apprenticeship program. He doesn’t think the NAB
Company will have to pay top
dollar for someone who has the willingness to join the NAB
company as a start up!
Mary Cates, JD: Melinda’s sister who was a senior executive
with the Federal Trade
Commission from 2001-2012. She left the FTC after a
significant 30 year career with the federal
government in which she lead the research and support of
numerous federal court findings
against companies that violated consumer deception and unfair
practices laws. She would enjoy
serving on the initial company planning group to make sure her
sister’s recipe is successfully
shared within the state!

177. Note #4:
Company
A. In 20
Green
bever
http://ma
B. Socia
The carb
volumes
and incre
ingredien
Soft drin
reduce th
largest U
Pepper S
American
NON
Here are so
y issues:
014, The Coc
n Mountain,
rages at hom
arketrealist.c
al pressures
onated soft d
in the past f
eased health
nts present in
k makers are
he calories in
US soda comp
Snapple Grou
ns consume
N-ALCOHO
me interestin
ca-Cola Com

178. Inc. (GMCR
me with the s
om/2014/11
s forcing cha
drinks (or C
few years. M
awareness a
n carbonated
e facing seve
n soft drinks
panies—The
up, Inc. (DPS
by 20% ove
OLIC BEVE
ng articles I
mpany (KO)
R). The deal
oon-to-be-re
/strategic-de
ange
SD) category
Mainly, this is
among consu
d drinks.
ere pressure
. In the Sept
e Coca-Cola
S)—pledged
er the next de
ERAGE CO
pulled off th
announced a
l will allow p
eleased Keur
eals-soft-drin
y of the soft

179. s due to chal
umers about
from civil s
tember 2014
a Company (
d to reduce th
ecade. To ac
OMPANY PO
he internet a
a long-term
people to enj
rig Cold mac
nk-industry/
t drink indus
llenging con
the side-effe
society group
Clinton Glo
KO), PepsiC
he number o
chieve this ta
ORTFOLIO
about other N
partnership
njoy ice-cold
chine.
/
stry has witn
nditions in de
fects of sugar
ps and gover
obal Initiativ
Co, Inc. (PEP
of sugary drin
arget, the thr
O

180. Non-Alcohol
with Keurig
d CocaCola
nessed declin
eveloped ma
r and other
rnments to
ve, the three
P), and the D
nk calories t
ree big playe
lic
g
ning
arkets
Dr
that
ers
plan to ex
consume
The chan
grow into
Ready-to
The nonannual
gr
from eme
Euromon
In the fir
water rec
categorie
including
product d
This new
increasin
industry.
NON

181. xpand low-c
rs about hea
nge in consum
o the still bev
o-drink bev
-alcoholic, re
rowth rate of
erging econo
nitor Internat
st half of 20
corded strong
es and are inv
g Dr Pepper
development
w focus on he
ng health con
N-ALCOHO
calorie produ
althier alterna
mer preferen
verages, or t
verages
eady-to-drin
f 5% betwee
omies. Since
tional estima
14, ready-to
g growth. Co
vesting heav
Snapple and
t in these cat
ealthier and n
nsciousness w
OLIC BEVE
uct portfolios
atives.

182. nces has prov
the non-carb
nk (or NART
en 2014 and
e 2010, NAR
ates this cate
o-drink tea an
oca-Cola and
vily for furth
d Monster Be
tegories in a
nutritious pr
will be a key
ERAGE CO
s, introduce
vided a new
bonated categ
TD) market i
2017. A larg
RTD retail va
egory will gr
nd coffee, sp
d PepsiCo h
her portfolio
everage Cor
n attempt to
roducts base
y growth driv
OMPANY PO
smaller port
w opportunity
gory of the r
s projected t
ge proportio
alue has incr
row by more

183. ports and ene
have a strong
expansion. O
rporation (M
cater to cha
d on changin
ver for the n
ORTFOLIO
tion containe
y for CSD m
ready-to-drin
to grow at a
on of this gro
reased by $1
e than $200 b
ergy drinks,
g presence ac
Other compa
MNST) are al
anging consu
ng consumer
non-alcoholic
O
ers, and educ
manufacturers
nk market.
compounde
owth will com
135 billion an
billion by 20
and bottled
cross these
anies
so investing
umer tastes.
r preference

184. c beverage
cate
s to
d
me
nd
020.
g in
es and
The Cons
soft drink
C. Why
By Sharo
Falling d
The nonfalling,
p
carbonate
demand h
respectiv
Key indi
The per c
2013, fro
and a slo
One of th
is weak c
US and E
NON
sumer Staple
k companies
growth is sl
on Bailey • N
demand
-alcoholic be
primarily in d
ed soft drink
has declined

185. vely.
icator—per
capita CSD c
om 701 8-oun
wer rate of U
he reasons fo
consumer sp
Europe.
N-ALCOHO
es Select Sec
s.
luggish in th
Nov 20, 201
everage indu
developed m
k (or CSD) v
d. Previously
capita cons
consumption
nce servings
US populatio
or the contin
ending, caus
OLIC BEVE
ctor SPDR E
he non-alcoh
4 12:09 pm
ustry is facin
markets. Beve
volumes in th
y, US CSD v
sumption
n in the US f
s in 2012. Re
on growth.
nued decline

186. sed by adver
ERAGE CO
ETF (XLP) p
holic bevera
EST
ng challenges
erage Digest
he US, maki
volumes decl
fell to about
educed cons
in soft drink
rse macroeco
OMPANY PO
provides an a
age industry
s. Carbonate
t indicates a
ng it the nin
lined by 1.2%
675 8-ounce
umption refl
k volumes ov
onomic cond
ORTFOLIO
attractive av
y
ed beverage v
3% fall in 2
nth straight y
% and 1% in
e servings pe
flects the dec
ver the past
ditions, espe
O

187. venue to inve
volumes are
2013 overall
year in which
n 2012 and 2
er person in
clining volum
few years
ecially in the
est in
e
h
2011,
mes
NON-ALCOHOLIC BEVERAGE COMPANY PORTFOLIO
Note #5
Health concerns
Another major reason is the shift in consumer preferences
toward healthier products. Carbonated
soft drink makers have faced severe criticism from health
officials, governments, and
communities alike for the ill-effects of high sugar content,
artificial sweeteners, and other
harmful ingredients in their products, including those in diet
soda variants. Consumers are
also more conscious of the health risks associated with soft
drinks such as obesity and nutritional
deficiencies, especially in youth. As a result, they’re opting for
other beverages that are noncarbonated
and have fewer calories.
The World Health Organization suggests that sugar should
account for only 5% of total energy
intake per day. That’s around 25 grams of sugar per day for an
adult of normal body mass index.
Health officials feel that this percentage should be even lower
for a better quality of life. A single

188. soda can contains around 40 grams of sugar.
The soda tax
Mexico, which has the highest rates of obesity in the world, has
imposed a 10% tax on sugary
beverages to discourage the consumption of these drinks. There
is a strong possibility that many
other countries will introduce a soda tax to reduce sugar
consumption through carbonated drinks.
In the next part of this series, we’ll discuss how soft drink
makers including The Coca-Cola
Company (KO), PepsiCo, Inc. (PEP), Dr Pepper Snapple Group,
Inc. (DPS), and Monster
Beverage Corporation (MNST) are sustaining business under
such challenging conditions. CocaCola
and PepsiCo are part of the Consumer Staples Select Sector
SPDR ETF (XLP).
D. Key indicators of the non-alcoholic beverage industry
By Sharon Bailey • Nov 20, 2014 12:09 pm EST
Factors influencing sector growth
The non-alcoholic beverage industry falls under the consumer
staples category (XLP), which is
non-cyclical in nature compared to the consumer discretionary
sector. In this part of the series,
we’ll look at the factors that impact the growth of the non-
alcoholic beverage industry.
Consumption expenditure
The Bureau of Economic Analysis (or BEA) releases the
personal income and outlays monthly
reports that indicate changes in individuals’ personal incomes,
savings, and expenditures.
US consumption spending accounts for over two-thirds of the
country’s gross domestic product
(or GDP). The US real personal consumption expenditure for
non-durable goods measures
consume
basis.

189. Disposab
Consump
less perso
Increase
Conferen
confiden
as reflect
Accordin
in emerg
expected
A favora
alcoholic
ETFs) th
(XLP) ha
PepsiCo,
(MNST).
NON
r spending o
ble income a
ption expend
onal current
in consumer
nce Board an
ce index, wh
ted in consum
ng to market
ing markets
d to continue
ble trend in
c beverage in
at invest in t
as holdings i
, Inc. (PEP),
.
N-ALCOHO
on non-durab

190. and consum
diture depend
taxes. Peopl
r confidence
nd the Unive
hich indicate
mer spendin
-intelligence
has surpasse
doing so.
consumer sp
ndustry. It’s
the consume
in the major
Dr. Pepper
OLIC BEVE
ble goods, su
mer confiden
ds on dispos
le tend to sp
e also increas
ersity of Mic
es the degree
ng and saving
e firm Eurom
ed that in de
pending on n
also good fo
er staple sect
soft drink co
Snapple Gro
ERAGE CO
uch as food a
nce
sable income
pend more w

191. ses consump
chigan each p
e of optimism
g activities.
monitor Inter
eveloped mar
non-durable
or the perform
tor. The Con
ompanies lik
oup, Inc. (DP
OMPANY PO
and beverag
e, which is m
with a rise in t
ption expend
provide mon
m about the
rnational, co
rkets every y
goods is a p
rmance of ex
nsumer Stapl
ke The Coca
PS), and Mo
ORTFOLIO
es, on an inf
measured as p
their disposa
diture. In the
nthly reports
state of the e
onsumer-exp
year since 20
positive indic
xchange-trad

192. les Select Se
a-Cola Comp
onster Bever
O
flation-adjus
personal inc
able income
US, the
on the cons
economy
penditure gro
000, and is
cator for the
ded funds (or
ector SPDR E
pany (KO),
age Corpora
sted
come
.
sumer
owth
nonr
ETF
ation
E. Under
By Sharo
Industry
Soft drin
producer
Bottling
Compani
finished p
Another,
make the
and other

193. beverage
Also, bot
fountain
beverage
Distribu
The exten
produce o
distribute
Corporat
Unilever
Pricing p
Coca-Co
Carbonat
soft drink
NON
rstanding th
on Bailey • N
y Partners
ks constitute
rs and bottler
and distrib
ies in the sof
products, ma
is by selling
e final produ
r ingredients
es to distribu
th bottling p
retailers. Fo
es for immed
tion: Third
nsive reach o
or distribute
e certain bran
tion (MNST)
and Starbuc

194. power
la and Pepsi
ted soft drink
k companies
N-ALCOHO
he value cha
Nov 20, 201
e a major par
rs play a vita
bution netwo
ft drink indu
ade at compa
g beverage c
uct by combin
s. The bottler
utors or direc
artners and c
ountain retail
diate consum
-party prod
of The Coca
third-party
nds of Dr Pe
). PepsiCo se
cks, respectiv
iCo’s wide d
ks have simi
s extend low
OLIC BEVE
ain of the so
4 12:08 pm
rt of the US
al role in the
ork
ustry reach th
any-owned b

195. concentrates
ning the con
rs then pack
ctly to retaile
companies m
lers include r
mption.
ducts
a-Cola Comp
brands. For
epper Snapp
ells Lipton a
vely.
distribution n
ilar prices du
er prices und
ERAGE CO
oft drink ind
EST
food and be
e value chain
he end marke
bottling facil
and syrups t
ncentrates wi
kage the prod
ers.
manufacture
restaurants a
pany (KO) an
instance, Co
le Group, In
and Starbuck
network give
ue to the inte
der promotio

196. OMPANY PO
dustry
everage indu
n of the soft d
et in two wa
lities, to dist
to authorized
ith still or ca
duct in conta
fountain syr
and convenie
and PepsiCo,
oca-Cola is l
nc. (DPS) an
ks brands un
es them sign
ense compet
onal offers. I
ORTFOLIO
ustry. Syrup o
drink industr
ays. One way
tributors and
d bottling pa
arbonated wa
ainers and se
rups and sell
ence stores,
, Inc. (PEP)
licensed to p
d Monster B
nder partners
nificant pricin
tition in the i
In recent tim
O

197. or concentra
ry.
y is by sellin
d retailers.
artners, who
ater, sweeten
ell these
l them to
which produ
allows them
produce and
Beverage
hips with
ng power.
industry. Oft
mes, such
ate
ng
then
ners,
uce
m to
ften,
promotio
because t
substitute
The nonsector
thr
holdings
F. A guid
By Sharo
Industry
The noncontain
c
coffee an
bottled w

198. sometime
beverage
Dominan
The glob
of $337.8
size of $1
NON
onal offers ha
they’re unde
es such as te
-alcoholic be
rough the Co
in Coca-Co
de to the non
on Bailey • N
y overview
-alcoholic be
carbonated o
nd tea. The s
water, readyes
referred to
e retail sales.
nt carbonat
bal soft drink
8 billion in 2
189.1 billion
N-ALCOHO
ave been use
er pressure d
ea, energy dr
everage indu
onsumer Sta
la and Pepsi
n-alcoholic b
Nov 20, 201
everage indu

199. r non-carbon
oft drink cat
to-drink tea
o as liquid re
In this serie
tes category
k market is le
2013. In the
n, and juice,
OLIC BEVE
ed to boost v
due to rising
rinks, and wa
ustry is part o
aples Select S
iCo.
beverage ind
4 12:08 pm
ustry broadly
nated water,
tegory domin
and coffee,
efreshment b
es, we’ll focu
y
ed by carbon
same year, C
with a mark
ERAGE CO
volumes of th
health conce
ater.
of the consum
Sector SPDR
dustry
EST

200. y includes so
a sweetener
nates the ind
and sports a
beverages (o
us on the sof
nated soft dri
CSDs were f
ket size of $1
OMPANY PO
he carbonate
erns and com
mer staples
R ETF (XLP
oft drinks and
r, and a flavo
dustry and in
and energy d
or LRBs). In
ft drink or L
inks (or CSD
followed by
146.2 billion
ORTFOLIO
ed soft drink
mpetition fro
sector. You
P), which has
d hot drinks
or, and hot d
ncludes carb
drinks. Soft d
the US, LR
LRB market.
Ds), which h
bottled wate

201. n. In a later p
O
ks. That’s
om healthy
can invest in
s notable
. Soft drinks
drinks includ
onates, juice
drinks are
RBs lead food
had a market
er, with a ma
part of this se
n this
s
de
e,
d and
t size
arket
eries,
NON-ALCOHOLIC BEVERAGE COMPANY PORTFOLIO
we’ll discuss why CSDs have been losing popularity, and why
sales of other
beverages, including juices and ready-to-drink tea, are
increasing.
Major companies
The non-alcoholic beverage market is a highly competitive
industry that includes two behemoths
—The Coca-Cola Company (KO) and PepsiCo, Inc. (PEP).
Collectively, these companies hold
about 70% of the US CSD market. Dr Pepper Snapple Group,
Inc. (DPS), Monster Beverage
Corporation (MNST), and Cott Corporation (COT) are some
other key players in the CSD

202. market.
Many international markets are also dominated by Coca-Cola
and PepsiCo, but include other
companies such as Groupe Danone, Nestle SA, and Suntory
Holdings Limited.
Non-alcoholic beverage manufacturers, like Coca-Cola and
PepsiCo, are part of the consumer
staple sector. You can invest in these companies through the
Consumer Staples Select Sector
SPDR ETF (XLP).
G. Statistics and facts on non-alcoholic beverages and soft
drinks
The non-alcoholic beverages industry encompasses liquid
refreshment beverages (LRB) such as
bottled water, carbonated soft drinks, energy drinks, fruit
beverages, ready-to-drink coffee and
tea, sports beverages and value-added water.
This is a great site to find statistics:
http://www.statista.com/topics/1662/non-alcoholic-beverages-
and-soft-drinks-in-the-us/
H. NY Times Article, February 2015
BEVERAGES - NON-ALCOHOLIC TODAY 5 DAY 1 MONTH
1 YEAR MKT CAP
+0.16% –0.37% +0.67% +20.48% 136.1B
The Beverages - Non-Alcoholic industry group consists of
companies engaged in manufacturing
non-alcoholic beverages, such as water, fruit drinks, soft drinks,
iced coffee and tea, as well as
other flavored beverages. The Beverages - Non-Alcoholic
industry excludes tea bags and instant
coffee manufacturing, fruit juices and concentrates, classified in
Food Processing.
Beverages - Non-Alcoholic
Defined by Thomson Reuters
Market
cap.

203. 1-day
%
change
1-month
%
change
YTD
%
change
Low High 52-
week
Page: 1 | 2 | Next »
NON-ALCOHOLIC BEVERAGE COMPANY PORTFOLIO
Defined by Thomson Reuters
Market
cap.
1-day
%
change
1-month
%
change
YTD
%
change
Low High 52-
week
Coca-Cola Enterpri... CCE: NYSE 10.5B +0.54 +3.14 +1.11
Coca-Cola FEMSA, S... KOF: NYSE 6.0B +2.42 +1.91 +0.90
Dr Pepper Snapple ... DPS: NYSE 15.2B +0.77 +0.39 +9.96
Embotelladora Andi... AKO.B: NYSE 2.5B –0.97 +3.04 +1.82
Fomento Economico ... FMX: NYSE 31.0B +2.01 +2.06 +1.70
Monster Beverage C... MNST:
NASDAQ
20.3B +0.11 +1.63 +11.92
PepsiCo, Inc. PEP: NYSE 146.8B +0.34 +0.54 +4.76

204. Sodastream Interna... SODA:
NASDAQ
393.3M –0.37 –2.75 –6.91
The Coca-Cola Co KO: NYSE 183.8B –0.33 –3.09 –0.59
Coca-Cola Bottling... COKE:
NASDAQ
947.9M +0.44 –1.70 +16.14
National Beverage ... FIZZ: NASDAQ 1.0B –1.53 –2.77 –0.53
Youngevity Interna... YGYI: OTHER
OTC
94.5M +3.15 +1.00 +1.00
Alkaline Water Com... WTER:
OTHER OTC
14.4M +23.33 +78.31 +50.00
Cott Corporation (... COT: NYSE 748.2M +1.14 +0.88 +16.13
DNA Brands, Inc. DNAX: OTHER
OTC
24.0K 0.00 –50.00 0.00
Hangover Joe's Hol... HJOE: OTCBB 778.0K –21.67 +11.90 –
12.96
NON-ALCOHOLIC BEVERAGE COMPANY PORTFOLIO
Defined by Thomson Reuters
Market
cap.
1-day
%
change
1-month
%
change
YTD
%
change
Low High 52-
week
Jones Soda Co. ( U... JSDA: OTHER

205. OTC
17.0M –0.36 +18.89 +18.86
Konared Corp KRED: OTHER OTC 8.0M +16.28 –6.54 –29.08
NOHO Inc DRNK: OTCBB 275.0K +13.60 –38.26 –71.60
Pulse Beverage Cor... PLSB: OTHER
OTC
8.4M –7.99 –13.46 –46.63
Beverages - Non-Alcoholic
Defined by Thomson Reuters Market cap.
1-day
% change
1-month
% change
YTD
% change Low High 52-week
Puresafe Water Sys... PSWS: OTHER OTC 383.3K 0.00 0.00
0.00
Reed's, Inc. REED: AMEX 71.1M 0.00 +0.37 –7.95
Uplift Nutrition I... UPNT: OTCBB 555.7K 0.00 –50.00 +28.62
Crystal Rock Holdi... CRVP: AMEX 15.8M 0.00 +1.37 –2.95
Global Future City... FTCY: OTHER OTC 19.1M 0.00 +131.82
+100.00
MOJO Organics Inc MOJO: OTHER OTC 3.4M 0.00 –4.81 0.00
New Leaf Brands In... NLEF: OTHER OTC 505.6K 0.00 –16.67
+36.36
Note #5:
I. Histor
The nonhas
a dire
support h
Beverage
the indus
billion at
commun
The Ame
non-alcoh

206. Carbonat
ABA rep
industrie
regular a
drinks, sp
ABA pro
maintain
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technical
J.
In-depth
advancem
1.) C
Omega-3
By Jamie
NON
ry of Americ
-alcoholic be
ect economic
hundreds of t
e companies
stry, provide
t the federal
ities across t
erican Bever
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ted Beverage
presents hund
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207. legislative an
ment beverage
l, regulatory,
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and their em
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rage Associa
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208. $141.22 bill
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209. mbers conven
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As the nation
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and employ
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association
1919 as the A
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U.S. econom
233,000 job
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n at the state

210. o charitable c
that represen
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percent juice
s common is
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my. Our indus
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heir liveliho
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causes in
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ottlers of
6. Today th
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The Associa
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211. ods.
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