FEATURE PHOSPHOLIPIDS AND DEPRESSION
By Jordan Robertson, BHSc. ND and Hammam A Alotaibi HBSc (Cand)
Phospholipids choline,
serine, and inositol
Effects on Major Depressive Disorder
Introduction
Depression or Major Depressive Disorder (MDD) is a serious
illness that interferes with a patient’s mental, physical and cognitive
well being (Soleimani 2011). It is described as “a broad and
heterogeneous diagnostic grouping, central to which is depressed
mood or loss of pleasure in most activities” (Middleton 2005). Since
depression affects the quality of life and productivity of the patient,
an early diagnosis is crucial for effective treatment. It has been
reported that 60-70% of patients with depression will respond to
treatment if diagnosed early and appropriately treated (Shah 1999).
The annual prevalence of depression in Canada is estimated at 4.8%
(Patten 2006). According to the National Comorbidity survey, the
average lifetime estimate of depression in the United States is 12%
for males and 26% for females with an average lifetime prevalence
of 17% (Shah 1999). The World Health Organization (WHO) in
the 1990s ranked depression to be the fourth cause of global disease
burden. In 2001, depression rose to be the third leading cause of
Global Disease Burden (GDB) worldwide (Murray 1997).
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The most important factor predicting the risk of a depressive
episode is having had depression in the past. Patients who have
had depression in the past have more than a 50% chance of having
another episode in the future. Females have double the risk of
being depressed than males in their lifetime and first-degree
relatives are three times more likely to develop depression than the
general public (Shah 1999).
Jordan Robertson, BHSc, ND
jordanrobertsonnd@gmail.com
Associate Faculty
Bachelor of Health Sciences Program, McMaster University
Lakeshore Clinic
2159 Lakeshore Road
Burlington, Ontario
905.333.1104
FEATURE PHOSPHOLIPIDS AND DEPRESSION
Two existing criteria are used to diagnose depression; the American
Psychiatric Association's Diagnostic and statistical Manual
version four (DSM-IV), and the World Health Organization’s
International classification of disease tenth revision (ICD-10).
The DSM-IV-RT defines depression as a mood disorder. A
patient is diagnosed with MDD based on the DSM-IV if they
meet the following criteria: the patient should not have a history
of bipolar disorder, the patient should have a depressive episode
for at least two weeks and the patient has to experience at least five
of the following symptoms: depressed mood, weight gain or loss,
psychomotor agitation or retardation, inability to enjoy activities
otherwise enjoyable, feeling guilty, feeling worthless, insomnia
and recurrent thoughts of death or suicide. Moreover, these
symptoms have to cause significant impairment to the patient’s
functioning and cannot be related to substance abuse (American
Psychiatric Association [DSM-IV-TR] 2000). After diagnosis,
symptoms will be classified according to severity to indicate
mild, moderate or severe depression. Mild depression is classified
by meeting the minimum criteria and slightly more symptoms;
moderate depression episodes are classified by meeting the
minimum criteria plus symptoms that interfere with the patient’s
social and occupational life. If psychotic features or suicidal
thoughts accompany an episode, the patient is considered to have
severe depression, even if they only meet the DSM-IV minimum
criteria (Hamilton 1960). Recommended treatment differs based
on disease severity.
The course of action for mild depression is often watchful waiting,
with the expectation that symptoms will subside in 14 days
(Whooley 2000). In the case of moderate or severe depression,
selective serotonin reuptake inhibitors (SSRIs) are used as the first
line of treatment. Patients with severe depression should be closely
monitored for suicidality with referral or admission to hospital if
necessary (Soleimani 2011).
A meta analysis published in 2010 found that SSRI treatment is
no better than placebo for mild to moderate depression (Fournier
2010). In addition, subgroup analysis from the Women’s Health
Survey study also found that women using SSRIs for depression
are at a significantly higher risk of sudden cardiac death (William
2009). This recent research highlights the need for safe and
effective treatment alternatives to drug therapy.
Interest in administering phospholipids for treatment of MDD
stems from animal and human data demonstrating that certain
areas of the brain, plasma and CSF can show deficiencies in
phospholipids in depressed patients. Phospholipids are also
integral in CNS second messenger systems raising questions as
to whether these deficiencies contribute to the symptomology
of major depression. This review will focus on the effects of
administering phosphatidylinositol, phosphatidylserine or
phosphatidylcholine on unipolar depression by reviewing current
human trials and animal data. A comprehensive literature review
was conducted and revealed one systematic review, three clinical
trials and four animal studies on inositol and depression, three
human and one animal study on phosphatidylserine and no human
or animal studies on the relationship between depression and
phosphatidylcholine. The remainder of the article will focus on
inositol and phosphatidylserine as possible treatments for major
depression.
Phosphatidylinositol
Inositol is a sugar alcohol that is a component of cell membrane
phospholipids and a part of the intracellular phosphatidylinositol
second-messenger system associated with receptors of
norepinephrine, serotonin and choline (Berridge 1989).
In total, four studies of inositol treatment for depression in rats
were found. Well- defined parameters of antidepressant response
based primarily on locomotion indices serve as endpoint measures.
All four studies demonstrated a significant antidepressant effect
from administration of inositol relative to placebo (Einat 1999,
Einat 2002, Kofman 1993, Kofman 1998).
In 1978 Barkai and colleagues found that patients with MDD
have significantly decreased inositol levels in CSF when compared
to healthy controls. This finding was investigated further in
1993 where inositol was administered to subjects and results
were recorded. The conclusion was that administering inositol to
depressed patients increases their CSF inositol levels significantly
(Levine 1993); the findings inspired the first randomized clinical
trial done by Levine and colleagues in 1995.
A total of three human trials were identified investigating the effects
of inositol administration on depression. Levine and colleagues
conducted the first randomized clinical trial using the Hamilton
Depression Rating Scale (HDRS) as their primary endoint measure
(Levine 1995). After administering 12g of inositol or placebo for
four weeks, the authors found a significant reduction in depression
scores in the inositol group compared to the placebo group.
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FEATURE PHOSPHOLIPIDS AND DEPRESSION
Plausibility of a physiologic reaction to inositol in MDD was
elevated by a follow up of this study group 10-12 months after
the initial study had ceased. 50% of patients who responded to
inositol in the initial trial had experienced a relapse in depressive
symptoms after discontinuing treatment and no patients in the
placebo arm who initially reported benefit experienced a relapse in
symptoms. (Levine 1995b)
In 1999, two studies were published that investigated inositol
effects on HDRS. Levine and colleagues (1999) administered
inositol and standard SSRI treatment in the experimental group
and used placebo with SSRIs as a control. After four weeks, authors
found that there was no significant difference between the groups
on HDRS scores, however there was an expected improvement in
the scores of both groups as both groups received SSRI therapy.
Nemets and colleagues (1999) conducted a study to investigate
the effects of inositol on depression after failed SSRI treatment.
Depressed patients that failed to respond to three weeks of SSRI
treatment were enrolled in this study and randomized into two
groups: inositol group or placebo group. Patients continued their
SSRI treatment during the four weeks period of the study. The
authors concluded that there was no significant difference in the
depression scores when comparing both groups.
Levine (1995) included 4 patients with bipolar depression in the
inositol group (N=9). Inclusion of patients with bipolar depression
could potentially explain the apparent improvement in mean
HDRS scores as almost half the treatment group was classified
as bipolar. This inclusion of patients with bipolar makes it difficult
to conclude whether inositol is effective in reducing depression in
patients with unipolar depression.
Each of the three studies reviewed above have two main limitations:
small sample size and a short study period. The duration of the
two studies conducted in 1999 was adopted from the first study
(Levine 1995) that reported significant reduction in HDRS after
4 weeks. A longer study is needed to define when inositol becomes
effective in reducing depression symptoms if at all. The patients
in the original study were not using concurrent SSRI treatment
and were not labeled as SSRI non-responders which may explain
the difference in results when compared to the studies conducted
in 1999. Thus, a follow up study with a greater sample size, longer
duration and patients with MDD who have no history of SSRI
use may produce more conclusive results. Future directions for the
study of inositol and MDD should also include investigation into
the potential applications of the different stereoisomers of inositol
including myo-inositol and d-chiro-inositol.
A Cochrane systematic review (Taylor 2004) combined all of
the three studies and included a study that recruited only bipolar
patients and found that even with a combined sample (n=141), the
effect of inositol on depression scores is still not significant.
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In conclusion, the three RCTs (Levine 1995, Levine 1999, Nemets
1999) show conflicting results regarding the treatment effect of
inositol.
Phosphatidylserine
Phosphatidylserine is one of the most important phospholipids in
the central nervous system. It mainly plays a role in the function and
homeostasis of nerve cells and is involved in cell-to-cell recognition
and communication and affects levels of neurotransmitters such as
dopamine, acetylcholine, and norepinephrine. For these reasons,
phosphatidylserine has mostly been studied for its role in memory
and cognitive functions (Kidd 1999).
One study was identified examining endpoints relating to
depression following administration of phosphatidylserine in rats.
Significant antidepressant outcomes were demonstrated relative to
administration of placebo (Castilho 2004).
Three studies have investigated the effects of administering
phosphatidylserine to patients with depression. Maggioni and
colleagues (1990) conducted a placebo- controlled crossover study
looking at the effects of administering phosphatidylserine to elderly
female patients with depression. All 10 patients received both the
treatment and placebo, thus served as their own controls. Symptoms
were measured using the HDRS. All patients received the placebo
for at least 7 days followed by a washout period before receiving
300mg/day of phosphatidylserine for 30 days. Depression scores
were recorded before placebo (phase I), before phosphatidylserine
treatment (phase II) and after phosphatidylserine treatment (phase
III). Rating scores before and after placebo administration did
not change. However, depression scores were reduced significantly
after phosphatidylserine treatment (Maggioni 1990).
Brambilla and colleagues (1995) recruited 10 elderly female
patients (8 with MDD and 2 with bipolar depression) to study
the effects of administering phosphatidylserine on depression.
Patients received a dose of 600mg of phosphatidylserine per day.
Patients had a significant reduction in the HDRS after 30 days
(Brambilla 1995).
Brambilla, & Maggioni (1998) studied phosphatidylserine and
depression in an elderly female sample. Ten females were recruited
for this study, 8 with MDD and 2 with bipolar depression. The
average age of the patients were consistent with earlier studies
and included women between the ages of 66 to 78 years. Patients
received 200 mg of PS three times a day for 30 days after 15 days
of hospitalization for depression. Effects were measured based on
HDRS and a significant improvement was seen after 30 days in the
treatment group when compared to controls (Brambilla 1998).
Discussion
The need for an alternative treatment for depression magnified after
FEATURE PHOSPHOLIPIDS AND DEPRESSION
a prospective study of nurses found that using SSRIs significantly
increases the risk of sudden cardiac death. The current findings
indicate that administering inositol to rats creates a significant
reduction in depressive symptoms as reported by several studies
(Einat 2000, Einat 2002, Kofman 1998, Kofman 1993). On
the other hand, only one (Levine 1995) of three (Levine 1999,
Nemets 1999) human studies found a significant effect following
administration of inositol on depressive symptoms. The type of
patients (MDD, unipolar depression versus bipolar disorder) and
the use of adjunct pharmacotherapy may explain the difference in
results. The positive effects of inositol in rats strengthen the case
for further investigation of inositol treatment for depression in
humans.
In studies of phosphatidylserine, three human trials and an
animal study showed a significant reduction in depressive scores
after treatment. The human studies presented in this paper
found that phosphatidylserine is effective in reducing depression
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Conclusion
Based on the current findings, the effect of inositol administration
on depressive symptoms is not clear and requires further
investigation in humans. For phosphatidylserine, three human
trials and one animal study confirm an antidepressant effect.
Administering between 300-600mg/day for 30 days has been
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treatment of depression is warranted given their high safety profile
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