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).
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).
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.
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.
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 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 scores in elderly female patients. Although it was very effective in treating depression, no studies have been published looking at the effects of phosphatidylserine on depression in a sample of adult males or younger adult females. Questions as to whether the antidepressant effects of phosphatidylserine are age or gender dependent requires further study across male and younger female patient populations.
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 shown to significantly reduce symptoms in elderly females with depression. Continued research in the use of phospholipids in the treatment of depression is warranted given their high safety profile and potential to improve symptoms in depressed patients.
References:
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th ed., text rev.). Washington DC. 2000.
Barkai AL, Dunner DL, Gross HA, Mayo P, Fieve RR. Reduced Myo-Inositol levels in cerebrospinal fluid from patients with affective disorder. Biological Psychiatry. 1978;13(1):65-72.
Berridge MJ, Irvine RF. Inositol phosphates and cell signalling. Nature. 1989;341(6239):197-205.
Blokland A, Honig W, Brouns F, Jolles J. Cognition-enhancing properties of subchronic phosphatidylserine (PS) treatment in middle- aged rats: comparison of bovine cortex PS with egg PS and soybean PS. Nutrition. 1999;15(10):778-783.
Brambilla F, Maggioni M, Cenacchi T, Sacerdote P, Panerai AR. T-lymphocyte proliferative response to mitogen stimulation in elderly depressed patients. Journal of Affective Disorders. 1995;36(1-2):51-56.
Brambilla F, Maggioni M. Blood levels of cytokines in elderly patients with major depressive disorder. Acta Psychiatrica Scandinavica. 1998;97(4):309-313.
Castilho JC, Perry JC, Andreatini R, Vital MA. Phosphatidylserine: an antidepressive or a cognitive enhancer? Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2004;28(4):731-738.
Einat H, Belmaker RH, Zangen A, Overstreet DH, Yadid G. Chronic inositol treatment reduces depression-like immobility of Flinders Sensitive Line rats in the forced swim test. Depress Anxiety. 2002;15(3):148-51.
Einat H, Karbovski H, Korik J, Tsalah D, Belmaker RH. Inositol reduces depressivelike behaviors in two different animal models of depression. Psychopharmacology. 2000;144:158 – 162.
Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, Fawcett J. Antidepressant drug effects and depression severity: a patient-level metaanalysis. JAMA. 2010 Jan 6;303(1):47-53.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23:56-62.
Kidd PM. Phosphatidylserine. Alternative Medicine Review. 1999; 4(2):115-8.
Kofman O, Agam G, Shapiro J, Spencer A. Chronic dietary inositol enhances locomotor activity and brain inositol levels in rats. Psychophamacology. 1998;139:239–242.
Kofman O, Bersudsky Y, Vinnitsky I, Alpert C, Belmaker RH. The effect of peripheral inositol injection on rat motor activity models of depression. Israel Journal of Medical Sciences. 1998;29:580 – 586.
Levine J, Rapaport A, Lev L, Bersudsky Y, Kofman O, Belmaker RH, Shapiro J, Agam G. Inositol treatment raises CSF inositol levels. Brain Res. 1993 Nov 5;627(1):168-70.
Levine, J, et al. Double-blind, controlled trial of Inositol treatment of depression. The American Journal of Psychiatry. 1995;152(5):792-794.
Levine J, Barak Y, Kofman O, Belmaker RH. Follow up and relapse analysis of an inositol study of depression. Israel Journal of Psychiatry and Related Sciences. 1995;32(1):14-21
Levine J, Mishori A, Susnosky M, Martin M, Belmaker RH. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression. Biol Psychiatry. 1999 Feb 1;45(3):270-3.
Maggioni M, Picotti GB, Bondiolotti GP, Panerai A, Cenacchi T, Nobile P,Brambilla F. Effects of phosphatidylserine therapy in geriatric patients with depressive disorders. Acta Psychiatr Scand. 1990 Mar;81(3):265-70.
Middleton H, Shaw I, Feder G. NICE guidelines for the management of depression. BMJ. 2005;330(7486):267-268.
Murray C, Lopez A. Global mortality, disability, and the contribution of risk factors: global burden of disease study. The Lancent. 1997;349(9063):1436-1422.
Nemets B, Mishory A, Levine J, Belmaker RH. Inositol addition does not improve depression in SSRI treatment failures. J Neural Transm. 1999;106(7-8):795-8.
Patten SB, Wang JL, Williams JV, Currie S. Descriptive epidemiology of major depression in Canada . Canadian Journal of Psychiatry. 2006;51(2):84-87.
Shah N, Eisner T, Farrell M, Raeder C. An overview of ssris for the treatment of depression. Journal of the Pharmacy Society of Wisconsin. 1999;July-August:33-46.
Soleimani L, Lapidus K, Iosifescu D. Diagnosis and treatment of major depressive disorder. Psychiatry for the Neurologist. 2011;29(1):177-193.
Taylor MJ, Wilder H, Bhagwagar Z, Geddes J. Inositol for depressive disorders. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD004049. DOI: 10.1002/14651858.CD004049.pub2.
Whang W, Kubzansky LD, Kawachi I, Rexrode KM, Kroenke CH, Glynn RJ, Garan H, Albert CM. Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses’ Health Study. J Am Coll Cardiol. 2009 Mar 17;53(11):950-8.
Whooley MA, Simon GE. Managing depression in medical outpatients. N Engl J Med. 2000 Dec 28;343(26):1942-50.
