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The interactive effects of ketamine and magnesium

upon depressive-like pathology
This article was published in the following Dove Press journal:
Neuropsychiatric Disease and Treatment
8 September 2016
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Sara Razmjou Abstract: Approximately one-third of patients with major depressive disorders (MDDs) are
Darcy Litteljohn resistant to current treatment methods, and the majority of cases relapse at some point during
Chris Rudyk therapy. This has resulted in novel treatments being adopted, including subanesthetic doses of
Shuaib Syed ketamine, which affects aberrant neuroplastic circuits, glutamatergic signaling, and the produc-
Melanie Clarke tion of brain-derived neurotrophic factor. Ketamine rapidly relieves depressive symptoms in
treatment-resistant major depressive disorder patients with effects that last for up to 2 weeks
Rowan Pentz
even after a single administration. However, it is also a drug with an abusive potential and can
Zach Dwyer
have marked side effects. Hence, this study aimed at enhancing the antidepressant-like effects
Shawn Hayley
of ketamine (allowing for lower dosing regimens) by coadministering magnesium hydroas-
Department of Neuroscience, partate (Mg2+ normally affects the same receptors as ketamine) and also assessed whether an
Carleton University, Ottawa,
Ontario, Canada Mg2+-deficient diet would modify the impact of ketamine. It was found that a single 15 mg/kg
dose of ketamine did indeed induce rapid antidepressant-like effects in the forced swim test but
did not affect brain levels of the brain-derived neurotrophic factor. Contrary to our hypothesis,
magnesium administration or deficiency did not influence the impact of ketamine on these out-
comes. Thus, these data do not support the use of magnesium as an adjunct agent and instead
suggest that further research involving other antidepressant and animal models is required to
confirm the present findings.
Keywords: ketamine, depression, treatment resistance, ghrelin, BDNF, NMDA

Introduction
Major depressive disorder is a recurrent chronic psychiatric condition that affects over
121 million people worldwide annually.1 Unfortunately, the currently used antidepres-
sants (even when used in combination) have several caveats, including a slow onset
of action, requiring weeks or months of treatment to produce therapeutic effects.2,3
Moreover, recent estimates indicate that approximately 30% of depressed patients do
not respond to these antidepressant therapies, and even in case of responders, residual
symptoms are still often present and there is a very high risk of relapse.4–7
Exciting emerging evidence indicates that the noncompetitive N-methyl-D-aspartate
(NMDA) glutamate receptor antagonist, ketamine, which is widely used for its anes-
thetic and analgesic properties, could be a useful treatment option for depression.8–10
When used at low doses, a single injection of ketamine was found to promote fast-acting
(within hours) antidepressant and antisuicidal effects.8,11–13 Importantly, ketamine was
Correspondence: Shawn Hayley rapidly effective in patients who were previously treatment-resistant.3,11,14
Department of Neuroscience, Carleton
University, 1125 Colonel By Drive, Ketamine rapidly (within hours) increases synaptogenesis, and thus, synaptic
Ottawa, Ontario, Canada K1S 5B6 plasticity involved in learning and memory.15 Such synaptogenic changes would be
Tel +1 613 520 2600 ext 6314
Fax +1 613 520 4052
expected to influence the cognitive processing of emotionally relevant stimuli. Indeed,
Email [email protected] brain-derived neurotrophic factor (BDNF) levels were reduced in major depressive

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disorder patients,16 and postmortem studies have reported hydroaspartate. The treatments were administered intraperi-
reduced BDNF expression in hippocampus and prefrontal toneally once daily for 14 days. Then each group of mice was
cortex (PFC) of depressed suicides.17,18 It has been reported subdivided into two groups (n=8 per group); one receiving
that ketamine-mediated NMDA receptor blockade increased ketamine (15 mg/kg) and the other saline on the test day.
hippocampal BDNF levels and that this effect might contrib- Injection side was randomized, and sterile procedures were
ute to its antidepressant effects.3,19,20 used to reduce the chances of any infection/inflammation.
Despite its beneficial antidepressant effects, ketamine’s
psychotomimetic effects and abuse potential limit its wide- Behavioral procedure
spread use. Likewise, high doses of ketamine and other On the test day, which was 24 hours after the last magne-
NMDA receptors have been associated with neurotoxic effects sium injection, mice were injected either with ketamine or
in animal models.21 A better potential treatment strategy might with saline. One hour later, animals were subjected to the
involve the coadministration of agents that can synergize with forced swim test (FST). The FST was performed based on
ketamine in the promotion of an antidepressant response. the methods suggested by Liu et al.15 Mice were placed in
This would allow for even lower doses and a less frequent a 2,500-mL beaker filled two-thirds with 22°C±1°C water.
ketamine-dosing regimen. In this regard, we posit that magne- They were allowed to swim for 6 minutes during which time
sium (Mg2+) could be a potential cofactor that might augment their activity was videotaped. Immobility was defined as the
the effects of ketamine. Indeed, Mg2+ is normally present as a absence of active, escape-oriented behaviors such as swim-
channel blocker on the NMDA receptor, upon which ketamine ming, jumping, rearing, and sniffing and was assessed during
exerts its antagonist actions. Moreover, there are reports indi- the last 240 seconds of the test. The recorded videos were
cating that Mg2+ is involved in the pathophysiology of mood later scored by a person blind to the treatment groups.
disorders22–24 and that administration of the Mg2+ organic In order to assess whether the drug treatments might
salt, magnesium hydroaspartate, created antidepressant-like be affecting the motor activity (which could confound
effects.25,26 In fact, elevated intracerebral Mg2+ levels were FST results), the open field test was used, as described by
reported with several existing antidepressant agents.27,28 Beurel et al.29 A 50 cm3 open, black Plexiglas arena floor
In this study, the potential additive or synergistic was divided into 36 squares (8×8 cm); then each animal
antidepressant-like actions of ketamine plus magnesium was randomly placed in one of the four corners, and their
treatment were explored. In order to ascertain whether any locomotor activity was recorded for a period of 10 minutes.
interactive effects of ketamine and magnesium might be The number of lines crossed by each mouse was counted by a
related to trophic brain changes, BDNF levels within the person blind to the study. The open field test was also used to
hippocampus and PFC were assessed. assess anxiety-like behaviors in mice, as previously described
by Litteljohn et al.30 The open, black Plexiglas arena was
Materials and methods divided into predefined zones (outer, middle, and inner/
Animals center). The amount of time spent in each zone was measured
Male mice (CD1, 6–8 weeks of age) were acclimatized to by a person blind to the study groups. Decreased time spent
the vivarium for a period of 1 week before experimental in the center zone is an index of anxiety-like behavior. The
procedures began. Animals were singly housed in standard arena was cleaned with 10% EtOH between trials.
polypropylene cages (27×21×14 cm), and a 12-hour light/ Immediately after testing, all the animals were rapidly
dark cycle (light phase: 8:00 to 20:00 hours) was maintained. decapitated and brains collected. The hippocampus and PFC
Water and Teklad Global mouse chow were provided ad were carefully microdissected from 0.5 mm coronal tissue
libitum, and the room temperature was maintained at 21°C. slices. All the tissues were placed on dry ice followed by
All the procedures were approved by the Carleton University storage at -80°C until assayed.
Animal Care Committee and adhered to the guidelines of the
Canadian Council for the care of animals in research. BDNF analyses
Prior to analysis, samples were removed from the freezer
Treatment procedures and weighed. Lysis buffer (100 mM PIPES [pH 7], 500 mM
This experiment examined the effects of chronic administra- NaCl, 0.2% Triton X-100, 0.1% NaN3, 2% BSA, 2 mM
tion of magnesium hydroaspartate prior to a single ketamine EDTA⋅Na2⋅2H2O), 200 µM Phenylmethylsulfonyl fluoride
injection. Thirty-two mice were randomly divided into (frozen in isopropanol), 10 µM leupeptin (frozen separately in
two groups. (n=16 per group): 1) saline and 2) magnesium deionized water), and 0.3 µM pepstatin (frozen separately in

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Dovepress Antidepressant effects of ketamine in stressor models

dimethyl sulfoxide) were then pipetted into each tube contain- 

,PPRELOLW\WLPHVHFRQGV
ing hippocampal or PFC samples (2 mL). Samples were then
homogenized and sonicated (Virtis Virsonic; Virtis Company, 
Gardiner, NY; with a microtip at power level 4 and pulses at
1-second intervals for 15 seconds). Then an additional 2 mL 
of lysis buffer was added to the samples, and they were again
sonicated. Samples were split and one half of each sample 
was spiked (artificially increasing the concentration of BDNF
by 250 pg/mL to determine percent recovery). Samples were 
centrifuged for 30 minutes at 16,000× g at 4°C. Supernatants 6DOLQH .HWDPLQH

were removed and frozen at -80°C until analysis. 6DOLQH 0J

BDNF expression was determined by Western blot
Figure 1 Immobility in the forced swim test.
analysis. Protein concentration in the supernatants of tissue Notes: Effect of ketamine and magnesium treatment on immobility time in the
extracts was determined using a bicinchoninic acid protein forced swim test. Mice treated with ketamine (15 mg/kg) spent significantly less
time immobile than the saline group (*P,0.05). No significant effect of ketamine and
assay kit (Pierce Biotechnology, Inc., Rockford, IL, USA). magnesium treatment on immobility time. A significant main effect for ketamine was
A quantity of 30–50 µg of total proteins was loaded onto a obtained by ANOVA. All data are expressed as mean ± standard error of the mean.

4%–15% gradient polyacrylamide gel, electrophoretically

transferred to polyvinylidene difluoride membrane and interaction between ketamine and magnesium (F(1, 30) =0.873,
probed with the following primary antibody: BDNF (1:1,000; P=0.359).
Santa Cruz Biotechnology, Inc., Dallas, TX, USA). β-Actin
(1:2,000; Sigma-Aldrich Co., St Louis, MO, USA) was used Locomotor activity in the open field test
as an internal control. Secondary antibodies were horserad- As shown in Figure 2, the overall locomotion activity
ish peroxidase conjugated to antimouse IgG (Sigma-Aldrich was not influenced by ketamine or magnesium treatment
Co.). The membrane was developed using an enhanced (F(1, 32) =0.886, P=0.358), indicating that the treatments
chemiluminescence detection system (Pierce Biotechnol- were not having general deleterious consequences on
ogy, Inc.). Densitometric analysis was performed using the motor behavior.
quantification of immunoblotting using the Scion Image
Software (Scion Corporation). Anxiety-like behavior in the open field test
In the open filed arena, no significant difference was found
Statistical analyses between the time spent in the center zone (F(1, 32) =0.143,
Statistical analyses were performed using SPSS (IBM Corpo- P=0.708), middle zone (F(1, 32) =0.148, P=0.734), or outer
ration, Armonk, NY, USA). Differences among experimental zone (F(1, 32) =0.066, P=0.798; Figure 3). Importantly, reduced
groups in the FST and in the assessment of BDNF levels will
be determined by analysis of variance. Independent t-test was 
used when two groups were compared. Where there was an
interaction effect, two-way analyses of variance were then
/LQHVFURVVHG

followed by Fisher’s planned comparisons (P,0.05). Data 

are presented in the form of mean ± standard error of the
mean. All data were analyzed using the statistical software
SPSS (Version 19.0), and the differences were considered 
statistically significant when P,0.05.

Results 
6DOLQH .HWDPLQH
Forced swim test
As shown in Figure 1, mice treated with ketamine (15 mg/kg) 6DOLQH 0J

spent significantly less time immobile than their saline-injected

Figure 2 Locomotor activity in the open field test.
counterparts (F(1, 30) =5.2, P=0.031). However, forced swim Notes: Locomotor activity was expressed as the total number of lines passed by
mice over 10 minutes in a 50 cm3 open white Plexiglas arena, which was divided into
immobility was neither affected by the magnesium treatment 36 squares, each 10 cm. No significant difference among groups was observed. All
(F(1, 30) =0.686, P=0.415) nor was there any indication of an data are expressed as mean ± standard error of the mean.

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Razmjou et al Dovepress

 

7LPHLQPLGGOH]RQH

7LPHLQFHQWHU]RQH


VHFRQGV
VHFRQGV







 
6DOLQH .HWDPLQH 6DOLQH .HWDPLQH



7LPHLQRXWHU]RQH
VHFRQGV 




6DOLQH .HWDPLQH
6DOLQH 0J

Figure 3 Anxiety-like behavior in the open field test.

Notes: Effect of ketamine and magnesium treatment on anxiety-like behavior in the open field test. Time spent in the center zone (P=0.708), middle zone (P=0.734), and
outer zone were measured in seconds. No significant difference was found in any of the groups. All data are expressed as mean ± standard error of the mean.

exploration of the central portion of this arena is typically BDNF protein levels did not vary by ketamine × magnesium
taken as an index of anxiety-like behavior. treatment interaction (F(1, 32) =1.244, P=0.356), and the
main effects of magnesium (F(1, 32) =0.916, P=0.347) or ket-
PFC and hippocampal BDNF expression amine (F(1, 32) =1.46, P=0.236) were not significant.
Western blot analysis of hippocampal BDNF protein levels
revealed no significant ketamine × magnesium treatment Discussion
interaction (F(1, 32) =0.08, P=0.90). The main effects of either Current pharmacotherapies for major depression include
magnesium (F(1, 32) =1.43, P=0.241) or ketamine (F(1, 32) =0.186, selective serotonin and noradrenaline reuptake inhibitors,
P=0.669; Figure 4) were also not revealed. Similarly, PFC which have a long delay of action and actually fail to work

 
+LSSRFDPSDO%'1)$8

3)&%'1)$8

 

 

 
6DOLQH .HWDPLQH 6DOLQH .HWDPLQH
6DOLQH 0J

Figure 4 Results of BDNF Western blot.

Notes: Prefrontal cortex BDNF on the right side and hippocampal BDNF on the left side. No significant difference was found among groups either for PFC BDNF or
hippocampal BDNF.
Abbreviations: BDNF, brain-derived neurotrophic factor; PFC, prefrontal cortex.

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Dovepress Antidepressant effects of ketamine in stressor models

in many patients.7 Therefore, there is an urgent need for Poleszak et al39 demonstrated the antidepressant-like
the development of faster-acting antidepressants, as well as effect of magnesium in conjunction with NMDA antagonists
novel nonmonoaminergic agents to benefit a large number (CGP 37849, MK-801, L-701,324) in mice; importantly,
of treatment-resistant patients. In this regard, a lot of recent these authors suggested that administration of magnesium
works have been devoted to examining the antidepressant could be an effective method to reduce the NMDA antagonist
efficacy of compounds targeting the glutamatergic pathway. dose. Magnesium as an iatrogenic NMDA receptor antago-
This research has been spurred on by the finding that the iono- nist has a proven antidepressant-like activity in the FST.25,26
tropic glutamate N-methyl-D-aspartate receptor is involved Furthermore, it has been used as a supplementary therapy
in the etiology of major depression.8,9,19 Since then, numerous for mood disorders, reducing significantly the use of lithium,
clinical and infrahuman studies have reported that NMDA benzodiazepines, and neuroleptics in joint therapy.40
receptor antagonists, most notably ketamine, can promote The present study evaluated the effect of ketamine,
rapid antidepressant-like behavioral consequences.15,19,29,31–33 delivered either as monotherapy or in combination with
In fact, a recent meta-analysis of several clinical studies also magnesium on hippocampal and PFC BDNF expression and
suggests the effectiveness of single administration of ket- behavioral performance. Locomotor activity and anxiety-like
amine in rapid treatment of major depressive episodes.34 behavior in an open field were unaffected by ketamine or
Despite the mounting evidence of ketamine’s antidepres- magnesium treatment. Similarly, previous studies demon-
sant potential, and notwithstanding some important recent strated that neither ketamine nor magnesium has any effect
advances in our understanding of various molecular and on locomotor activity in mice.22–24,41–43 However, as expected,
cellular sequelae following low-dose ketamine treatment, we found that ketamine reduced immobility in a FST, and this
the precise mechanisms underlying ketamine’s antidepres- indicated that the drug had antidepressant-like effects that
sant effects are still largely unknown. It has been suggested were unrelated to any anxiety or locomotor parameters.
that the antidepressant effect of ketamine may be due to Magnesium-deficient diets were reported to induce
an increased expression of BDNF, which, in turn, induces anxiety-related behavior in mice,44 and there are studies
synaptic plasticity.19,35 Indeed, NMDA receptors interact indicating an anxiolytic-like activity of magnesium in
with BDNF/Trk B pathway to promote synaptic plasticity. mice.22–24 This, however, contradicts the results of our pres-
Conversely, blockade of NMDA receptor by ketamine ent study. Furthermore, animal data regarding the impact of
deactivated eukaryotic elongation factor 2 kinase, which ketamine on anxiety behaviors are contradictory: in a study
leads to reduced eukaryotic elongation factor 2 phosphoryla- conducted by Silvestre et al,45 ketamine was found to produce
tion and consequent desuppression of BDNF translation.2,20 anxiogenic-like effects in rats, but in another study, the drug
It also bears mentioning that a recent study36 highlights was shown to promote anxiolytic responses (in the elevated
the role of early and sustained activation of α-amino-3- plus maze).46 Similarly, the evidence for an anxiolytic-like
hydroxy-5-methyl-4-isoxazole propionic acid receptors in effect of ketamine in humans is equivocal and is probably
ketamine’s antidepressant responses rather than NMDA subject to complex dose-and-time effects. For instance,
receptor inhibition. in a study of healthy human volunteers, the participants
While there remains much to be discovered about how reported a decrease in anxiety after a low dose of ketamine
ketamine promotes antidepressant outcomes, it is important (0.1 mg/kg intravenously), but an increase in anxiety at a
to keep in mind that a major impetus of this line of inquiry higher dose (0.5 mg/kg intravenously).47 Ketamine is often
has been the considerable concern over the drug’s potential used as a preoperative agent for painful medical procedures
adverse effects (tolerance, abuse, side effects).2,19,37 Indeed, for both adults and children, presumably due to its dissocia-
the hope is that a better understanding of the molecular and tive anesthetic and anxiolytic properties.48,49 However, the
cellular pathways subserving ketamine’s antidepressant potential antianxiety effects of ketamine may be secondary
action will lead to the development of novel glutamater- to sedation and analgesia,50 which is particularly evident with
gic drugs that share with ketamine its mode of action/ doses higher than the subanesthetic ones that are used in this
antidepressant potential but not its unwanted effects.38 In the study (usually substantially .30 mg/kg).
meantime, further studies are needed to find the minimum Pochwat et al51 evaluated the effect of three different doses
effective and safe dose of ketamine or to find a favorable of magnesium (10, 15, and 20 mg/kg) in the chronic mild stress
ketamine combination therapy that could permit the down- model of depression in rats. They observed an antidepressant-
titrating of drug doses. like effect of magnesium at a dose of 15 mg/kg in the sucrose

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Razmjou et al Dovepress

preference test, beginning from the third week of treatment. In summary, the results of this study do not support the
Moreover, the antidepressant-like behavioral effect of magne- utility of magnesium as an adjunct treatment with ketamine
sium coincided with reduced brain regional (hippocampus, PFC, for depression. Our data also suggest that although ketamine
and amygdala) expression of proteins related to glutamatergic has robust antidepressant-like effects, its effectiveness as
signaling (including GluN1, GluN2A, and PSD-95). an anxiolytic was not obvious in our open field paradigm.
The underlying mechanism(s) of the rapid antidepressant Finally, lack of brain BDNF changes induced by ketamine
effect of ketamine is/are not known. However, it has been and magnesium treatment might speak to the sensitivity
suggested that the fast-acting behavioral antidepressant- of our procedures but more likely is related to timing.
like effect of ketamine is related to the rapid upregulation Specifically, it is expected that BDNF changes would have
of BDNF and the consequent potentiation of synaptic occurred early following ketamine administration; but it is
plasticity.20 Indeed, acute administration of ketamine was perhaps not surprising that these effects were not prolonged
shown to induce increased hippocampal and PFC BDNF for the 3-week period of our study. Thus, ketamine did not
levels, which coincided with improved behavioral responses sensitize or have enduring effects upon the ability of chronic
in rodents.19,52,53 Yet, we presently failed to detect any effect of magnesium treatment to influence BDNF. Similarly, the
ketamine on hippocampal or PFC BDNF levels. This might be magnesium dose alone was clearly not sufficient to trigger
due to the fact that we did not use mice with depression-like BDNF alterations. Thus, further studies are clearly needed to
phenotype in our study, as ketamine was shown to improve ascertain whether magnesium really has any potential as an
decreased BDNF expression in inflammation-induced adjunctive agent with ketamine or even other more traditional
depressed mice54 and learned helplessness rats.55,56 Indeed, antidepressants, such as fluoxetine or citalopram.
Zhang et al57 found that 8 days after a single injection, ket-
amine did reverse the stressor-induced reduction of BDNF in Acknowledgments
the PFC and hippocampus on Day 20 of a daily social defeat This paper includes work based on the master thesis sub-
stressor paradigm. However, Garcia et al58 failed to detect mitted by coauthor Sara Razmjou to Carleton University:
any change in hippocampal BDNF levels after chronic mild https://curve.carleton.ca/cc1977e4-6b95-4ad3-84c4-
unpredictable stress as well. The reason for the discrepancies 42cd6c0cb5a5.
between the studies is not immediately apparent but could
certainly have to do with the obvious stress/testing procedural Disclosure
differences, as well as species/strain differences. In particular, The authors report no conflicts of interest in this work.
the Garcia et al58 study used rats, whereas Zhang et al57 used
C57BL/6 mice, and we used CD1 mice in our study. References
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