Balancing Brain Chemistry to Treat Depression By Liz Butler This article first appeared in CAM magazine Introduction It is taking a long time for the scientific community to fully accept that what a person eats can influence their mental state but in the last few decades progress in this area has been rapid. Taking a very basic view of the subject there can be no doubt that nutrition is intimately involved with mental health as the brain and its chemical messengers are ultimately derived from food. Convincing doctors used to the traditional approach of treating mental disturbance and depression (drugs or psychotherapy) to consider the nutritional treatment approach is more difficult than simply pointing out this fact. Fortunately there is now a large amount of research supporting the view that nutrition has a role to play in promoting mental health, this article will review some of this research. It is well established that neurotransmitter imbalances can lead to mental dysfunction and depression and in fact most drugs currently being used in this area of disease aim to restore chemical balance within the nervous system (1). As some of the research mentioned in this review shows, certain nutritional factors may be able to promote chemical normality in the same way as current pharmaceutical treatments but without the side effects associated with drug therapy. Within a discussion about depression there must be some mention of genetic factors as there is no denying that the risk of developing depression, particularly a severe form, is influenced by genetics (2). It is likely that certain people are born with a predisposition to biochemical imbalances within the brain and then an inadequate nutrient intake compounds the problem. Eventually the situation deteriorates until there is expression of disease. What this means however, is that even disease with a genetic component may possibly be reversed given the correct nutrients to balance brain chemistry. Brain chemistry The brain is composed of about 100 billion neurones, the cells of the nervous system that communicate messages to each other, making up what is termed grey matter. The processes that extend from the cells to meet up with other cells constitute the white matter of the brain. Amongst the neurones are cells called neuroglia. Their role is to support, protect, and repair the neurones. Neurotransmitters are chemical substances that pass between neurones relaying messages. Examples include acetylcholine, histamine, adrenaline, noradrenaline, dopamine, and serotonin. All of these are well-studied neurotransmitters, and the effects of too much, or too little on the mental state are well observed. In addition neuromodulators and neurohormones are further classes of chemicals that affect nervous function. Neuromodulators modulate signal transmission either pre- or post-synaptically and neurohormones behave like neurotransmitters but act at a site distant
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Unicamp.sibi.usp.brEffect of preoperative use of topical prednisolone acetate, ketorolac
tromethamine, nepafenac and placebo, on the maintenance of intraoperative
mydriasis during cataract surgery: A randomized trial
Fernando Roberte Zanetti, Enzo Augusto Medeiros Fulco, Fernando Rodrigo Pedreira Chaves,
Alexandre Paashaus da Costa Pinto, Carlos Eduardo Leite Arieta, Rodrigo Pessoa Cavalcanti Lira
Purpose: To compare the effects of preoperative use of topical anti-inflammatory prednisolone acetate,
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ketorolac tromethamine, nepafenac and placebo, on the maintenance of intraoperative mydriasis during Website:
cataract surgery. Design: Randomized clinical trial. Materials and Methods: This single-center, masked,
randomized clinical study comprised 140 patients scheduled for cataract surgery. Patients (35 in each group) were randomized to receive placebo, prednisolone acetate, ketorolac tromethamine 0.4% or nepafenac. These 10.4103/0301-4738.98705 eye drops were administered three times daily for the two days prior to surgery. The pupillary diameters were measured by the surgeon using a compass prior to the corneal section and at the end of surgery. The Quick Response Code:
primary outcome was the number of patients with pupil ≥ 6mm at the end of the surgery; the secondary outcome was the number of patients with pupil ≥ 6mm at the beginning of the surgery. Results: All the
patients achieved pupil ≥ 6mm at the beginning of the surgery. The number of patients in the prednisolone (29/35), nepafenac (31/35) and ketorolac (30/35) groups with pupil ≥ 6mm was greater than in the placebo group in the maintenance of intraoperative mydriasis (19/35 – P =0.003). There was no statistical difference among the prednisolone, nepafenac and ketorolac groups in the maintenance of intraoperative mydriasis (P =.791). There were no complications during surgery or related to the preoperative use of the eye drops. Conclusion: Preoperative use of ketorolac, prednisolone and nepafenac was effective in maintaining
intraoperative mydriasis when compared with placebo.
Key words: Cataract, inflammation, mydriasis, prevention and control, surgery
Cataract extraction increases the concentration of prostaglandins of maintaining well dilated pupils (> 6mm) during cataract (PGs) E and PGs F in aqueous humor, resulting in hyperemia, miosis and breakdown of the blood-aqueous barrier. Topical steroids are the most prescribed medication for Topical anti-inflammatory drugs are commonly used in postoperative periods. It comprises the steroid group derivative the management of ocular inflammation and cystoid macular of cholesterol. Prednisolone is one of the most commonly used. edema related to cataract surgery.[2-4] It has been suggested the Although prolonged use of steroids may result in cataract use of anti-inflammatory drugs before surgery, to achieve better formation, and secondary ocular infections, there are no intraoperative mydriasis. The miosis that occurs during cataract previous reports showing that its use for a short period before surgery is in part mediated by PGs. Preoperative treatment surgery has side effects superior to the use of nonsteroidal anti- using nonsteroidal antiinflammatory drugs (NSAIDs) has been inflammatory drugs (NSAIDs). Furthermore, steroid-induced shown to be effective in maintaining mydriasis during cataract IOP elevation almost never occurs in less than five days.[11,12] surgery. The mechanism of their action is dependent on their ability to cause cyclooxygenase inhibition and thereby inhibit Nonsteroidal anti-inflammatory drugs do not comprise the production of PGs in response to surgical trauma. Steroids the steroid group derivative of cholesterol. The main options block the release of arachidonic acid, which is also a precursor for eye drops are ketorolac tromethamine, diclofenac, for PGs synthesis. Unlike nonsteroidal agents, steroid eye drops flurbiprofen, indomethacin and nepafenac. Less influence on have not been extensively studied for their antimiotic effect.[7-9] intraocular pressure control is one of the main advantages of these medications when used for a long period. Nepafenac, a Cataract surgery complications increase when miosis new prodrug, which is hydrolyzed by intraocular tissues to occurs. It was reported that, when mydriasis is greater than amfenac has demonstrated superior intraocular penetration 6mm, the incidence of posterior capsule rupture is reduced when compared with other anti-inflammatory drugs in both by half. In addition, the increasing number of toric and anterior segment and retinal tissue following topical ocular multifocal intraocular lenses draws attention to the importance The objective of the original study was to compare the effect Department of Ophthalmology, State University of Campinas – of preoperative use of topical anti-inflammatory prednisolone Unicamp, Rua Irmã Maria David, Recife, PE, Brazil acetate, ketorolac tromethamine, nepafenac and placebo, in the Correspondence to: Prof. Rodrigo Pessoa Cavalcanti Lira, Rua maintenance of intraoperative mydriasis in cataract surgery.
Irmã Maria David, 200 ap 1302, Recife, PE, Brazil - 52061-070. Materials and Methods
Manuscript received: 13.01.11; Revision accepted: 05.06.11 This single-center, masked, randomized clinical study comprised 140 patients with cataract [Fig. 1]. The study took Patients with cataract were randomized to receive either place in Campinas, Brazil. Eligible participants were recruited placebo carboxymethylcellulose sodium 0.5%, prednisolone from March 2009 to March 2010.
acetate 1%, ketorolac tromethamine 0.4% or nepafenac 0.1%. The inclusion criteria were as follows: patients with nuclear These eye drops were administered 48 hours before surgery by cataract density of 2 and 3 by LOCS II (> 50 years old), with mask fashion, three times daily for two days prior to surgery.
indication for cataract surgery with intraocular lens implant, The randomization was done in a blocking manner. Each under local anesthesia.
of the four intervention groups received 35 different numbers The exclusion criteria were as follows: diabetes, hypertension, from a random number table. These numbers were transferred patients using nonsteroidal anti-inflammatory, alphablocker, to small individual envelopes and also fixed at one of the topical eye drops (including antiglaucoma drugs), history opaque eye drop bottles. It helped not only to randomize of uveitis, macular disease, pseudoexfoliation syndrome, the patients but also to mask the treatment groups until data congenital ocular abnormalities, cataract density of 1 and 4 by analysis. Four small envelopes, one of each intervention group, LOCS II and previous intraocular surgery. were sealed and placed into a larger envelope, totalizing 35 Assessed for eligibility (n = 140 patients scheduled for cataract surgery) Prednisolone acetate
1% eye drops
sodium 0.5% eye drops
Allocated to intervention Received allocated Received allocated Received allocated Received allocated Lost to followi-up Lost to followi-up Lost to followi-up Lost to followi-up Analyzed (n = 35) Analyzed (n = 35) Analyzed (n = 35) Analyzed (n = 35) Figure 1: CONSORT flow diagram: Effect of preoperative use of topical prednisolone acetate, ketorolac tromethamine, nepafenac and placebo,
in the maintenance of intraoperative mydriasis during cataract surgery July - August 2012 Zanetti, et al.: Preoperative use of anti-inflammatory in cataract surgery large envelopes containing four small individual envelopes To ensure the standardization of illumination during in each one. This comprises the block length of four to assure pupillary measurement, the surgeon used the same microscope that every four patients have received all four interventions. (Leica M820, Germany) and the illumination was kept constant When a patient was included in the study, a pharmacist took in all cases. The horizontal and vertical diameters of the pupil for him a small individual envelope and after discovering the were measured in millimeters using a compass under the random number, she took the respective eye drop bottle. The microscope (directly on the eye) at the following stages: before surgeon and the ophthalmologist who collected the data did surgery (prior to the corneal incision) and at the conclusion of not know the randomized groups.
surgery. The preset standard magnification of the operating microscope was ensured at each of the two time points.
The eye drop group was revealed to the researchers once recruitment, data collection, and statistical analyses were The primary outcome was the number of patients with complete. All study participants were masked to treatment pupil ≥ 6mm (vertical and horizontal diameters) at the end of the surgery to measure the efficacy of each medication in the maintenance of intraoperative mydriasis during cataract Gatifloxacin was prescribed four times daily for two surgery. The secondary outcome was the number of patients days prior to surgery, with interval time of at least 15 with pupil ≥ 6mm (vertical and horizontal diameters) at the minutes between two eye drops. Preoperative mydriasis was beginning of the surgery (prior to the corneal section) to accomplished with tropicamide 0.5% and phenylephrine 5% measure the efficacy of each medication to achieve preoperative eye drops, one drop instilled into the patient's eyes 60, 45 and 30 minutes before surgery (three doses). Peribulbar anesthesia was performed with lidocaine 2% (3ml) in the inferior-temporal Ethics committee approval was obtained and all participants quadrant, associated with an oral dose of diazepam 5 mg, 30 gave informed consent (Conep - National Research Ethics minutes before surgery, without additional sedation. Lidocaine Committee – Brazil – 0816.0.146.000-10). Also the study was was not used intraocularly. The phacoemulsification (Infiniti®, registered at Clinical Trials protocol NCT00865540. Alcon Inc., Hünenberg, Switzerland) was performed by a A sample size of 140 patients (35 per group) was planned to compare groups for primary outcome (pupil > 6mm at the The surgeon used the same standardized small-incision end of the surgery). With an assumption of a 50% rate of pupil phacoemulsification technique in all patients. In short, ≥ 6mm in the placebo group, this sample size provided a 80% 1.0mm and 3.0mm clear corneal incisions were made and probability of detecting a difference as small as 35% in the a capsulorhexis 4.0mm in diameter was created. A stop- other groups. Results of these analyses were considered as chop phacoemulsification technique was used and foldable statistically significant when the P-values were < 0.05. Measures intraocular lenses were implanted in the capsular bag. The of central tendency and dispersion were determined by median, phacoemulsification parameters were established prior to all mean and standard deviation. Categorical variables were surgeries and were the same for all patients. Cataract surgery analyzed using the chi-square (Yates) test and, for continuous was conducted using the Legacy® Series 2000 Machine (Alcon variables, one-way analysis of variance (ANOVA) tables were Laboratories, Inc.). The parameters used were as follows: balanced saline solution, with the height of the bottle set at 100 cm, 40 ml/minute aspiration flow rate, 450mmHg vacuum and phaco power 50%. Intracameral adrenaline was not used in the No patient loss was registered from the day of inclusion in the irrigation solution. Ultrasound time and surgical times were trial to the end of surgeries. registered at the end of each surgery [Table 1]. Baseline demographic and clinical characteristics were The eye drop was revealed to the researchers once similar in all groups. There were no differences regarding recruitment, data collection, and statistical analyses were ages (P = 0.930), neither in age-related cataract density (P = complete. All study participants were masked to the treatment 0.852), nor in gender distribution (P = 0.896), ultrasound time (P = 0.986) and surgical time (P = 0.666) [Table 1]. Table 1: Baseline demographic and clinical characteristics. Effect of preoperative use of anti-inflammatory topical agents
on the maintenance of intraoperative mydriasis during cataract surgery
Ultrasound time‡ Surgical time‡‡ *Years (standard deviation); †Nuclear cataract grade (NCG) LOCSII: density of nuclear cataract 1-4 15; ‡Minutes (standard deviation), ‡‡Minutes (standard deviation) All patients achieved pupil ≥ 6mm at the beginning of groups. Because of this confounding bias, there was a failure the surgery. The number of patients in prednisolone (29/35), when assessing the anti-inflammatory effect of eye drops. nepafenac (31/35) and ketorolac (30/35) groups with pupil ≥ 6mm was greater than the placebo group in the maintenance of Epinephrine is one of the alternatives to improve intraoperative mydriasis at the conclusion of surgery (19/35 – intraoperative mydriasis that were not analyzed in this study. P = 0.003 – Tables 2 and 3). There were no complications during Although the potential for systemic absorption of epinephrine surgery or related to the preoperative use of the eye drops.
can lead to sympathomimetic effects (such as excessive sweating, pallor, faintness, occipital headaches, hypertension, There was no statistical difference among the prednisolone, palpitations, tachycardia, and cardiac arrhythmias, particularly nepafenac and ketorolac groups in the maintenance of in patients with preexisting cardiac disease), its use has intraoperative mydriasis (P = 0.791).
additive benefit for inhibiting intraoperative miosis, regardless of whether antiprostaglandins were used.[17-21] However, in undiluted and weakly diluted solutions, the bisulfite In the present study, the use of ketorolac 0.4%, prednisolone preservative included in most epinephrine preparations is 1% and nepafenac 0.1% three times daily for two days shown to cause corneal endothelial damage and subsequent preoperatively demonstrated a statistically significant corneal haziness.[22,23] difference in the maintenance of intraoperative mydriasis when Our results with ketorolac were similar to those of Stewart compared with the placebo group.
et al., who demonstrated that ketorolac 0.5% used before Nepafenac 0.1% was superior to placebo in the inhibition surgery provided effective and well-tolerated inhibition of of intraoperative miosis. These results were similar to those of surgically induced miosis during cataract surgery when Cervantes-Coste et al., who also found that the prophylactic compared with placebo. use of nepafenac 0.1% was safe and effective in maintaining An interesting finding from this study (with economic mydriasis during cataract surgery. impact) was the fact that, since there been no significant The use of topical prednisolone 1% to maintain intraoperative differences among ketorolac, prednisolone and nepafenac in mydriasis was superior to placebo. Shaikh et al., analyzed the the maintenance of intraoperative mydriasis during cataract antimiotic effect of topical prednisolone and flurbiprofen. surgery, these medicines can be used in surgical practice with In the analysis of the study, there were no significant similar efficacy. Considering that prednisolone has a lower differences in maintaining mydriasis at any stage of surgery cost than ketorolac or nepafenac and, moreover, during the in the prednisolone and flurbiprofen groups when comparing post-operative period, steroid use is mandatory, while the with the placebo group. Unfortunately, the comparison of the use of non-steroidal anti-inflammatory drugs is optional, it prednisolone and flurbiprofen groups with the placebo group becomes an option for a single drug as a mydriatic adjuvant (sodium chloride 0.9%) was not ideal, since the author used at preoperative care and as an anti-inflammatory agent at epinephrine 1:106, a potent direct-acting mydriatic agent, in all postoperative period of cataract surgery. In spite of its topical use, preoperative steroids theoretically reduce immunity with increased risk of opportunist infection (herpes and fungi); in this study, it did not increase the risk of surgical complications. Table 2: Effect of preoperative use of topical anti-
In addition the ocular surface precipitation of prednisolone did inflammatory agent on the maintenance of intraoperative
mydriasis during cataract surgery. Distribution of patients
not interfere with surgical view. according to pupil size at the end of the surgery
The disadvantages of this study are excluding diabetics, eyes Prednisolone Ketorolac Nepafenac Placebo
with hard cataracts or pseudoexfoliation limits the applicability of the results considered for these specific patients. We are unaware of previous clinical trial reports about the maintenance of intraoperative mydriasis during cataract surgery, simultaneously including, a relatively new NSAID eye drop (nepafenac), the most prescribed NSAID eye drop for that purpose (ketorolac), as well as the steroid eye drop already used routinely during the postoperative period, (prednisolone) Table 3: Effect of preoperative use of topical anti-
and we could find no reference to it in a computerized search inflammatory agent on the maintenance of intraoperative
at PubMed. Additional studies are warranted to confirm our mydriasis during cataract surgery. Distribution of patients
according to pupil diameter at the beginning and at the end
of the surgery
Pupil Diameter (mm)
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9. Dubé P, Boisjoly HM, Bazin R, Chamberland G, Laughrea PA, 19. Bhallil S, Andalloussi IB, El Abdouni O, Mahjoubi I, Tahri H. Is there Dubé I. Comparison of prednisolone acetate and indomethacin for a perioperative circulatory side effect of intracameral epinephrine maintaining mydriasis during cataract surgery. Can J Ophthalmol in hypertensive patients undergoing phacoemulsification? Oman J Ophthalmol 2010;3:161-2.
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nonsteroidal prodrug with potential utility in the treatment of 24. Stewart R, Grosserode R, Cheetham JK, Rosenthal A. Efficacy trauma-induced ocular inflammation: II. In vitro bioactivation and safety profile of ketorolac 0.5% ophthalmic solution in the and permeation of external ocular barriers. Inflammation 2000;24: prevention of surgically induced miosis during cataract surgery. Clin Ther 1999;21:723-32.
14. Lindstrom R, Kim T. Ocular permeation and inhibition of retinal inflammation: An examination of data and expert opinion on the Cite this article as: Zanetti FR, Fulco EM, Chaves FP, da Costa Pinto AP,
clinical utility of nepafenac. Curr Med Res Opin 2006;22:397-404.
Arieta CL, Lira RC. Effect of preoperative use of topical prednisolone acetate, ketorolac tromethamine, nepafenac and placebo, on the maintenance of 15. Chylack LT, Leske MC, McCarthy D, Khu P, Kashiwagi T, intraoperative mydriasis during cataract surgery: A randomized trial. Indian J Sperduto R. Lens opacities classification system II (LOCS II). Arch Source of Support: Nil. Conflict of Interest: None declared.
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Managing fallow deer (Dama dama) andred deer (Cervus elaphus) for animalhouse research ANZCCART Facts Sheet Z.H. MiaoA, P.C. GlatzA, A. EnglishB and Y.J. RuA A: SARDI -Livestock Systems, Roseworthy Campus, Roseworthy SA 5371 B: Faculty of Veterinary Science, University of Sydney, PMB 3, Camden NSW 2570