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Functional Brain Imaging Alterations
in Acne Patients Treated With Isotretinoin
J. Douglas Bremner, M.D.
Objective: Although there have been
after 4 months of treatment with isotreti- case reports suggesting a relationship be- noin (N=13) or an antibiotic (N=15).
Negar Fani, M.S.
Results: Isotretinoin but not antibiotic
Ali Ashraf, M.D.
depression and suicide, this topic remains John R. Votaw, Ph.D.
brain metabolism in the orbitofrontal cor- controversial. In order for isotretinoin to Marijn E. Brummer, Ph.D.
Thomas Cummins, M.D.
isotretinoin on brain functioning in acne Viola Vaccarino, M.D., Ph.D.
no differences in the severity of depres- purpose of this study was to assess the ef- Mark M. Goodman, Ph.D.
fects of isotretinoin on brain functioning and antibiotic treatment groups before or Lai Reed, M.B.A.
Sajid Siddiq, M.D.
Method: Brain functioning in adults was
Conclusions: This study suggests that
isotretinoin treatment is associated with Charles B. Nemeroff, M.D., Ph.D.
(Am J Psychiatry 2005; 162:983–991)
Isotretinoin (13-cis-retinoic acid) is a retinoid that in- concentration, tearfulness, psychotic symptoms, and hibits sebaceous gland functioning, keratinization, and guilty rumination (17–19) that resolved with discontinua- inflammatory responses and is currently approved by the tion of vitamin A. Among reports to the World Health Or- Food and Drug Administration (FDA) for the treatment of ganization and the FDA of adverse events associated with cystic acne (1, 2). Isotretinoin has been prescribed to 2 acne treatments, adverse events related to depression and million patients in the United States and over 8 million pa- suicide have been more common with isotretinoin than tients worldwide and is highly effective for acne. The exact with other treatments for acne, such as antibiotics (4, 11).
mechanism of action of isotretinoin remains unknown.
The relationship between isotretinoin treatment and In the last several years there has been controversy over depression and suicide, however, remains controversial.
the possible role of isotretinoin in the development of de- Although the manufacturer, on the basis of FDA guide- pression and suicide (3–6). Case reports in the literature lines, lists depression as a possible side effect, there is no describe depression that developed in conjunction with consensus on a causal role for isotretinoin in the develop- isotretinoin treatment, resolved with discontinuation of ment of depression and suicide. The high incidence of de- the medication, and in some cases returned when the pression in the general population makes it difficult to medication was restarted (7–14). Estimates of the inci- identify small increases specifically related to an addi- dence of depression following treatment with isotretinoin tional factor, such as isotretinoin administration. One include 1% (14), 4% (15), and 6% (10). Other reports have large epidemiological study did not demonstrate a signifi- noted suicidality, behavioral disturbances, and psychotic- cantly increased risk for suicide in patients treated with type symptoms with isotretinoin treatment in addition to isotretinoin (3). Some authors have argued that cases of the typical symptoms of depression (8, 12). Isotretinoin ischemically similar to the retinoid vitamin A, a fat-soluble depression associated with isotretinoin administration vitamin stored in high concentrations in the liver. Vitamin are merely coincidental (20) or that isotretinoin actually A is converted after oxidation to retinoic acid, when it has leads to an improvement in anxiety and depression be- biological effects. Arctic explorers who fed on polar bear cause of the clearing of disfiguring acne (21). Studies have liver developed symptoms of confusion and psychosis.
shown an improvement in feelings of general well-being Large doses of vitamin A can have a number of other neu- or self-image (22, 23) or in feelings of anxiety (20, 24–28) rological and mental effects, including fatigue, decreased among patients with cystic acne following isotretinoin ad- interest, headache, and diplopia (double vision) (16, 17).
ministration, although the findings were more directly re- Published case reports of vitamin A toxicity include symp- lated to improvement in measures of patient satisfaction, toms of aggression, personality changes, depression, poor rather than clinical symptoms of depression.
ISOTRETINOIN AND BRAIN FUNCTIONING
To establish a causal role of isotretinoin in the develop- 2), and erythromycin (N=1). The subjects continued treatment ment of depression and suicide, it is critical to establish a until they completed the second PET scan.
plausible biological pathway. This requires that isotreti- Psychiatric diagnoses were established with the Structured Clinical Interview for DSM-IV, Patient Edition (SCID-P) (57).
noin must enter the central nervous system (CNS) and There were no current psychiatric conditions in any subject ac- have an effect on the functioning of brain areas and neu- cording to the SCID-P. Two of the subjects in the antibiotic group rochemical systems that mediate depression. Retinoids had past psychiatric conditions, including a past history of major have important effects on the developing brain in animal depression in one and a past history of bulimia and alcohol de- studies (29, 30), and use of isotretinoin during pregnancy pendence in another. None of the isotretinoin subjects had a cur-rent or past psychiatric disorder. None of the subjects had current has long been known to result in CNS defects in newborns alcohol or substance abuse or dependence.
(31). Multiple positron emission tomography (PET) andsingle photon emission computed tomography (SPECT) Behavioral Assessment
studies have shown low metabolism and/or blood flow at Symptoms of depression were measured by using the Hamilton baseline in depressed subjects in the left (32–35) and bilat- Depression Rating Scale at baseline and every month after the ini- eral (36–43) dorsolateral prefrontal cortex and medial pre- tiation of treatment (58). The severity of acne was measured witha clinician-administered acne questionnaire before and after frontal cortex/anterior cingulate (34, 38, 41–48) or blunted treatment, on a scale of 0 (no acne) to 6 (very bad acne). The pa- activation with cognitive tasks in the anterior cingulate (49, tients’ subjective evaluations of the severity of acne on the face 50). Other PET and SPECT studies of patients with unipolar and back and their feelings of depression related to their acne, on depression showed low metabolism and/or blood flow in a scale of 0 (not at all) to 4 (very severe), were recorded before and the caudate (36–41, 51, 52), thalamus (37), temporal cortex after treatment by using the Skindex questionnaire (59). The Skin-dex is a 16-item self-report questionnaire with questions about (37, 38, 51, 53, 54), parietal cortex (34, 40, 51), and left puta- emotional, functional, and symptomatic aspects of acne that has men (37). Experimental induction of depression resulted been validated for use in acne patient populations. It was also ad- in a specific decrease in metabolism in the orbitofrontal ministered before and after treatment. The patients were also cortex (part of the prefrontal cortex) (55, 56). The purpose evaluated during the course of treatment for symptoms related to of the current study was to assess the effects of isotretinoin treatment on brain functioning. We hypothesized that PET and MRI Scanning
treatment with isotretinoin, but not antibiotic, would be Two PET scans of resting brain metabolism were performed 4 associated with a decrease in orbitofrontal cortical brain months apart, before and after treatment with isotretinoin or an- metabolism as measured with [18F]fluorodeoxyglucose tibiotic. The PET scans took place at 11:00 a.m. The subjects were scanned with an ECAT EXACT 921 PET camera (CTI MolecularImaging, Knoxville, Tenn.). The ECAT EXACT has an axial field ofview of 16.2 cm, the total system sensitivity is 216 kcps/µCi per ml for a 20-cm cylinder phantom in two dimensions, and the ap-proximate axial resolution is 5.0 mm (60). Each subject was Subjects
placed in a preparation room adjacent to the PET scanner room, The study participants included 28 healthy men and women and an intravenous line was inserted in the hand and warmed between the ages of 18 and 50 years with treatment-resistant with a heating pad for measurement of arterialized venous blood acne, as defined by a failed 3-month antibiotic trial, who were samples. This method has been shown to yield metabolic values seeking a second trial of an antibiotic or isotretinoin. Subjects equivalent to those obtained by arterial line placement (61). The were recruited by advertisement. They were not randomly as- subject then received an intravenous injection of 10 mCi (370 signed to treatment with isotretinoin or placebo; they had de- MBq) of FDG in a single bolus. Twenty-three arterialized venous cided with their physicians to take either a second trial of an anti- blood samples were obtained at multiple time points after injec- biotic or a trial of isotretinoin. Because of the side effects of tion for measurements of radioactivity in the plasma, which were isotretinoin (severe skin dryness) it was decided that it would not used for construction of a plasma time activity curve. Three blood be possible to blind the subjects or the raters to treatment condi- samples were also obtained for measurement of plasma glucose tion. Subjects with serious medical or neurological illness, or- concentrations. The subject was then placed in the scanner with ganic mental disorder or current psychiatric illness according to his or her head held in a head holder to minimize patient motion.
the Structured Clinical Interview for DSM-IV (57), premenstrual The head was positioned with the canthomeatal line parallel to dysphoric disorder, current alcohol or substance abuse or depen- the external laser light. Following positioning within the camera dence, retained metal that would prevent magnetic resonance gantry, postinjection transmission data were collected by using imaging (MRI) scanning, a history of head trauma or loss of con- rod windowing with three orbiting 67Ga/68Ge rod sources (60).
sciousness, a history of cerebral infectious disease, or dyslexia These data were used to correct the emission data for attenuation were excluded. Postmenopausal women were excluded.
due to overlying bone and soft tissue. The subject underwent This project was approved by the Emory University Human emission scanning of the brain over the 40–60 minutes after injec- Investigation Committee. All subjects provided written in- tion with his or her eyes open in a dimly lit room. Brain and tissue formed consent for participation. The subjects were paid for measurements were used to estimate the cerebral glucose meta- bolic rate (in milligrams per minute per 100 milliliters) (62, 63). In Each subject received a PET brain scan at baseline and again one patient blood samples could not be obtained, and this pa- after 4 months of treatment with an antibiotic (N=15) or isotretin- tient’s data were used only for the analysis of the ratio of regional oin (N=13). The subjects were treated by their outpatient physi- metabolism to whole brain metabolism. A 20-cm cylindrical cians with 1 mg/kg of isotretinoin or with an antibiotic in a stan- fluid-filled phantom with a known amount of radioactivity was dard 4-month course of treatment for acne. The antibiotics used scanned in order to obtain calibration factors for conversion of included doxycycline (N=10), minocycline (N=2), tetracycline (N= native pixel values into units of millicuries per milliliter.
BREMNER, FANI, ASHRAF, ET AL.
MRI scans were obtained in all subjects for coregistration with FIGURE 1. Flow of Subjects in a Brain Imaging Study of
the PET scans and determination of regions of interest from the Patients Receiving Isotretinoin or Antibiotic Treatment for
MRI scans resliced to correspond to the PET slices. MRI scans in the same subjects were obtained on a 1.5-T Philips Gyroscan In-tera device (Philips Medical Systems, Andover, Mass.). Axial im- Initially screened for participation (N=88) ages were acquired with a T1-weighted gradient echo three-di-mensional sequence with TR=35 msec, TE=12 msec, flip angle= 35°, number of excitations=2, matrix=256×256, field of view=22 Lack of follow-up/lack of interest (N=30) Image Processing and Analysis
Current or previous isotretinoin treatment (N=10) Psychiatric disorder (N=1) The PET and MRI scans were transferred to a workstation for analysis. A surface-matching algorithm and the ANALYZE soft- Met criteria for participation, signed informed consent ware package (Mayo Clinic, Rochester, Minn.) were used for statement, and were identified for treatment (N=44) coregistration of images (64). Brain surfaces from PET and MRIwere matched by using this program. The MRI scan was reslicedto correspond to the PET slices. Using this technique (65), we have shown a registration error of 2.86 mm. Regions of interest were drawn on the resliced MRI scans by a blinded rater usingspecific criteria based on anatomical landmarks with a method that we have shown to be highly reliable (66). Multiple brain re- gions were selected for analysis, including the temporal cortex, inferior, middle, and superior frontal gyri, superior portion of the dorsolateral prefrontal cortex, thalamus, putamen, caudate, oc- cipital cortex, subcallosal gyrus, orbitofrontal cortex, anteriorcingulate, postcentral gyrus, hippocampus, amygdala, and mid- brain. These regions correspond to the regions measured in our prior studies of neural findings associated with a return of depres-sive symptoms induced by tryptophan depletion (55) and alpha- Dropped out (N=2): Lack of follow-through methylparatyrosine (56), since a primary aim of the current study was to replicate the brain findings of those prior studies. Global brain metabolism was calculated as the mean of brain tissue ac-tivity in all slices, including gray and white matter and the ventric- Data Analysis
The brain regions were separated into those that were and were not hypothesized to change with isotretinoin. The region most consistently affected in our two prior studies of depression wasthe orbitofrontal cortex (55, 56). This region has also been re- ported to be smaller in volume in depressed patients than in The data were analyzed to determine differences in the changes from pre- to posttreatment in regional brain metabolic a Of the 88 subjects screened initially, 44 were identified to start rates between the isotretinoin and antibiotic treatment groups, treatment with isotretinoin or antibiotics. Sixteen later dropped out by using repeated-measures analysis of variance with time (be- because of medical conditions (N=2), psychiatric diagnoses as de- fore and after treatment) as the repeated factor and treatment sta- termined with the Structured Clinical Interview for DSM-IV (N=6), a tus (isotretinoin versus antibiotic) and hemisphere (left versus change of mind about the study (N=2), or a lack of follow-through right) as factors in the analysis. The interaction between treat- ment status and time was examined in this model. Secondaryanalysis examined the ratio of regional to whole brain metabo-lism, and it added baseline global metabolism as a factor in the the Skindex. Corrections were made for multiple comparisons (p= model. Bonferroni corrections were performed to correct for mul- tiple comparisons (p=0.05/12=0.004).
The data were analyzed by using the SAS System for Windows Correlations between brain metabolism and behavioral vari- ables were also examined by comparing the relationships be-tween the changes, from before to after treatment, in scores on the Hamilton depression scale, clinician-administered acnequestionnaire, Skindex, and acne severity self-report and the Recruitment and Demographic Factors
change in regional brain metabolism (mean of left and right of Subjects
orbitofrontal metabolism) in the isotretinoin and antibiotic treat-ment groups. Corrections were made for multiple comparisons Eighty-eight subjects were initially screened for partici- (p=0.05/4=0.0125). Analyses also examined the correlation be- pation in the study. Of these, 44 met the criteria for partic- tween baseline orbitofrontal brain metabolism and age, educa-tion, and behavioral factors related to self-assessment of acne se- ipation according to the initial screening, signed informed verity, depression, and emotions related to acne, measured with consent statements, and were identified as acne patients ISOTRETINOIN AND BRAIN FUNCTIONING
TABLE 1. Pretreatment Demographic and Behavioral Characteristics of Patients Receiving Isotretinoin or Antibiotic
Treatment for Acne
Score on clinician-administered acne questionnairea Skindex (59) score for behavioral effects of acneb a On a scale of 0 (none) to 6 (very bad).
b On a scale of 0 (not at all) to 64 (very bad).
c On a scale of 0 (not at all) to 4 (very severe).
who were beginning a second trial of antibiotic (N=22) or brain metabolism (F=4.64, df=1, 110, p<0.05). A secondary who were going to be treated with isotretinoin (N=22) (Fig- analysis included pretreatment whole brain metabolism ure 1). Twenty-eight subjects completed participation in in the model and also showed greater reductions in orbito- this protocol, including pre- and posttreatment imaging.
frontal metabolism after treatment in the isotretinoin Of these, 13 were treated with isotretinoin and 15 with group than in the antibiotic group (F=9.66, df=1, 104, p= 0.002). The value for the interaction between treatment Demographic, behavioral, and acne-related variables status (isotretinoin versus antibiotic) and time (before and related to the two treatment groups before the initiation of after treatment) and the percentage change in the mean treatment are presented in Table 1. The isotretinoin sub- metabolic value with treatment are presented for each re- jects had fewer years of education and were younger, but gion in Table 2. Differences in functioning between the the latter difference was not statistically significant. They groups at the p<0.05 level were also seen for the middle did not differ significantly from the antibiotic group in frontal gyrus, thalamus, hippocampus, caudate, and puta- their reasons for receiving treatment (cystic acne, psycho- men. These differences were not significant after correc- logical distress, scarring, or a combination). According to tion for multiple comparisons, however, and there were no the clinician ratings, the isotretinoin subjects had more differences after we corrected for whole brain metabolism severe pretreatment acne than the subjects receiving anti- by examining differences in the ratios of regional to whole biotics. However, according to the self-ratings there were no differences in acne on the face or back or in feelings of The mean pretreatment rate of metabolism in the or- depression related to the acne. There were no differences bitofrontal cortex was higher for patients in the isotretinoin between the two groups in behavioral, emotional, and group than for those in the antibiotic group (F=2.05, df=7, functional effects of acne as measured by the Skindex.
107, p=0.03). This was not hypothesized a priori and was There were also no differences in baseline depressive not significant after correction for multiple comparisons.
symptom levels as measured by the Hamilton depression Relationship Between Behavior
and Brain Metabolism
Effects of Isotretinoin on Regional
Five patients treated with isotretinoin had symptoms of Cerebral Metabolism
headache. These patients also had subtle changes in irrita- Administration of isotretinoin but not antibiotic was as- bility and/or mood as assessed by self, family, or the re- sociated with decreased brain metabolism in the orbito- search staff. These subjects all had decreases in brain frontal cortex after 4 months of treatment (Figure 2, Figure metabolism with isotretinoin administration (Figure 2). A 3). This effect was seen for both absolute metabolism (Fig- representative subject is shown in Figure 3. However, ure 2, Table 2) and for the ratio of orbitofrontal to whole these subjects did not show clinically significant depres- BREMNER, FANI, ASHRAF, ET AL.
FIGURE 2. Effects of Isotretinoin and Antibiotics on Orbito-
FIGURE 3. Effects on Re gional Brain Metabolism in a
frontal Cortical Metabolism in Patients Receiving Treat-
Representative Patient Receiving Isotretinoin Treatment
ment for Acnea
for Acnea
Orbitofrontal cortex
Baseline
Posttreatment
a There was a visible decrease in metabolism in the orbitofrontal cor- Glucose Metabolic Rate (mg/min per 100 g)
tex following isotretinoin administration in this patient. This pa- tient suffered from headache, was noted by her family and clini- cian to have disturbed behavior, and dropped out of school. She did not, however, have a clinically significant increase in depression Subjects Treated
Subjects Treated
as measured by the Hamilton depression scale.
With Isotretinoin
With Antibiotics
a Isotretinoin but not antibiotic administration resulted in a signifi- treatment in the isotretinoin group was correlated with a cant decrease in orbitofrontal cortical metabolism (p<0.001,ANOVA). The mean percentage change with treatment within indi- single item of the Skindex at baseline, effect of acne on vidual subjects was –21% for isotretinoin and 2% for antibiotic.
ability to work (r=–0.67, N=9, p=0.03). This correlation wasnot significant after correction for multiple comparisons.
sion as assessed with the Hamilton depression scale (Fig- There was no relationship between “worrying about skin ure 4). One subject in the isotretinoin group and one in the condition” as measured with the Skindex and orbitofron- antibiotic group had a clinically significant increase in de- tal metabolism at baseline or with treatment. There was pression as measured by the Hamilton scale (greater than no correlation between acne-related depression at base- 9-point increase); however, there were no significant in- line and decrease in orbitofrontal cortical metabolism creases in Hamilton depression scores in the groups as a whole and no significant differences between groups.
There was no correlation between age or education and Patients in the isotretinoin group had more severe acne baseline orbitofrontal cortical metabolism or change in as rated by clinician assessment at baseline (F=18.80, df=1, 25, p<0.05), and they had a greater improvement withisotretinoin treatment, as indicated by less severe acne ac- Discussion
cording to the clinician-administered questionnaire after A 4-month treatment trial with isotretinoin was associ- treatment than before treatment, than did patients receiv- ated with a decrease in brain functioning in the orbito- ing antibiotics (F=22.73, df=1, 25, p<0.05). There was also a frontal cortex, a brain region implicated in depression.
greater improvement with isotretinoin in self-reported These changes were not seen after a similar course of acne (F=2.62, df=4, 88, p<0.05). There were no differences treatment with an antibiotic. After correction for differ- in change in feelings of “depression related to acne” be- ences in whole brain metabolism, this effect was specific tween the groups. There was no relationship in either the to the orbitofrontal cortex. The greatest magnitude of de- isotretinoin or antibiotic group between baseline orbito- crease was observed in subjects who developed symptoms frontal cortical metabolism and depression as measured of headache during the course of treatment with isotreti- with the Hamilton scale, self-reported or clinician-assessed noin. Isotretinoin was not associated, however, with any acne severity as measured with the analogue scales, feel- changes in depressive symptom severity as measured with ings of depression related to acne as measured with the analogue scale or the Skindex, effects of acne on work Isotretinoin has a variety of effects on brain neurochem- functioning as measured by the Skindex, or overall psy- ical systems (69–71). Retinoids modulate gene expression chological effects of acne as measured with the Skindex.
in the brain in a broad spectrum and have effects on sev- The decrease in orbitofrontal cortical metabolism with eral neurochemical systems, including the dopamine sys- ISOTRETINOIN AND BRAIN FUNCTIONING
TABLE 2. Regional Brain Metabolic Rates of Patients Before and After Isotretinoin or Antibiotic Treatment for Acne
a Percent change in mean metabolic rate.
FIGURE 4. Effects of Isotretinoin and Antibiotic on Symp-
mesolimbic dopamine functioning (75). Retinoids are as- toms of Depression in Patients Receiving Treatment for
sociated with an inhibition of neurogenesis in the hippo- campus (76), a brain area with connections to prefrontalcortical areas, including the orbitofrontal cortex. Inhibi- tion of neurogenesis in the hippocampus has been hy- pothesized to play a role in depression (77–80). Retinoids also have effects on brain trophic factors (81). These find-ings have led to the hypothesis that retinoids play a role inthe development of psychiatric disorders (69, 82).
A number of limitations of the current study are worthy of mention. This was a pilot study designed to evaluate thepossibility of an effect of isotretinoin on brain functioning.
For this reason the study group was small, which may havecontributed to the fact that we did not observe treatment- Mean (±SD) Score on
related changes in mood as assessed by the behavioral rat- ings in this study. Some patients, however, complained of Hamilton Depression Rating Scale
headache with isotretinoin, and these patients exhibitedgreater decreases in orbitofrontal brain metabolism dur- ing isotretinoin treatment. Because of the costs of isotret- Time of Treatment (months)
inoin we were unable to pay for this medication for all a Depression was measured with the 21-item Hamilton Depression subjects. Therefore, we were unable to randomly assign Rating Scale. There was no significant effect of either isotretinoin or subjects to treatment with isotretinoin or antibiotic and antibiotic on depressive symptom severity.
were unable to control which antibiotic the subjects weretaking. We therefore recruited subjects who were prepar- tem, which has been hypothesized to play a role in dys- ing to undergo a second treatment course with an antibi- regulation of mood and emotion (70). High levels of the otic or to switch to isotretinoin on the basis of a decision enzyme involved in retinoid synthesis, aldehyde dehy- made in conjunction with the subject’s own physician.
drogenase, are found in mesostriatal and mesolimbic This method likely contributed to the fact that the isotret- dopamine pathways (72, 73). Dopamine mesocortical inoin subjects had more severe acne at baseline. The pathways involve release of dopamine transmitter in the isotretinoin group also had less education. We examined a orbitofrontal cortex and other parts of the prefrontal cor- variety of demographic factors, including age, education, tex. Isotretinoin may influence these pathways. Adminis- psychological distress, and self- and clinician assessments tration of retinoids causes changes in dopamine receptors of acne severity, and found no relationships with baseline (74), while genetic mutations of retinoid receptors are as- orbitofrontal metabolism or change in orbitofrontal func- sociated with deficits in dopamine receptors as well as tioning with treatment. An unexpected finding was a pat- BREMNER, FANI, ASHRAF, ET AL.
tern of greater baseline functioning in the orbitofrontal sults of an international survey. Dermatology 1997; 194:351– cortex in the isotretinoin group than in the antibiotic 2. Goulden V, Layton AM, Cunliffe WJ: Current indications for group. One might question whether factors in the isotret- isotretinoin as a treatment for acne vulgaris. Dermatology inoin group, such as increased worrying related to more severe acne, might have contributed to differences in 3. Jick SS, Kremers HM, Vasilakis-Scaramozza C: Isotretinoin use brain functioning. Obsessive-compulsive disorder has and risk of depression: psychotic symptoms, suicide, and at- been associated with higher orbitofrontal metabolism tempted suicide. Arch Dermatol 2000; 136:1231–1236 (83). However, we did not observe any differences in de- 4. Wysowski DK, Pitts M, Beitz J: An analysis of reports of depres- sion and suicide in patients treated with isotretinoin. J Am pression, psychological distress, or even self-rating of acne severity between the two groups before treatment. We also 5. Byrne A, Costello M, Greene E, Zibin T: Isotretinoin therapy and did not find a correlation between orbitofrontal metabo- depression: evidence for an association. Irish J Psychosomatic lism at baseline or change with treatment and the item re- lated to “worrying about skin condition” on the Skindex.
6. Bremner JD: Does isotretinoin cause depression and suicide? Antibiotics act by inhibiting bacterial protein synthesis.
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