Case # 1: (9/16/11):  46 y.o.  single male with Bipolar I Disorder who was successfully treated with left  dlPFC excitatory  treatment.    He had been treated for 10 years by one author (-RDM).   He was in a severe TRD (treatment resistant depression) for 6 months, and could not work   He on :    Divalproate 1500 lithium 600 bid  bupropion  75 fish oil 6   multivitamin     vitamin D3: 50,000/ wk    L-methylfolate/5-MTHF  15mg            carbamazepine  100

            History: His first episode was a mania at 21 y.o.,  for which he was hospitalized.  Subsequently he was maintained on mood stabilizers but had several mixed states or major depressions for which he had to take time off work.  He also had many minor episodes of mania, depression and mixed states over the years and had never been completely euthymic. Episodes involved intense anger, suicidal ideation, and breaking things.

He was treated on the L dlPFC  with 10 hz for 4 seconds, 5000P, 100% MT.             Initially his MADRS was  36   and  HAM-D-21 was  24After treatment 10 treatments her scores were:   MADRS:  2    HAM-D-21: 1   He had a setback after #18, and plummeted to  MADRS  23 briefly.    He  received a total of  30 Tx’s, at which time his MADRS was 0.

             In the 4 and ½ years since the initial TMS, he had two relapses of moderate depression.

#1:  The first was a moderate depression after one year.  He received 3 treatments and was in remission.

#2:  2½  year later, 3½ year after the initial TMS, he had  another moderate depression, and received a different form of TMS:  4 treatments in 4 days of deep TMS,  using a Brainsway H1 helmet  18 hz for 2 sec, interval 20 sec,  1980 pulses  at 120% MT.   For the first time, TMS cycled him, putting him into a few days of each of the following:  a mixed state, euthymia, a severe depression, and then he gradually returned to euthymia, where he remained.

Four and one third years after the initial TMS, he says it has completely changed his mood disorder—and his life.  He is on the least medication he was ever on:  Depakote 1500mg,   fish oil 4 to 6 grams/day,  and   vitamin D3  50,000 I.U. /week.  “I am able to get through the lows on my own.   I have had no deep depressions where I cannot even get up to get the controller for the TV.” He occasionally has a moderate depression for a day or so, “and then I wake the next day not depressed.”   He typically is euthymic at work during the day, and maybe feels he a little depressed some evenings– “but I may mistake tiredness for depression”.  He does hard physical work.  He is euthymic on weekends.

His psychiatrist of fifteen years has witnessed the dramatic change.  For the 11 years prior to TMS, he was one of those patients one worried about.  There were frequent psychopharmacology visits, frequent phone calls, various crises, and a few times when had had to stop work for a period.   Since the initial TMS the only psychopharmacology visits were when he had touchup TMS treatments.

 

Case # 2:

A 22 y.o. single woman, who I had treated since she was 16 y.o., with the following problems:

  rapid cycling  Bipolar II disorder–mainly depression, severely impairing her ability to study in high school and college.  She would have a few days of euthymia here and there, but never functioned well.    The onset of the mood disorder  was at about 10 y.o.

  Panic Disorder, moderate,  with moderate agoraphobia;  severe anxiety started at 13 y.o.

  PMDD (Premenstrual Dysphoric Disorder)  for 7-9 days/month, relatively severe

 Attention Deficit Disorder

She was headed for a lifetime of dysfunction  as a chronic mental patient, struggling to control mood and anxiety.   She felt like a “loser”.  She could not concentrate or think clearly enough  to study.  Stimulants for her ADD aggravated her bipolar disorder, so we had to avoid them.  She could only take minimal clonazepam for her Panic Disorder because it sedated too much.   She had difficulty holding even a part time job.

She made her first and only suicide attempt in October, 2011.    It happened that in the first 2 weeks of February, 2012, she was approximately euthymic—or at least as good as she gets.  Even when apparently euthymic, she did not function well.  Over the next 2 weeks, with no apparent precipitant, she gradually went into a severe mixed state,   associated with an increase in exercising and not going to sleep until 2-4AM.  At the end of Feb she was severely depressed during the day and manicky late at night.  There was also some brief manicky/ mixed state periods during the day.   During the month of March she was steadily in severe major depression with no mania and no mixed states.  She was cycling only slightly between different degrees of depression.  There was significant  passive suicidal ideation.  She was extremely demoralized by the unremitting depression.    There was no immediate risk of suicide, but the long term risk seemed high.     At the beginning of  a visit, in March, 2012,  she stood up sideways (she is taller than I), looked me in the eye, and said,  “Dr McMullen.  I am 22 y.o. and I have not finished a single college course.  How will I ever find a husband?  How will I ever have a career?”

At this point she was taking  carbamazepine  500mg HS lamotrigine 300mg   Lithium 300mg  HS  gabapentin 800AM & 1600 HS   methylphenidate SR 40mg q AM  levothyroxine 400mcg ,  Vitamin D3 50,000 I.U. per week  lorazepam 3 mg HS

Over a 6 year period, she  had been tried on many medication and nutritional cocktails with only partial benefit.

The first treatment was right DLPFC (dorsolateral prefrontal cortex)   2000 P at 1hz at 80% , followed by  left DLPFC 3000 P at 10hz  at 120% MT.  She immediately began cycling a few times per day and was in an unpleasant hypomania the next day.

We assumed that the left excitatory treatment was cycling her.    So for the 2nd and 3rd  treatments

[on the 2nd and 3rd days],  we changed to unilateral right dlPFC 4000 P 1hz at 90% MT.  Then she began to experience 3-4 days of severe depression, extreme anxiety, and, finally, passive suicidal ideation.

Because of this relapse of depression, at treatment  #4 (on the 7th day), we resumed bilateral treatment for 5 treatments.

She began feeling manicky for several days while on bilateral treatment, so at treatment #9 (on the 14th day),  we switched back to right unilateral inhibitory treatment and stayed there.  All of the subsequent  20 treatments remained the same:   unilateral dlPFC 4000 P,  1 hz, at 100% of MT.

She improved rapidly, reaching euthymia in a month, after 20 treatments. From my notes:

“MSE : amazingly normal;  she smiles easily, is not hyper-emotional.  She is very afraid of stopping the TMS as it has worked so well.   I have never seen her this normal, especially for several days in a row. ” Over the next 3 weeks we did 8 more treatments.

Three weeks after the last (28th ) treatment, she had a relapse of mild depression for two days, which remitted spontaneously.

Nine months after the last TMS treatment, she had 3 to 4 weeks of building anxiety, which culminated in a panic attack.  Since she also had racing thoughts,  she felt she was entering a high, but it soon resolved with no additional TMS.

Her change in scores  for before and after TMS was dramatic:  CGI  5 → 1  [markedly ill →  normal]   MADRS: 34 → 2   PHQ-9:  20 → 4.

Her medication at the end of treatment was:

After TMS, her medication was approximately the same:  carbamazepine 600mg  HS Lamictal 200mg HS                     Lithium 300mg  HS                            levothyroxine  400 mcg lorazepam 3mg HS                           vitamin  D3  50,000 I.U./week.

gabapentin 1600mg HS: the 800mg morning dose was stopped as her anxiety diminished

methylphenidate  0 –she stopped this because it destabilizes her

In the first year after TMS, she says she had a lot of anxiety and worry (but not the anxiety associated with panic attacks) concerning  #1: could  actually study, and #2: would she relapse?   She decided to become a nurse.  In the 2nd year the anxiety dissipated.  Her PMDD  had become attenuated and lasted only 2 days instead of 5 to 7.  She discovered the lectures at the NY Academy of Medicine, which aroused wider interests in science and medicine. She began taking calculus, physics and advanced biology.   She has now finished 3½ years of college, with mostly A’s,  and will soon be going to medical school.   I cannot express the astonishment and gratitude both of us have had over her recovery.   In 35 years of practice, I cannot remember a more dramatic remission—or a more durable remission.

6/3/2016:  She transferred to Cornell in the fall of 2015, as she wanted a more competitive school.  She will graduate in 2017 and then will go to medical school in September of 2017.

 

Case # 3:  18 y.o. male   His problems with depression and anxiety were so severe, that he was in a special school, despite a high IQ.

  • Bipolar II Disorder, onset of depression at 10 y.o. , with rapid cycling for the last four   years, primarily manifested by treatment resistant depression
  • Panic Disorder, severe.  severe anxiety started at 10 y.o.  Free floating anxiety was virtually continuous.
  • OCD, mild, since 5 y.o. The OCD was more severe when younger.

With the Neurostar machine [from Neuronetics] he received  47 TMS bilateral treatments.    2000 R 1hz at 100% MT, followed by 3000 L  10 hz at 100% MT

His MADRS decreased from 32 to 8;  21-item-Ham-D decreased from  31 to 7.   CGI went from 6 to 4.  The rapid cycling ceased.   Despite the dramatic remission of his depression and his rapid cycling,   his anxiety did not improve.   Hix  anxiety symptoms put his depression scores just into the depressed range, but he felt completely euthymic. .

2nd course of TMS:   He had a relapse of moderate depression a year later, but not a recurrence of the rapid cycling. He remained far better than he had been prior to TMS.  He received  8 touch up TMS treatments  with partial benefit.

 

Case # 4:      60 y.o. Bipolar I male, who received this diagnosis when he was hospitalized at 21 y.o. for a manic episode.  Thereafter he was frequently rapid cycling.   In his 30’s the cycling became intransigent.  He alternated between a few weeks of mild mania and a few weeks of moderately severe depression for years.    This cycling  resolved when he was kept on high dose lithium for 18 months.   Thereafter, despite some residual cycling, he was kept relatively comfortable primarily with lithium, carbamazepine, lamotrigine, and Seroquel/ quetiepine.

From from 50 to 52 y.o., he was  almost continually in severe depression.  He was  then hospitalized and received 8 ECT treatments.   The ECT seemed to “reboot” his system.  He returned, for the next eight years,  to relatively mild cycling between depression and hypomania,  controlled primarily by lamotrigine, divalproate, lithium and aripiprazole.

His depressions became very  severe again at 60 years old and he accepted TMS.

He was treated with a figure 8 coil –the B60 coil with the Magpro X100 machine from Magventure.  Midway through his treatments he was changed to the B80 coil, with no change in apparent efficacy.    Initially he was treated with 2000 P 1hz on right dlPFC at 90% of MT.   Overtime he was gradually increased to 120% of MT.  

The first 13 treatments over a 9 month period rapidly brought him to euthymia:

1/23/13:   TMS #1    60 y.o.   #1 TMS treatment  R 2000 at 90%→ mild hypomania for a few days, then euthymic.    His  MADRS  went from 30 to  0  with that single treatment.

Relapse after 2 months → TMS x 2:  MADRS 38 → 0

Relapse at 5 months → TMS x 3  MADRS 15 → 0

Relapse at 6 months (7/10/13):  TMS x 4 MADRS 14 → 0

Relapse at 9 months  TMS x3

ver the following 2 year period he had 16 treatments.   Every 1-2 months, when he was in a severe depression, or slipping into depression, he had 1 or 2 treatments, which brought him out of depression in a few days—sometimes in only one day.

 

Case # 5: 44 y.o. man  with Bipolar II Disorder.   Bipolar II Disorder  successfully treated with 37  R inhibitory treatment. He relapsed in 2 months later.  and needed a  2nd course of TMS with 36 treatments over 3 months.    He stayed in remission for one year.   Then he began having little relapses and subsequently received  71 TMS maintenance treatments over a one year period, and remained in remission for at least 8 months.    Twice excitatory left treatment was briefly tried, but agitated him.

He presented in a major depression, which had aspects of a mixed state.  He received  Neurostar R 1hz at 80%MT 4000 P. For treatments #18 through #22, he received bilateral treatment:   3000 left 120% MT  10 hz and right 2000 1hz at 90% MT.  He became manicky, irritable and started drinking alcohol. WE change back to unilateral R  4000 P at 90% MT . After 37 treatments  the MADRS was 7 and PHQ-9 was 2.

Two and half months later,  he relapsed and had a 2nd course of TMS, receiving 26 treatments in 3 months.

Ten months after the initial TMS we began to do maintenance treatment—71 treatments over a one year period,.  He seemed to remain in depression because of strong feelings of hopelessness and helplessness:  he was unemployed, with no job prospects, and his family was having severe economic problems. He had an intermittent diathesis to severe depression with suicidal ideation.  Since a treatment or two of TMS helped significantly, we did the treatments as needed.   During this time he received excitatory treatment for two treatments on the left dlPFC with iTBS (intermittent theta burst stimulation) as well as his usual right inhibitory treatment.   He became agitated and the iTBS was stopped.

He remained in mild, not severe depressed over the 8 months  after the maintenance treatment was stopped.

#6       43 y.o. woman with Bipolar I Disorder  who had been in a severe major depression for over 6 years, wherein she stayed in bed most if the time and rarely left the house.   Prior to the depression  she apparently had had a long non-psychotic, relatively mild mania.  She receceived 243 TMS treatments  over 24 months.  Steady depression gradually changed to cycling between depression and euthymia, with the period of euthymia finally becoming permanent.   Early in the treatment left excitatory treatment caused a severe mixed state.   Later, when on adequate mood stabilizers, bilateral treatment was resumed without incident. 

Treatments started with inhibitory treatment to the right dlPFC.     She received cTBS (continuous theta burst stimulation)  on two spots –F4 and the 6 cm anterior to the hotspot, since these spots were over 2cm apart.  For treatments #8 to #10 she received bilateral with excitatory iTBS (intermittent theta burst stimulation) on the left dlPFC at F3.    This caused a severe mixed state, which lasted almost a week.  The patient made a long angry phone call to the physician.  She had pressured speech and would not let him speak.

She began to have an occasional day or two here and there of mild depression instead of severe depression.  She was rapid cycling.

At treatment  #36 excitatory iTBS treatment was added to the left dlPFC  because

#1: her severe depression seemed so intractable and she had been continuously weeping for a week,  and #2: now she was on a significant amount  of mood stabilizers, so that perhaps it would not drive her into a mixed state.   She was on: asenapine 10mg  ↓   divalproate 1000mg      lamotrigine  200mg   lithium 900mg   (1&2)  amphetamine salts 20mg tid     folic acid 1mg   fish oil 3 grams.

The next day she was vastly better, and from then on we did left iTBS and RcTBS at the two spots, all at 80% MT.      Because it was such a desperate situation, for ten treatments, we repeated the treatment after ½ hour [and counted it as one treatment per day].

At treatment #63, we changed back to right cTBS at 90% MT at two spots, and repeated the treatment after one hour.

It was discovered that the patient had significant symptoms of OCD, so at treatment #162 we added cTBS  at 80% MT at the OCD spot and changed the right inhibitory treatment to 2000 pulses 1hz at 120% MT..

She she was gradually have longer periods of euthymia and shorter periods of depression, and the treatments became less frequent, based on her schedule and how depressed she was.

At treatment #243, after two years of treatment, her MADRS was 4, whereas initially it was 44.    TMS was stopped and she remained completely euthymic for 7 months.

Then she had a relapse, because of significant medication changes.

 

#7      25 y.o. single male with severe Bipolar I Disorder.  He was treated with R inhibitory treatment while euthymic, to try to prevent future manias. There were  no adverse reactions.

            He had had 3 manic episodes, with psychosis.   The last two were very prolonged (each was over 2 years) and difficult to control.  He has never experienced  more than mild depression.

              He was treated while euthymic, at the family’s request, on the chance the TMS would be prophylactic against his manic diathesis. He received #30 TMS  Right inhibitory treatments.  Each was repeated after 1 hours, so one could argue he had 60 treatments.   He had

R cTBS at 100% MT,  followed an hour later by R 2000  120% MT.  There was no negative effect. It is not clear it helped.  He remains euthymic and stable 2 years after TMS.

 

#8  :  63 y.o. woman with Bipolar II Disorder.  She had been cycling between major depression and dysthymia for 23 years (She said, “I realize I have lost 23 years of my life” when she became euthymic.  She was after  seven L 5000 10 hz treatment.  She received a total of 21 treatments.   MADRS 48 → 0; 21-item-Ham-D: 30.5 → 0;  PHQ-9: 19 → 1

Two months later she had a severe relapse and became euthymic with 4 bilateral treatments. Over the next 4 years, she had 6 treatments for brief relapses [usually 1-2 per episodes ].  She also received 2 treatments as prophylaxis when she made a psychopharmacology visit.  In total she has had 30 treatments over 4.5 years.    Her touch-up treatments were right inhibitory because concern about her bipolarity:  right dlPFC 2000 P 120% MT

 


Case #9:  58 y.o. male senior engineer with Bipolar I Disorder

#1:  Phenomenologically, he seemed bipolar spectrum.  He had suffered lifelong depression associated with significant anxiety.  Despite excellent psychiatric care he had never been euthymic.

#2:  On at least two occasions, 20 years prior to TMS and two years prior to TMS, he had periods of psychotic paranoia, which seem to have been manic equivalents. 

Summary:  He became euthymic after 30 treatments in the first 6 weeks.   2½ months later be began having  sudden little relapses and had 20 additional treatments over the next 9 months.   After that he stayed euthymic for 3 years and 5 months.  Then he relapsed, and 53 treatments in 9 months have had minimal benefit.

This married 58 y.o. senior businessman suffered from lifelong depression with significant associated anxiety and obsessive compulsive symptoms.   He had done reasonably well for some 20 years on Parnate, though he was never euthymic.

Two years prior to TMS n early 2008 he had a few weeks of  his second episode of psychotic paranoia..  Thereafter, his depression gradually worsened, until he was in a severe agitated depression.   He was filled with irrational guilt, unable to function at work, and was in danger of losing his job.  He called his psychiatrist several times a day.  He had a delusion that he had not learned anything in 5 years and that he could not learn the new computer system.  He was so severely depressed that he could not function, so there was an element of truth to this.

His psychopharmacologist stopped Parnate, tried other medications, and then rechallenged him with Parnate—with no benefit.  Then the first author [-RDM] spent 1½ years trying medication combinations in high doses with virtually no benefit.  He had a dramatic partial response for a few months when inositol was added, but lost the benefit.   He was so dysfunctional, it was surprising he was not  yet fired.  He was shaking all over.  He often called the doctor in the morning as he was too frightened to enter his office building.  When he did go in, he locked himself in his office and did nothing.

In 6 weeks, we did 30 TMS treatments: left 10 hz 3000P at 120% MT .  His 21-item-Ham-D  dramatically went from 45 to 4. His PHQ-9 went from 24 to 2.  His GAD went from 6 to 1.    He became a cheerful and animated, and  was more competent at work than he had ever been.  In retrospect he had  never  been euthymic prior to TMS.  Medication had brought him close to normal, but he had always been excessively anxious and depressed.  He did not have major depressions in his  20’s,  but he was continuously very anxious, and at minimum dysthymic.

2.5 months after treatment #30, he began having little relapses.   For the next 9 months, he had another 20 treatments (1 to 3 treatments here and there) as he began to sink into moderate depression.   He was euthymic at the last 2 treatments, which were a month apart and the beginning of our prophylaxis plan of doing one treatment per month.  A month after treatment #50, he slipped to MADRS 18.   His TSH was 4.95.  I elected not to give him TMS.  T3 (liothyronine)  25mcg was added and the depression quickly remitted.

Other than that small relapse, after treatment #50, he remained completely euthymic for 3 years and 5 months.   He became very involved with his synagogue, acquired many friends, and did  extremely well at work.  His family, who had been inured to an anxious, depressed, and obsessive compulsive man, was astonished at the transformation.

He remained euthymic for 3 years and 5 months.  Then he slowly entered a moderate to severe depression (MADRS 18 to 43).  Despite an additional 53 treatments over 10 months, we could not give him significant benefit. Several different parameters were tried.   Our conclusion was that he needed to have the treatments  4 to 5 days  per week, as he had had in the first course.  But he could not arrange this with his job.

Addendum re tremor:  Interestingly,  prior to TMS, he had such severe tremor and shaking that he could not hold a cup of water when I gave it to him—it flew out of his hand.  It was a nightmare for him to say kaddish, especially when he married off a son. With TMS, his shaking stopped and the tremor became minimal!! — though he was on the same medication.   Prior to TMS I had thought his tremor was largely secondary to medication, but apparently it was part of his agitated depression

 

 

Discussion:

In this case series TMS was effective and safe for successful treatment of bipolar depression.

With regard to stimulation parameters used, the choice of low-frequency rTMS was motivated by theoretical reasons such as a lower risk of accidental seizure [9] and a better tolerability [10]. In terms of stimulation site, besides positive results reported with right DLPFC stimulation in major depressives [10], [11], some neurophysiological and imaging studies have pointed out a contrasting role in mood regulation between right and left hemispheres [12], [13]. Thus, it has been hypothesized that right DLPFC stimulation at low frequency may produce the same antidepressant effect as left DLPFC stimulation at high frequency [10].

Limitations:

Firstly, we included both Bipolar I and Bipolar II subjects, although they are clearly different clinically. Secondly, There is also the issue of medications. Although if our patients had been medication-free this report would have been stronger scientifically, but we felt this was ethically unwise given the potential for inducing manias with TMS, and the clear cases of treatment refractoriness following discontinuation of mood stabilizers[14]. We thus compromised by allowing continuation of mood stabilizers and anti-depressant medications. Third, the point of stimulation i.e DLPFC is usually determined by identifying the optimal site on the primary motor cortex for the stimulation of the contralateral peripheral hand muscle, and from there the coil is placed 5 cm forward. However, this empirical method for locating the DLPFC seems to be anatomically imprecise and may be improved by navigating procedures taking individual anatomy into account [15]. Fourth, treatment intensity was not same in all the patients. We adjusted the treatment intensity according to the patient’s convenience. This might have led to a varied interpretation of treatment response obtained from different patients.

 

 

 

 

 


References:

[1]      F. K. Goodwin and R. K. Jamison, “Pathophysiology, in Manic-Depressive Illness,” Second., F. K. Goodwin and R. K. Jamison, Eds. London, UK: Oxford University Press, 2007, pp. 411–698.

[2]      G. S. Sachs, J. M. Dupuy, and C. W. Wittmann, “The pharmacologic treatment of bipolar disorder.,” J. Clin. Psychiatry, vol. 72, no. 5, pp. 704–15, May 2011.

[3]      K. R. Chengappa and P. Williams, “Barriers to the effective management of bipolar disorder: a survey of psychiatrists based in the UK and USA.,” Bipolar Disord., vol. 7 Suppl 1, pp. 38–42, Jan. 2005.

[4]      L. L. Judd, H. S. Akiskal, P. J. Schettler, W. Coryell, J. Endicott, J. D. Maser, D. A. Solomon, A. C. Leon, and M. B. Keller, “A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder.,” Arch. Gen. Psychiatry, vol. 60, no. 3, pp. 261–9, Mar. 2003.

[5]      D. R. Kim, A. Pesiridou, and J. P. O’Reardon, “Transcranial magnetic stimulation in the treatment of psychiatric disorders.,” Curr. Psychiatry Rep., vol. 11, no. 6, pp. 447–52, Dec. 2009.

[6]      G. Saba, J. F. Rocamora, K. Kalalou, R. Benadhira, M. Plaze, H. Lipski, and D. Januel, “Repetitive transcranial magnetic stimulation as an add-on therapy in the treatment of mania: a case series of eight patients.,” Psychiatry Res., vol. 128, no. 2, pp. 199–202, Sep. 2004.

[7]      S. K. Praharaj, D. Ram, and M. Arora, “Efficacy of high frequency (rapid) suprathreshold repetitive transcranial magnetic stimulation of right prefrontal cortex in bipolar mania: a randomized sham controlled study.,” J. Affect. Disord., vol. 117, no. 3, pp. 146–50, Oct. 2009.

[8]      K. N. Fountoulakis, H. Grunze, P. Panagiotidis, and G. Kaprinis, “Treatment of bipolar depression: an update.,” J. Affect. Disord., vol. 109, no. 1–2, pp. 21–34, Jul. 2008.

[9]      E. M. Wassermann, “Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996.,” Electroencephalogr. Clin. Neurophysiol., vol. 108, no. 1, pp. 1–16, Jan. 1998.

[10]    C. K. Loo and P. B. Mitchell, “A review of the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy.,” J. Affect. Disord., vol. 88, no. 3, pp. 255–67, Nov. 2005.

[11]    R. L. Tamas, D. Menkes, and R. S. El-Mallakh, “Stimulating research: a prospective, randomized, double-blind, sham-controlled study of slow transcranial magnetic stimulation in depressed bipolar patients.,” J. Neuropsychiatry Clin. Neurosci., vol. 19, no. 2, pp. 198–9, Jan. 2007.

[12]    E. K. Silberman and H. Weingartner, “Hemispheric lateralization of functions related to emotion.,” Brain Cogn., vol. 5, no. 3, pp. 322–53, Jul. 1986.

[13]    R. J. Davidson and K. Hugdahl, Brain Asymmetry. The MIT Press.

[14]    M. Maj, R. Pirozzi, and L. Magliano, “Nonresponse to reinstituted lithium prophylaxis in previously responsive bipolar patients: prevalence and predictors.,” Am. J. Psychiatry, vol. 152, no. 12, pp. 1810–1, Dec. 1995.

[15]    U. Herwig, F. Padberg, J. Unger, M. Spitzer, and C. Schönfeldt-Lecuona, “Transcranial magnetic stimulation in therapy studies: examination of the reliability of ‘standard’ coil positioning by neuronavigation.,” Biol. Psychiatry, vol. 50, no. 1, pp. 58–61, Jul. 2001.

 

 

 

Bipolar disorders are frequently associated with pharmacotherapy resistant depression

Bipolar disorder is an episodic illness that affects 1.0%–1.8% of the population (Goodwin et al 2007) Challenges to its management include the limited number of pharmacologic and psychosocial interventions supported by evidence for both short-and long-term efficacy, and limitations to individual tolerance and adherence, and potential emergent mania. Repetitive transcranial magnetic stimulation (rTMS) has been widely tested and shown to be effective for unipolar depression. Although it has also been investigated for bipolar depression (BD), there is only a small number of rTMS studies in BD, with mixed results (Fountoulakis et al., 2008) data on the safety and efficacy of TMS in bipolar disorder are preliminary but intriguing

We evaluated the effectiveness of rTMS as a treatment tool for bipolar depression.

Mean age of patient was 64 years and most were female (n=5). The majority (5 out of 6) were diagnosed with major depressive disorder (MDD). Reasons for transition from ECT to TMS were in order of frequency: cognitive side effects, fear of general anesthesia, time burden, lack of remission with ECT, and stigma associated with ECT. The mean frequency of TMS sessions was 1 every 3.5 weeks. Based on BDI scores, all patients maintained or improved their clinical status achieved with ECT at 3 and 6 months of TMS treatment. At last observation (Range: 7 to 23 months) 4 patients maintained or improved their clinical status (total BDI score remained constant or decreased by 1–8 points). Two patients relapsed after 8 and 9 months. Stimulation was well tolerated with side effects limited to headache and scalp discomfort.

Introduction:

Bipolar disorder is an episodic illness that affects 1.0%–1.8% of the population (Goodwin et al 2007) Challenges to its management include the limited number of pharmacologic and psychosocial interventions supported by evidence for both short-and long-term efficacy, and limitations to individual tolerance and adherence, and potential emergent mania. Repetitive transcranial magnetic stimulation (rTMS) has been widely tested and shown to be effective for unipolar depression. Although it has also been investigated for bipolar depression (BD), there is only a small number of rTMS studies in BD, with mixed results (Fountoulakis et al., 2008) data on the safety and efficacy of TMS in bipolar disorder are preliminary but intriguing

It has been hypothesized that TMS could be effective in bipolar depression by stimulating the left prefrontal cortex or inhibiting the right prefrontal cortex.

 

 

In this study, we considered the number of rTMS sessions as the outcome as clinicians define the number of sessions based on patient’s response. Therefore, an important question is to understand the factors associated with the need of longer rTMS treatment in remitted patients.(Cohen et al 2010)

In this context, it is critical to have additional knowledge on the optimal parameters of rTMS to design such studies.

the efficacy of TMS as an augmenting treatment during the acute and maintenance treatment of bipolar depression

 

 

 

Characteristic 1 (PH) 2 3 4 5 6
Gender Male          
Age 36 yo          
Disease duration            
Diagnosis BP I          
Baseline MADRS            
Post rTMS MADRS            
Total # of sessions            
Medication Depakote, Wellbutrin, Lithium          
             
             

 

Fitzgerald et al., 2003; Fitzgerald et al., 2006;  Fitzgerald, Hoy, Daskalakis & Kulkarni, 2009; Isenberg et al., 2005; Fitzgerald et al., 2009; . Schutter (2010)

 

 

 

 

 

 

In the largest controlled study on LF-rTMS in depression, 130 patients were initially assigned to a stimulation protocol of either 1 or 2 Hz  (Fitzgerald et al., 2006). Of the 130 patients enrolled, approximately 51% could be classified as responders after 10 days of treatment. Interestingly the response rates between the 1 Hz and 2 Hz did not significantly differ. Although LF-rTMS is a more recently developed protocol and is less well studied, it appears to have beneficial effects comparable to HF-rTMS.

 

In order to systematically investigate if HF or LF-rTMS is more beneficial, protocols were directly compared (Fitzgerald et al., 2003; Fitzgerald, Hoy, Daskalakis & Kulkarni, 2009; Isenberg et al., 2005). In a double-blind, randomized, sham-controlled study, 60 treatment resistant patients were divided into three groups; one received HF-rTMS trains to the left prefrontal cortex at 10 Hz, the second group received five LF-rTMS trains at 1 Hz to the right prefrontal cortex and the third group received sham treatment. The clinical results showed that the groups treated with HF-rTMS and LF-rTMS had a similar reduction in depressive symptoms, and for both groups, treatment response was better than within the sham group  (Fitzgerald et al., 2003). In another study with a similar aim, 27 subjects were assigned to either HF-rTMS (10Hz) or LF-rTMS (1Hz) rTMS. It was concluded that both treatment modalities appeared to be equally efficacious (Fitzgerald et al., 2009). Schutter (2010), based on a meta-analysis of all randomized controlled LF-rTMS studies in depression, suggested that LF-rTMS might even be more beneficial than HF-rTMS. However, direct comparisons of the effect sizes of HF and LF-rTMS did not show a statistically significant difference. More research with larger samples is required to confirm these findings and demonstrate if LF-rTMS and HF-rTMS are similarly efficacious, or if LF-rTMS is more efficacious than HF-rTMS. Aside from the comparison of clinical effects, it appears that LF-rTMS is better tolerated i.e. patients reported less headaches. It may also minimize the risk of inducing adverse events like seizures (Schutter, 2010).

 

Although the vast majority of studies have focused on low frequency stimulation applied to the right and high frequency stimulation applied to the left prefrontal cortex, it is to be noted that in a few studies parameters have varied from these traditional sites. Some have suggested that low frequency stimulation applied to the left may also have antidepressant effects, thus questioning the traditional model of laterality in depression.