8.5.1 Abnormal Brain Waves Produ ed Routine LithiumTherapy . . . . . . . . . . . . . . . . . . . . . . 3138.5.2 Lithium Disruption of the CompromisedBrain . . . . . . . . . . . . . . . . . . . . . . . . 3138.6 Brain Damage As Treatment . . . . . . . . . . . . . . . 3148.6.1 General Toxi ity to Neurons and Other Cells . . 3148.6.2 The \Prote tive" and Therapeuti E�e ts of Poi-soning Brain Cells . . . . . . . . . . . . . . . . 3168.7 The Relative Ine�e tiveness of Lithium in A ute Mania 3198.8 E�e tiveness of Lithium . . . . . . . . . . . . . . . . . 3208.9 Mania and Depression As LithiumWithdrawal Rea tions . . . . . . . . . . . . . . . . . . . 3218.10 Adverse Rea tions to Lithium Withdrawal . . . . . . . . 3228.11 Lithium in Your Drinking Water . . . . . . . . . . . . 3238.12 Other So-Called Mood Stabilizers . . . . . . . . . . . . 3238.13 Why So Many \Bipolar" Patients? . . . . . . . . . . . 3268.14 Con lusion . . . . . . . . . . . . . . . . . . . . . . . . . 327

ii

Brain-Disabling Treatments in Psy hiatry

8 - Lithium and Other Drugs for Bipolar Disorder

Drugs, Ele trosho k, and thePsy hopharma euti al Complex

Se ond Edition, 2008

Peter R. Breggin, MD

Contents8 Drugs for Bipolar Disorder 2958.1 Claims of Lithium Spe i� ity for Mania . . . . . . . . . 2958.2 Brain-Disabling E�e ts . . . . . . . . . . . . . . . . . . 2968.2.1 Subduing E�e ts on Animals . . . . . . . . . . . 2968.2.2 Subduing E�e ts on Normal Infants . . . . . . . 2988.2.3 Disabling E�e ts on Normal Volunteers . . . . . 2998.2.4 Turning Down the Dial of Life . . . . . . . . . . 3058.2.5 Crushing Creativity . . . . . . . . . . . . . . . . 3078.2.6 Cade Supports the Brain-Disabling Hypothesis . 3088.3 Spellbinding and Iatrogeni Helplessness and Denial . . 3098.4 Toxi ity to the Central Nervous System . . . . . . . . . 3108.4.1 The Produ tion of Cognitive De� its . . . . . . 3108.4.2 A ute Organi Brain Syndromes . . . . . . . . . 3118.4.3 SILENT: Irreversible Lithium-Indu ed Neurotox-i ity . . . . . . . . . . . . . . . . . . . . . . . . 3118.5 Neurotoxi E�e ts in Low-Dosage . . . . . . . . . . . . 312i

298 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERliterature will on�rm that their primary e�e t is the rushing of spon-taneity with a loss interest in autonomously generated, imaginative, reative, and so ial a tivities.Lithium is toxi in rats at the same serum on entrations as inhumans (S hou, 1976 [83℄). In a rat study by Smith and Smith (1973)[94℄, lithium 'as administered in the low therapeuti range for a periodof only 1 week. The authors summarized, \The most onsistent e�e tof lithium was to de rease the voluntary a tivity of the rats."The onsistent �nding of generalized behavioral suppression in an-imals undermines the laim that lithium is a spe i� magi bullet formania. Suppression of voluntary or spontaneous a tivity is perhapsthe lost on ise des ription of the primary impa t of all brain-disablingtherapies on animals and humans alike.

8.2.2 Subduing E�e ts on Normal InfantsIf a drug subdues the human fetus or infant, it is likely that its ef-fe t is not spe i� for a parti ular psy hiatri disorder. Lithium freely rosses the pla ental barrier in utero and an be passed through breastmilk (An3nth, 1978). The e�e ts of lithium in produ ing lethargyand hypotonia (loss of mus le fun tion) in babies at relatively low serum levels has been thoroughly do umented (Rane et al., 1978 [77℄;Strothers et al., 1973 [97℄). Hollister (1976) [41℄ noted that lithium auses \lethargy, yanosis, poor su k and Moro re exes". Lethargyin an infant des ribes the primary brain-disabling e�e t. As in ani-mal studies, lini al reports on erning newborn and nursing babiesdemonstrate that lithium suppresses, and even disables, the entralnervous system.

Chapter 8

Lithium and Other Drugs forBipolar Disorder

Lithium for the treatment of mani episodes or bipolar disorder wasoriginally promoted to the publi and to the mental health profes-sion as the ultimate example of a spe i� bio hemi al treatment fora spe i� psy hiatri disorder. To bolster this laim, it was said thatlithium la ks any brain-disabling e�e ts on either patients or normalvolunteers. This view lithium dire tly hallenges the on ept of med-i ation spellbinding and brain-disabling prin iple of psy hiatri treat-ment. Although a number of new drugs have now been added to themood stabilizer armamentarium, lithium remains the prototype.

8.1 Claims of Lithium Spe i� ity for ManiaIn 1970, a booklet published by the National Institute of MentalHealth (NIMH) [71℄ and intended for publi onsumption laimed thatlithium produ es \no unwanted e�e ts on mood and behavior" and\only the symptoms are lea hed out while the rest of the personal-295

296 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERity remains una�e ted". e NIMH report on ludes that \the drug isunique among psy hopharma euti als in that it rarely produ e anyundesirable e�e ts on emotional d intelle tual fun tioning". It allsthe substan e \the �rst spe i� hemi al treatment for a mental dis-ease".Five years later, the Ameri an Psy hiatri Asso iation (APA, 1975)[5℄ published \The Current Status of Lithium Therapy: Report of theAPA Task For e." Without iting eviden e, the authors stated, \Thetask for e has on luded that lithium is a more spe i� anti-mani agent than neurolepti s and that its therapeuti results are a hieved ina unique pharma ologi e�e t rather than nonspe i� alming a tion."Ronald Fieve be ame one of the leading advo ates of lithium. Inhis book Moodswing (1989) [29℄, he stated, \I have not found an-other treatment in psy hiatry that works so qui kly, so spe i� ally,and so permanently as lithium for re urrent mani and depressivemood states" (p. 4). He des ribes this extraordinary therapeuti ef-fe t as o urring with no dis ernible adverse e�e ts. The eviden e willreveal that instead that lithium is neither qui k nor spe i� nor per-manent in its impa t. Nor is lithium relatively free of adverse e�e ts.It is one of the more dea tivating, disabling drugs in the psy hiatri armamentarium.8.2 Brain-Disabling E�e ts on Animals, Infants,Patients, and Volunteers8.2.1 Subduing E�e ts on AnimalsCade (1949) [16℄ dis overed the potential therapeuti value of lithiuma identally while experimenting with guinea pigs and immediatelyde ided to try administering it to human beings. In his own words,

8.2. BRAIN-DISABLING EFFECTS 297here is the dedu tive leap he made:\A noteworthy result was that after a latent period of abouttwo hours the animals, although fully ons ious, be ame ex-tremely lethargi and unresponsive to stimuli for one to twohours before on e again be oming normally a tive and timid."\It may seem a long distan e from lethargy in guinea pigsto the ex itement of psy hoti s, but as these investigationshad ommen ed in an attempt to demonstrate some possiblyex reted toxin in the urine of mani patients, the asso iationof ideas is expli able."Cade's leap from produ ing a toxi lethargy in animals to \treat-ing" human beings shows his intuitive re ognition of the entral roledea tivation in psy hiatri treatment. As reviews by S hou (1957 [86℄,1968 [82℄, 1976 [83℄) indi ated, no large studies on primate behaviorwere ondu ted before the widespread use of lithium in humans. Onereason for this be indi ated in S hou's summary of how lithium af-fe ted mi e and rats. In a 1957 review, he noted, \A ertain apathyand slowness of rea tion have been frequent symptoms in the exper-imental animals." Or, as he remarked in a later review (S hou, 1976[83℄), there is \de reased spontaneous exploratory a tivity".This suppression of \spontaneous and exploratory a tivity," as wellas the suppression of other expressions of volition and vitality, are thehallmarks of most biopsy hiatri treatments and helped to inspire my on ept of dea tivation and the brain-disabling prin iples of psy hi-atri drugs. In studies of lobotomy and in the early and most forthrightearly dies of neurolepti drugs, the primary or essential e�e t was iden-ti�ed the produ tion of indi�eren e. In the antidepressant literature,this same e�e t is gaining re ognition in regard to how these drugsprodu e apathy in long-term use. Stimulant advo ates have failed tore ognize these same e�e ts in regard to Ritalin, Adderall, and otherdrugs used for the ontrol of behavior in hildren; but the s ienti�

302 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERdysphori and hara terized by lassitude, lethargy, and feelingsof negativism and depression. In addition, feelings of agitation,anxiety, tension, and restlessness are related to lithium arbon-ate maintenan e. There is also some eviden e that subje ts in-di ated they did not want to have to deal with the demands ofintera ting with their human environments. Finally, there are onsistent self-reports of inability to on entrate, mental on-fusion, feeling muddleheaded, and a loss of lear-headedness."Although not as pi turesque as S hou et al.'s self-des ribed lithiume�e ts [86℄, the impression of brain-disabling e�e ts is similar. In1979 [49℄, Judd summarized the results of studies with 42 healthyyoung men. He on luded that lithium produ es a \general dullingand blunting of various personality fun tions" and a \generalized sub-je tive dysphoria". Consistent with the brain-disabling prin iples, heattributed the therapeuti e�e t of lithium to a general slowing of ognitive pro esses.An espe ially interesting aspe t of Judd's resear h on�rms thetrained independent observers are not likely to report adverse druge�e ts, even when they are apparent to those who administered thedrug and to those personally asso iated with the persons re eiving thedrug (Judd et al., 1977a [46℄):\It was of interest to �nd that the e�e ts of lithium arbonatein normal subje ts were not per eptible to trained independentobservers in the experimental situation. We initially spe ulatedthat these hanges, although profound to the individual expe-rien ing them, were not su h that they were easily dis ernible,even to trained observers. In ontrast to this was the fa t thatthe `signi� ant other,' an individual who had a mu h more ex-tensive interpersonal experien e with the subje t, was able toidentify alterations in behavior and mood during the time thesubje ts were being maintained on lithium arbonate. Further,their observations were ompletely onsistent with qualitative

8.2. BRAIN-DISABLING EFFECTS 2998.2.3 Disabling E�e ts on Normal VolunteersBe ause they onsidered lithium to be disease-spe i� for mania, advo- ates of the drug initially laimed that it had little or no e�e t normalindividuals (Dempsey et al., 1977 [25℄;. Hollister, 1976 [40℄). Even vanPutten (1975a) [101℄, usually a keen observer of drug e�e ts, statedthat \lithium prophylaxis does not a�e t normal mental fun tioningor deprive a pane of normal human sorrow or elation".Claims that lithium has no e�e t on normal volunteers are oftenbased on a study by S hou et al. (1968) [84℄, who stated: \The moststriking observation seems to be how little lithium a�e ts normal men-tal fun tions: in prophyla ti dosage not at all and in higher thera-peuti dosage only moderately."However, S hou et a1.'s (1968) [84℄ own data do not support thisview. It is true that the resear hers found no impa t in six volunteerswhen the drug was given at low doses for only 1 week. However, theauthors also administered lithium to themselves within the therapeuti dose (1.0 mEq/L) for 1-3 weeks. The authors, who now be ame thesubje ts of the experiment, experien ed the ommon initial somati side e�e ts, in luding \transient nausea, diarrhea, slight tremor of thehands, et ". In addition, they su�ered from a straitja keting e�e t:\A feeling mus ular weakness or heaviness was prominent in all thesubje ts. They had to over ome a ertain resistan e against risingand moving and also had a feeling that mental e�ort was needed toundertake any physi al task."The most remarkable e�e ts were subje tive. Keep in mind thatS hou et al. (1968) [84℄ are trying to substantiate how little e�e tlithium on normal mental fun tion when they des ribed the followinge�e ts themselves:\Psy hologi al e�e ts were, on the whole, subtle and ill de-�ned. There was no onsistent hange of the mood level, but

300 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERirritability or emotional lability ould at times be noted. Theremight be hypersensitivity to everyday sights and sounds. Onother o asions responsiveness to environmental stimuli was di-minished; this was in one of the ases wel omed by the family(`Dad is mu h easier and ni er than usual'), while the fami-lies of the two other subje ts omplained about their being sodull. The subje tive experien e was primarily one of indi�er-en e and slight general malaise. This led to a ertain passivity.The subje ts often had a feeling of being at a distan e fromtheir environment, as if separated from it by a glass wall. Thesubje tive feeling of having been altered by the treatment wasdisproportionately strong in relation to obje tive behavioral hanges. The subje ts ould engage in dis ussions and so iala tivities but found it diÆ ult to omprehend and integratemore than a few elements of a situation. One of the subje tsnoted, for example, that whereas he had unaltered ability ina game su h as hess with only two parti ipants, he was lessgood at bridge with its four players. Intelle tual initiative wasdiminished, and there was a feeling of lowered ability to on- entrate and memorize; but thought pro esses were una�e ted,and the subje ts ould think logi ally and produ e ideas. Theassessment of time was often impaired; it was diÆ ult to de idewhether an event had taken pla e re ently or some time ago."Referen es to diminished \responsiveness to environmental stim-uli," diminished \intelle tual initiative," \indi�eren e and a slightgeneral malaise," and \a ertain passivity" de�nitively des ribe thedea tivating, in-disabling e�e ts of lithium ( hapter 1). The languageused is identi al that used to des ribe lobotomy e�e ts.Most interesting, perhaps, the authors, in writing about themselves,seem medi ation spellbound. That is, they fail to re ognize how mu hharm the drugs are doing to their mental apa ities, even as theyreport them. They used their study as the basis for their widely pub-li ized laim that lithium has little or no e�e t on normal volunteers.8.2. BRAIN-DISABLING EFFECTS 301Their study was published in su h an obs ure foreign-language jour-nal that it was not even available in the National Library of Medi ine,and therefore other resear hers and professionals had to rely upontheir laims on erning their results1.That one of the author's hildren thought he was improved by de-a tivation on�rms the brain-disabling prin iples. At least from this hild's viewpoint, it was a relief to have her father be ome subduedand withdrawn.Small et al. (1972) [93℄ examined the mental e�e ts of lithium on11 normal volunteers in a more systemati fashion. Three had su hserious rea tions that there were \obje tive indi ations of impairmentin work and s hool performan e". A fourth developed a \severe, pre- ipitous toxi delirium on the tenth day of taking lithium". A �fthvolunteer dropped out of the study in the �rst week with \severe mus- le weakness, onfusion, and depression," whi h, the authors argue,without eviden e, was \more likely" related to psy hologi al fa torsthan to the drug.Linnoila et al. (1974) [58℄ fo used on behavioral rea tions in sim-ulated automobile driving and found lithium-indu ed impairment inresponse and rea tion times, and in judgment.Judd et al. (1977a&b [46℄ & [47℄) also studied the rea tions ofnormal volunteers to lithium (mean, 0.9 mEq/L) over a 2-week period.In one study (Judd et al., 1977 [46℄) they reported the e�e ts of lithiumon mood and personality in 23 subje ts. They expressed surprise attheir �ndings, whi h in luded a de reased \sense of well-being" amongtheir volunteers and a \large number of spontaneous omplaints". Theauthors des ribed their results in no un ertain terms:\These subje tive hanges are not mood elevating, but rathermood lowering. In general, these feeling-tone alterations are1I obtained a translation of the original arti le from one of the authors.

306 CHAPTER 8. DRUGS FOR BIPOLAR DISORDER\I just don't get irritated and upset at things as I used to".\Things that used to bother me don't seem so important any-more". \I don't have any energy, an't a omplish what I usedto be able to.S hlagenhauf et al. (1966) [81℄ found that \when improvement was�rst noted the patients omplained of feeling internally ' urbed,' asubje tive experien e that all of them had onsiderable diÆ ulty indes ribing very pre isely". The patients felt \unable to talk, thinkor move as fast as they would like". Again, lithium is obviously andgrossly disabling the brain mind.Demers and Davis (1971) [24℄ examined the attitudes of spousestoward patients treated with lithium. Without intending to emphasizethe point, the study made lear that there is an overall redu tion inall forms of lively expression or vitality:\An apparent unfavorable result of lithium treatment was aredu tion in enthusiasti behavior, as well as sexual respon-siveness in the mani -depressive. Hypomani joviality, enthu-siasm, and spontaneity are often regarded as so ial pluses; andmani -depressives and their spouses omplain about the lossof these valued attributes. When pressed to dis uss the sex-ual ompatibility of the marriage, frequently they will say it isworse sin e lithium treatment started, as the lithium-treatedspouse has less libidinal strivings."This ex erpt illustrates the brain-disabling prin iple that the eval-uation treatment su ess depends upon the observer's attitude towardthe g-indu ed mental disability. In these instan es, the spouses are de-s ribed as missing their partners' vitality and sexuality. On the otherhand, the do tors label these valued attributes \hypomani " in orderto justify the brain-disabling e�e t of their treatments.

8.2. BRAIN-DISABLING EFFECTS 303 hanges obtained from the self-rating data from the subje tsthemselves. Thus, these hanges due to lithium arbonate arenot just subje tively experien ed, but are apparent to indepen-dent observers who are well a quainted with the normal rangeof behavior of ea h of the subje ts."The adverse e�e ts most frequently noted by personal asso iates ofthe subje ts in luded \in reased levels of drowsiness and lowered abil-ity to work hard and to think learly" (Judd, 1979 [49℄). The groupwho reported these hanges in the subje ts onsisted of \friends, room-mates, girlfriends, et ." The ba kground of the \trained independentobservers" not des ribed, but presumably they are mental health pro-fessionals.It is striking that the trained observers were \unable to dete t anybehavioral hanges in the subje ts indu ed by lithium" when theywere apparent to personal asso iates and ould be measured on test-ing. Judd (1979 [49℄) attributed their failure to a la k of familiaritywith the subje ts in their normal surroundings. But various �ndingsin this book on�rm that this failure to observe adverse drug e�e tsis hara teristi of the vast majority of resear h reports and reviewarti les in the drug literature. It the do tor's part in iatrogeni de-nial: the tenden y to deny the brain disabling e�e ts of psy hiatri treatments ( hapter 18).Studies have ontinued to demonstrate adverse e�e ts of lithiumon normal subje ts (Glue et al., 1987 [33℄; Kroph et al., 1979 [52℄;Muller-Oerlinghausen et al., 1977 [69℄; Weingartner et al., 1985 [104℄).S hatzberg and Cole (1991) [80℄ appropriately warned that the pa-tient's subje tive experien e of mental dysfun tion should be takenseriously:\Some patients on lithium omplain of slowed mentation andforgetfulness and, on testing, a memory de� it has been found.

304 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERAlthough su h patients are often suspe ted or a used of `us-ing' su h symptoms to avoid ne essary lithium therapy, ourimpression is that these omplaints are often real and onsti-tute a basis for lowering the dos age or trying another therapy."(p. 159)Je�erson (1993) [43℄ summed up the dea tivating e�e t of lithium,\Neurologi adverse e�e ts of lithium in lude redu ed rea -tivity, la k of spontaneity, intelle tual insuÆ ien y, memoryproblems, diÆ ulty in on entration, dysphoria. Some of thesee�e ts may be related to the therapeuti a tion of lithiumin redu ing hypomania. However, hypothyroidism, weaknessand fatigue due to hyper al emia, and breakthrough depres-sion must be onsidered in the presen e of these symptoms."The produ tion of thyroid disorders by lithium is ommon and re-quires onstant on ern throughout the treatment. Lithium-indu edhypothyroidism an produ e depression and other mental dysfun tion,greatly onfusing and ompli ating the patient's lini al pi ture.In a review of the literature on erning the impa t of psy hiatri drugs on ognition in normal subje ts, Judd et al. (1987) [48℄ foundthe following:\In summary, lithium often indu es subje tive feelings of og-nitive slowing together with de reased ability to learn, on- entrate and memorize. In addition, ontrolled studies have onsistently des ribed small but onsistent performan e de re-ments on various ognitive tests, in luding memory tests. Theavailable data suggest that the slowing of performan e is likelyto be se ondary to a slowing in the rate of entral informationpro essing." (p. 1468)

8.2. BRAIN-DISABLING EFFECTS 305Studies of normal volunteers should lay to rest the laim thatlithium only a�e ts a disease pro ess. It should also put an end tothe laim that lithium has a spe i� antimani e�e t, rather thana generalized brain-disabling, dea tivating e�e t. This e�e t may attimes redu e the o urren e of mani episodes, but it does so by redu -ing overall brain fun tion. Even in regard to redu ing the frequen y ofmani episodes, its eÆ a y is doubtful and it auses mani withdrawalrea tions (see following se tions).

8.2.4 Turning Down the Dial of LifeCon�rming the brain-disabling prin iple, lithium has the same subdu-ing e�e ts on psy hiatri patients as on normal volunteers. Speakingof individuals su essfully treated with lithium, Dyson and Mendelson(1968) [26℄ observed the following:\It is as if their `intensity of living' dial had been turned downa few not hes. Things do not seem so very important or imper-ative; there is greater a eptan e of everyday life as it is ratherthan as one might want it to be; and their spouses report amu h more pea eful existen e."As a demonstration of the brain-disabling on ept of psy hiatri treatment, the referen e to the spouse's report of a more pea eful ex-isten e' reminis ent of S hou et al.'s (1968) [84℄ observation that one ofthe hildren preferred it when Dad's \responsiveness to environmentalstimuli was diminished". The omparison to neurolepti dea tivationand to lobotomy again seems apparent.A ording to Dyson and Mendelson (1968) [26℄, even on e�e tivemaintenan e therapy, the dial of life remains turned down. Theyquoted some of their patients:

310 CHAPTER 8. DRUGS FOR BIPOLAR DISORDER8.4 Toxi ity to the Central Nervous System8.4.1 The Produ tion of Cognitive De� itsIt is now generally a epted that lithium an impair intelle tual fun -tion. For example, Shaw et al. (1987) [87℄ found impairments ofmemory and hand motor speed on lithium. In Mani -Depressive Ill-ness, a book written wholly from a biopsy hiatri perspe tive, Freder-i k Goodwin and Kay Jamison (1990) [34℄ nonetheless on luded thatlithium does ause serious ognitive impairments. They summarizedmu h of the literature up that time and de lared,

\Sin e the drug's primary a tion is mediated through the en-tral nervous system, it is not surprising that lithium an ause ognitive impairments of varying types and degrees of severity.Indeed, memory problems are among the side e�e ts of lithiumtreatment that patients report most frequently. Although af-fe tive illness itself ontributes both to ognitive de� its and omplaints about su h de� its, it is important to bear in mindthat impairment of intelle tual fun tioning aused by lithium isnot un ommon and, in many patients, leads to non omplian e.Creativity an also be a�e ted." (p. 706)

More re ently, Stip et al. (2000) [95℄ summarized the literatureon lithium-indu ed memory problems: \Several studies have shown ognitive impairment in short-term memory, long-term memory andpsy homotor speed in bipolar patients taking lithium." Their studyaimed at testing the e�e t of lithium in normal subje ts in a double-blind, 3-week study. They found that lithium-treated volunteers hadlong-term memory de� its on re alling words ompared to the pla ebogroup.

8.2. BRAIN-DISABLING EFFECTS 3078.2.5 Crushing CreativityRonald Fieve, of the New York State Psy hiatri Institute, a hievednational attention (\New Old Treatment," 1973) in newspapers andmagazines when he presented theatri al produ er-dire tor Joshua Lo-gan at the annual meeting of the Ameri an Medi al Asso iation, whereLogan ve a testimonial for lithium.The entire question of testimonials for various treatments is a dif-� ult and omplex one. Qua k ures, for example, often have avidsupporters. Logan (1976) [60℄, in his autobiography, des ribed hismany onta ts with psy hiatri treatment over the years, in ludingearlier publi testimonials for psy hiatry. He expressed surprise thatpeople are riti al of ele trosho k treatment, whi h he found to bevery \benign".Logan's own psy hiatrist, Fieve, oauthored an arti le (Polatin etal., 1971 [74℄) des ribing three individuals (rare ases, in the authors'opinion) who reje ted maintenan e lithium, two of whom did so spe if-i ally on the grounds that it interfered with their reativity as writersof bestsellers: \These patients report that lithium arbonate inhibits reativity so that e individual is unable to express himself, drive isdiminished, and there is no in entive."Despite their laim that lithium does not interfere with reativityS hou and Baastrup (1973) [85℄ des ribed its inhibiting, atteninge�e t:\It is not always the elation that is missed. An undertaker's ustomers, mistaking depressive sadness for ompassion, om-plained about his appearan e of indi�eren e when he was inlithium treatment. Another patient regretted that in dis us-sions he was unable to attain the level of ex itement he on-sidered ne essary: `Do tor, I am a ommunist and I must getex ited when I dis uss.' There are also patients who feel thatlithium treatment makes life ` at' and less olorful, ` urbs' their

308 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERa tivity, and prevents them from going as fast as they wouldlike. 10 most ases these omplaints disappear when the pa-tients be ome used to the stable life ourse."Whether these omplaints do in fa t disappear in most ases hasnever been arefully investigated. Even if the omplaints be ome lessfrequent, there may be many unfortunate reasons for this, in ludingthe extremely spellbinding e�e t of lithium. In my lini al experien e, hild and adults exposed to any psy hiatri drug for a lengthy periodof time lose their ability to per eive their emotionally subduing e�e ts;but spellbinding e�e t of lithium is espe ially potentJe�erson (1993) [43℄ and Goodwin and Jamison (1990) [34℄ also on�rmed that loss of reativity is experien ed by some patients onlithium; but it did not daunt their advo a y for the drug.8.2.6 Cade Supports the Brain-Disabling HypothesisThere is a parti ular irony in the date of the �rst publi ation on theuse lithium in mental patients: Cade's arti le [16℄ appeared in 1949,the same year that Cor oran et al. [21℄ published \Lithium Poison-ing From the Use of S. Substitutes" in the Journal of the Ameri anMedi al Asso iation.In regard to neurolepti s, we found that pioneers in their use WImost straightforward about its brain-disabling e�e ts. We �nd thesame phenomenon with lithium. Cade (1949) [16℄ indi ated that lithium,when used for other medi inal purposes, produ ed \a tual mental de-pression in a variety of patients, not just those su�ering from maniaor mani depression. The drug enfor ed a so- alled quieting e�e t onpersons onsidered s hizophreni (dementia prae ox, in his nosology):\An important feature was that, although there was no funda-mental improvement in any of them, three who were usually

8.3. SPELLBINDING AND IATROGENIC HELPLESSNESS AND DENIAL309restless, noisy and shouting nonsensi al abuse . . . lost their ex- itement and restlessness and be ame quiet and amenable forthe �rst time in years."

Cade (1949) [16℄ preferred lithium to lobotomy on \restless andpsy hopathi mental defe tives" in order \to ontrol their restless im-pulses and ungovernable tempers".

8.3 Spellbinding and Iatrogeni Helplessness andDenialThe previously ited resear h by Judd demonstrates how profession-als utterly fail to see lithium-indu ed disabilities that are obvious tofriends and dete table with psy hologi al testing. Due to medi ationspellbind" patients themselves have diÆ ulty evaluating their mentalstatus on lithium. Toxi ity often reeps up slowly over many days orweeks so that their judgment is impaired in an almost imper eptiblygradual manner. In fa t, patients annot be relied on to noti e whenthey are be oming severely toxi , even though the symptoms in ludemarked gastrointestinal disturban es, tremor, and disturbed mentalfun tions. Instead of relying on the per eptions of patients, bloodlevels must be arefully monitored and the patients arefully wat hed.In keeping with this medi ation spellbinding e�e t, normal volun-teers on small doses su�er impairments of their re exes but do not re-alize a knowledge the impairment (Linnoila et al., 1974 [58℄). Lithiumpatients who report no side e�e ts often have grossly obvious tremors.The failure of patients on maintenan e therapy to noti e their ownneurologi defe ts learly demonstrates that long-term treatment withlithium is medi ation spellbinding.

314 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERtimes irreversible (Baldessarini, 1978 [6℄; Cohen et al., 1974 [20℄).There is a ase report of a similar rea tion from ombining lithiumwith the newer neurolepti , risperidone (Swanson et al., 1995 [99℄).Lithium administered in ombination with ele trosho k produ esmore severe a ute organi brain syndromes (Weiner et al., 1980 [103℄).Remi k (1978) [79℄ and Hoenig and Chaulk (1977) [39℄ reported sin-gle ases of an a ute severe delirium resulting from this ombination.Mandel et al. (1980) [62℄ reported on two more ases of this nature. In1980 [92℄, Small et al. reviewed 25 patients given ele trosho k whilebeing treated with lithium a found that the patients had more se-vere memory loss, more severe onfusion, and o asional neurologi dysfun tions. The authors re ommend, against the use of ele tro on-vulsive therapy (ECT) in patients re eiving lithium therapy.The literature on erning lithium administration to individuals withpreexisting brain disease is sparse but indi ates the expe ted in rease,brain disability, in luding in the elderly (Baldessarini, 1978 [6℄).Beitman (1978) [9℄ des ribed a ase of rea tivation of tardive dysk-inesia as a result of lithium therapy; the tardive dyskinesia had beenquies ent for many years. Crews and Carpenter (1977) [22℄ also de-s ribed a ase whi h lithium aggravated a preexisting tardive dyski-nesia.8.6 Brain Damage As Treatment8.6.1 General Toxi ity to Neurons and Other CellsWriting from the viewpoint of the pharma ologist, rather than thepsy hiatrist, Pea h (1975) [72℄ observed:\The a umulation of lithium in the intra ellular environment

8.4. TOXICITY TO THE CENTRAL NERVOUS SYSTEM 3118.4.2 A ute Organi Brain SyndromesConsidering how vigorously lithium is promoted as relatively free ofoverpowering mental e�e ts, it is surprising how many ases of toxi delirium during routine lithium therapy were reported soon after thedrug ame into use (Johnson et al., 1968 [45℄; May�eld et al., 1966 [64℄;Prien et a 1972 [75℄; Shopsin et al., 1971 [89℄; Strayhorn et al., 1977)[96℄. Prien et al. (1972) [75℄ found that almost one-third of the patientsin their highly a tive ategory su�ered \severe" rea tions, in ludingseveral with toxi onfusion des ribed as \disorientation, onfusion,la k of ontinuity of thought, and redu ed omprehension". Lithiumis highly neurotoxi .8.4.3 SILENT: Irreversible Lithium-Indu ed Neurotoxi- ityIn 1987 [1℄, Adityanjee dis ussed so- alled lithium poisoning and madean observation that remains true today: \There is a general la k ofawareness about irreversible and untreatable ompli ations of lithiumtreatment despite eviden e to the ontrary."Originally, it was thought that, ex ept in extreme ases, lithiumindu ed neurotoxi ity was reversible. However, it eventually be ame,apparent that many patients develop irreversible brain damage anddysfun tion, often involving the erebellum (Grignon et al., 1996 [36℄).In the last two de ades, resear hers have de�ned a syndrome of ir-reversible lithium-e�e tuated neurotoxi ity (SILENT). Adityanjee etal. (2005) [2℄ viewed the literature from 1965 to 2004 for ases oflithium neurotoxi ity with the persisten e of sequelae for at least 2months after essation of treatment. They found 90 ases of SILENT,with persistent erebellar dysfun tion as the most ommonly reportedpersistent aftere�e t. These hroni ally disabled patients may need

312 CHAPTER 8. DRUGS FOR BIPOLAR DISORDER\physi al rehabilitation for gait ataxia, spee h training for dysarthria,and ognitive training for dementia memory impairments" (p. 47).The most likely ause, a ording to the authors, is \demyelination aused by lithium in multiple sites in the nervous system, in luding the erebellum". Not surprisingly, lithium toxi ity also ause hroni neu-ropsy hologi al hanges, in luding impaired memory, attention, exe -utive ontrol fun tions, and visuospatial de� its (Brumm et al., 1998[15℄).Irreversible neurotoxi ity an o ur at relatively low serum doses.Lang and Davis (2002) [54℄ des ribed \the ase of a 44 year old manwho presented with a two-month history of dysarthria, ataxia and legweakness whilst on maintenan e lithium for bipolar disorder". He hadsigni� ant erebellar and pyramidal dysfun tion. His serum lithiumwas 1.5 mmol/L, a moderate elevation for this patient. His re ov-ery was only partial, leaving him mainly with erebellar ataxia. Theauthors warned about the insidious onset of persistent neurotoxi ityduring routine treatment.

8.5 Neurotoxi E�e ts in Low-DosageMaintenan e Therapy

Bran hey et al. (1976) [13℄ published a follow-up of patients on long-term lithium maintenan e (6 months to 7 years). Only 10 of 36 were\free of neurologi symptoms," even with the low maintenan e dosesemployed. Four 6 patients had parkinsonian symptoms at a \low levelof severity".

8.5. NEUROTOXIC EFFECTS IN LOW-DOSAGE 3138.5.1 Abnormal Brain Waves Produ ed Routine LithiumTherapyFrom early on, the ele troen ephalogram (EEG) was found to demon-strate signi� ant pathologi response to lithium therapy, on�rmingthe intoxi ating e�e t of the drug (Baldessarini, 1977 [7℄; Cor oran etal., 1949 [21℄; May�eld et al., 1966 [64℄; Pea h, 1975 [72℄; S hou, 1957[86℄; Small et al., 1972 [93℄). Consistent with the brain-disabling prin- iple, May�eld and Brown (1966) [64℄ orrelated EEG abnormalitieswith the therapeuti response to treatment. Muller-Oerlinghausen etal. (1977) [69℄ reported grossly abnormal brain wave patterns in pa-tients and normal volunteers. These persisted in the volunteers at the�nal testing 7 days after the withdrawal of lithium therapy.Two review arti les on�rmed reports of persistent brain wave han-ges in patients treated with lithium (Friedman et al., 1977 [30℄; Reis-berg et al., 1979 [78℄). Reisberg and Gershon (1979) de lared, whollywithout proof, that \the eviden e is that these e�e ts are benign".Be ause some studies had shown hanges in fun tional imaging inpatients diagnosed with bipolar disorder during ognitive testing, Bellet al. (2005) [10℄ sought to separate out the in uen e of medi ation. ondu ted a double-blind study of volunteers taking lithium or val-proate using fun tional MRI. Both medi ation groups showed a signif-i ant de rease in the magnitude of the blood-oxygen-level-dependent(BOLD) signal. The authors linked these hanges to the ognitivedysfun tion measured in many studies of lithium.

8.5.2 Lithium Disruption of the CompromisedBrainIn ombination with neurolepti s, espe ially haloperidol, there is an in- reased likelihood of severe en ephalopathi syndromes that are some-

318 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERation of brain ells in the hippo ampus. They made the leap to laimthat this neurotrophi e�e t may make lithium \of use in long-termtreatment of other neuropsy hiatri disorders". In other words, stim-ulating the brain to make abnormal brain ells is likely to be goodfor a variety of psy hiatri disorders. This kind of giant leap, utterlyignoring the obvious toxi e�e ts of lithium, has be ome ommon inthe literature.Not all resear hers are so qui k to assume that any drug-indu edabnormal growth in brain ells will be bene� ial to human beings.Harada et al. (1996) [38℄ set out to \understand the me hanism under-lying the neurotoxi ity of lithium". They found that lithium impairedthe fun tion of nerve growth fa tor in rat ells. In doing so, it ausedsome of the abnormalities seen in lithium treated ells, in luding at-tenuated neurite growth.Meanwhile, it does not o ur to these resear hers that lithium auses demonstrable memory dysfun tion and that the hippo ampusplays a major role in memory pro esses, suggesting instead that theywere looking at how lithium harms the brain-and not how it mighthelp it. Indeed, there is resear h that addresses the e�e t of lithiumon bio hemi al pro esses that spe i� ally a�e t mental fun tions su has memory and spatial dis rimination. Ban haabou hi et al. (2004)[8℄ gave rats lithium for weeks to rea h a typi al human therapeuti serum level. This resulted in suppression of a bio hemi al fa tor in thehippo ampus asso iated with ognitive pro esses (Nurr 1) and also re-sulted in impairment of spatial dis rimination in the animal. (Nurr 1also plays a role in dopamine ell fun tion and perhaps in the develop-ment of parkinsonism, Zetterstrom et al., 1997 [108℄; lithium-indu eddysfun tion in Nurr I may be asso iated with the drug's apa ity to ause dopamine-related neurologi al disorders, su h as parkinsonism.)The �nding of abnormal ell growth stimulated by mood stabilizersis onsistent with resear h showing that bipolar patients taking lithiumand valproi a id have in reased hippo ampal regions measured on8.6. BRAIN DAMAGE AS TREATMENT 315 ould be envisioned to perturb any event that is modulated bymonovalent ations, e.g., sodium or potassium. These possi-ble intera tions signify the enormous magnitude of the task ofdetermining pre ise me hanisms of a tion of the lithium ion."Lithium disrupts almost every measurable ellular a tivity pertain-ing nerve transmission as well as many other vital fun tions. In addi-tion, its distribution is fairly uniform throughout the entral nervousm, with no known areas of spe i� on entration. It produ es whatWilson et al. (1975) [106℄ alled a nonsele tive diminution in neu-ronal a tivity. The neurophysiology of lithium, even without support-ing lini al data, renders absurd the notion of a spe i� bio hemi altreatment for a spe i� disease and on�rms the brain-disabling e�e t.Be ause of its neurotoxi impa t, lithium appears to in rease theof tardive dyskinesia for patients taking neurolepti s (Ghadirian etal., 1996 [31℄). Consistent with this, there have been reports of ex-trapyramidal symptoms in patients taking lithium without neurolep-ti exposure, ding parkinsonism (Le amwasam et al., 1994 [55℄), horea (Podskalny et al., 1996 [73℄), tardive parkinsonism (Muthane et al.,2000 [70℄), tardive dystonia (Chakrabarti et al., 2002 [18℄), and tar-dive dyskinesia (Meyer-Lindenberg et al., 1997 [66℄). The existen e ofextrapyramidal side e�e ts on maintenan e lithium has been found innumerous studies (e.g., Kane et al., 1978 [51℄; Shopsin et al., 1975 [89℄).Shopsin and Gershon's (1975) [89℄ patients, like those of Bran heyet al. (1976) [13℄, did not omplain about their neurologi symp-toms, suggesting further mental impairment and a profound medi a-tion binding e�e t.Lithium also impairs the fun tion of the peripheral nervous system,redu ing motor nerve ondu tion velo ity (Faravelli et al., 1999 [28℄).It auses many metaboli adverse e�e ts, resulting in hypothyroidism,hyperthyroidism (rare), hyperparathyroidism, and diabetes insipidus(Livingston et al., 2006 [59℄).

316 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERPsy hiatry has gone from denying that lithium auses kidney dam-age to trying to ignore it. The threat is very real. Lepkifker et al.(2004) [56℄ viewed the �les of 140 patients exposed to lithium for atleast 4 years and found that 20% developed reeping reatinine (alaboratory test for ney malfun tion) and renal insuÆ ien y. Overall,lithium is very toxi ells (Yao et al., 1999 [107℄).8.6.2 The \Prote tive" and Therapeuti E�e ts of Poi-soning Brain CellsAn in reasing number of psy hiatri drugs have been shown to auseabnormal proliferations of brain ells. The pro ess is abnormal, �rst,be ause it is aused by the toxi impa t of a drug; se ond, be ause thedrugs are already known to ause many lini ally obvious toxi e�e tson brain ells and many organs of the body; and third be ause thenumber and morphology of the ells are abnormal. Yet resear hersare dependent on the psy hopharma euti al omplex, both emotion-ally and e onomi ally, that many persist in seeing these abnormal-ities as eviden e of a spe i� therapeuti me hanism. Laga e andEis h (2005) [53℄ review the so- alled neuroprote tive e�e ts of mood-stabilizing agents, in luding lithium, valproi a id, arbamazepine,and neurolepti s. Two separate e�e ts were studied: neuroprote tiveand neurogeni hanges aused by mood stabilizers.First, these drugs exert a so- alled prote tive e�e t on ell ultures,preventing ell death from o urring in response to ertain trauma.For example, a rat is stressed by immobilizing it in a glass tube (Limet al., 2005 [57℄). This auses hanges to take pla e in the respon-siveness of brain ells to ele tri al stimulation, as measured in thede apitated animal postmortem brain. If 1 hour after death, sli es ofthe animal's brain are bathed in lithium, the brain hanges in responseto stimulation do not o ur. Unbelievably, this laboratory �nding inanimal brain sli es has been leaped on by resear hers, in luding La-8.6. BRAIN DAMAGE AS TREATMENT 317ga e and Eis h (2005) [53℄, as an indi ation that this postmortemprote tion may have something to do with the lini al e�e t of thesedrugs in living human beings. Never mind that lithium, for example,is extremely toxi to the human entral nervous system and peripheralnervous system, a virtual poison to brain ells; this quirk in a Petridish may nonetheless show that these drugs prote t brain ells.Se ond, these drugs produ e abnormal ell growth. The resear hes all this pro ess neurogenesis as if it were benign; but the neurons arenot normal in appearan e. A ording to Laga e and Eis h (2005) [53℄,\In general, these studies have assessed neuron proliferation,neurite [axonal℄ outgrowth, regeneration, and di�erentiation.In sensory neurons, lithium, valproi a id, and arbamazapinehave a ommon e�e t of in reasing growth of one formation,leading to a spreading of the neuron and a shorter neuronalaxon . . . .Re ently, lithium has been shown to indu e prolifer-ation and neuronal di�erentiation of rap hippo ampal progen-itor ells . . . .Like lithium, valproi a id treatment has beenshown to indu e neurogenesis in vitro, spe i� ally indu ingneurite growth, ell reemergen e, and the formation of matureneurons in embryoni orti al ells."These authors are a little more skepti al than others; they do wantto make the omplete leap to lini al, therapeuti e�e ts. But they arehoping: \To determine if the lini al eÆ a y of mood-stabilizing drugsis dependent on the neuroprote tive or neurogeni properties of thesemedi ations, greater strides need to be made in relating �ndings from ell ulture and animal models to human imaging and pathology." Theobvious brain-disabling, mood- attening e�e ts of lithium are ignoredin the interest of promoting a more benign e�e t based on the most imsy experimental grounds.Chen et al. (2000) [19℄ gave lithium to rats in their how, a hievingblood levels omparable with human treatment, and found a prolifer-

322 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERrarely, if ever, told that their relapse was probably aused by lithiumwithdrawal. Instead, they are told that the new mani episode provesthe need to take the medi ation for the rest of their lives.Many psy hiatrists advise patients who are diagnosed bipolar mani that they must take lithium for many years, or even for the rest oftheir lives. They are told that it is irresponsible for them not to do so.Families and psy hotherapists are pressured to urge or oer e patientstake their lithium. The data do not on�rm this strong advo a y fordrug.On the basis of the general observation that the brain tends to�ght ba k against psy hoa tive interferen es in the brain, any medi- ation used to ontrol mania should be viewed as having the potentialto ause mania during withdrawal. For example, Jess et al. (2004)[44℄ des ribed a ase of rebound mania during withdrawal from arba-mazepine.8.10 Other Adverse Rea tions to Lithium With-drawalSwartz and Jones (1994) [100℄ reviewed the literature and presentedthree ases on erning severe and often persistent adverse rea tionsto the abrupt withdrawal of lithium in patients su�ering from ele-vated serum levels during routine treatment. One of the patients be- ame severely demented. In their review of 50 ases obtained fromthe Lithium Information Center of the University of Wis onsin, theyfound that many patients be ame demented or otherwise deterioratedseverely when abruptly withdrawn from lithium. Patients subje tedto kidney dialysis for lithium toxi ' often deteriorated mentally witha rapid drop in lithium levels. Neurologi sequelae persisted in 30%of the 50 patients. The authors found substantial neurotoxi risks in

8.7. THE RELATIVE INEFFECTIVENESS OF LITHIUM IN ACUTE MANIA319MRI. Beyer et al. (2004) [11℄ found that this in rease in hippo ampalsize orrelated with the use of lithium. They also related it to thelaboratory studies of neurogenesis. .There are, of ourse, many ontradi tory �ndings in the literature,but it is apparent that exposure to mood stabilizers, espe ially lithium,profoundly impairs the fun tion of the brain, even ausing abnormal ell proliferation in some ases, and ell loss in others (Blumberg etal. 2003 [12℄). The distorted thinking in the psy hiatri s ien es is sorampant that none of the studies view these re ently do umented ab-normalities in ell growth and brain size as a ause for alarm. Instead,they are automati ally promoted as eviden e of bene�t and ause forhope.8.7 The Relative Ine�e tiveness of Lithium inA ute ManiaThe myth of lithium spe i� ity is shattered in exa tly that arena inwhi h one would expe t to �nd the most support: lini al use as de-s ribed by its advo ates. Early on, it be ame generally a epted thatthe neurolepti s, not lithium, are most e�e tive in stopping a ute ma-nia (Baldessarini, 1978 [6℄; Juhl et al., 1977 [50℄). Even with thedevelopment of ombine, neurolepti -lithium therapy, some authori-ties advo ate ECT, as well, as the ontrol of espe ially severe ases(Hollister, 1976 [40℄).The lini al preferen e for the neurolepti s as the treatment fora ute mania was based on the single most omprehensive, ontrolledstudy whi h was ondu ted by Prien et al. (1972) [75℄. They spe i�- ally ontradi ted the thesis that lithium has any spe i� ity for maniaor the \underlying mani pro ess". They autioned that \unfortu-nately, these observations have been all but lost in the vast number

320 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERof unquali�ed endorsements of lithium arbonate therapy that havedeluged the literature". Alexander et al. (1979) [3℄ and Growe et al.(1979) [37℄ also opined that lithium is not disease-spe i� for mania.In the past, a great deal was written about the use of lithium forthe ontrol of violen e (Fieve, 1989 [29℄; Marini et al., 1977 [63℄; Mi eret al., 1974 [67℄; Morrison et al., 1973 [68℄; Sheard et al., 1976 [88℄,reviewed in Breggin, 1983b [14℄). While these laims have not been on�rmed, they fo us on e again on the tenden y to use or advo atelithium for a variety of purposes.

8.8 How E�e tive Is Lithium in Preventing theRe urren e of Mani Episodes?Lithium has been promoted so strongly within psy hiatry and to thepubli as a method of preventing re urren es of mania that few pra -titioners or onsumers doubt its eÆ a y. In reality, lithium's e�e tive-ness in this regard remains questionable. At the height of lithium'spopularity, Prien et al. (1974) [76℄ reviewed the literature and foundthat studies showed a relapse rate as high as 50% over 2 years dur-ing lithium prophyla ti treatment. Lithium did redu e the numberof mani episodes in patients o had a history of infrequent atta ks.But in patients with a high rate of past mani episodes, lithium didno better than pla ebo, and all patients in this group eventually re-lapsed. If lithium were a disease-spe i� treatment, it surely wouldhave performed better than this.Continuing resear h has been even more dis ouraging. Gitlin etal. (1995) [32℄ ondu ted a prospe tive study of patients treated withlithium bipolar disorder. The patients were arefully monitored for ef-fe tive drug treatment. Despite this, 73% of the patients relapsed intomania depression within 5 years. Of those who relapsed, two-thirds8.9. MANIA AND DEPRESSION AS LITHIUMWITHDRAWAL REACTIONS321had multiple episodes. Even among those patients who did not om-pletely relapse, many su�ered serious emotional diÆ ulties. The au-thors on luded, \even aggressive pharma ologi al maintenan e treat-ment does not prevent relatively poor out ome in a signi� ant numberof bipolar patients" (p. 1635).

8.9 Mania and Depression As LithiumWithdrawal Rea tionsAlthough little noti e was given of the phenomenon within the profes-sion, I re all my own patients telling me about painful emotional re-a tions that they su�ered during lithium withdrawal. The eviden e isnow substantial in regard to serious adverse psy hiatri e�e ts ausedby lithium withdrawal.Suppes et al. (1991) [98℄ analyzed 14 studies and found that therate of relapse into mania in reased following the dis ontinuation oflithium. e patients, who tended to y le into mania about on e ayear (mean .6 months), developed a new episode less than 2 months(mean 1.7 months) after stopping their medi ation. In other words,dis ontinuation treatment with lithium produ ed a mu h more rapidonset of mania than the untreated patients would have endured.Numerous studies have now on�rmed that withdrawal from lithium auses adverse psy hiatri rea tions. Cavanagh et al. (2004) [17℄, ina 7-year follow-up, found that lithium withdrawal aused both ma-nia and depression. They on luded, \These results on�rm thata ute dis ontinuation of lithium leads to a high immediate relapserate." However, they did not �nd that this justi�ed the ontinuationof lithium. To the ontrary, \out ome was not worsened by dis ontin-uation".Unfortunately, patients who relapse soon after taking lithium are

326 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERepisodes asso iate, with bipolar disorder. In reality, Proza should notbe pres ribed to patients with bipolar disorder, given the frequen ywith whi h SSRIs ause and exa erbate mani rea tions.The lengthy list of attempts to substitute for lithium suggests, 001again, that it is hardly a spe i� magi bullet for mania or bipolardisorder.8.13 Why So Many \Bipolar" Patients?When I was in my psy hiatri training, we rarely saw a patient un-dergoing a orid mani episode. When a ase was admitted, it wouldbe ome a subje t for grand rounds for everyone to see and evaluate.I an remember only a handful of su h ases during nearly 4 yearsworking in psy hiatri hospitals. Nowadays, the diagnosis of bipolardisorder has be ome a fad, and many patients are given it withoutmeeting the diagnosti riteria. But many other ases do involve pa-tients who have undergone mani like episodes. Why the in rease? Aswe saw in hapters 7 and 6, the newer antidepressant drugs ommonly ause mania.When a patient develops a mani like adverse drug rea tion, the orre t diagnosis, a ording to the oÆ ial Ameri an Psy hiatri Asso- iation (2000) [4℄ diagnosti manual, is substan e-indu ed mood dis-order. Yet I annot re all a single patient who was properly diagnosedin this manner in either my lini al or forensi experien e (Breggin,in press). Do tors do not want to admit to their own mistakes, andthey do not want to disease the mistakes of their olleagues, so it is somu h easier to diagnose patient as having a mani episode or bipolardisorder than as having adverse drug rea tion with mani features.Even when the drug is su h an obvious ulprit that its role annotbe denied, the typi al health are provider is likely to tell the patientand the family that the drug merely unmasked an underlying disor-

8.11. LITHIUM IN YOUR DRINKING WATER 323rapidly withdrawing patients from high lithium levels.If rapid withdrawal from high lithium levels an produ e mania anddisable neurologi rea tions, then it is probable that rapid withdrawalfrom lower levels may produ e more subtle adverse rea tions.

8.11 Lithium in Your Drinking WaterIn 1970 [23℄, Dawson et al. tried to support a fantasti thesis: In- reased rainfall dilutes ertain minerals in reservoirs, in luding lithium,produ ting a orrelation between areas of lesser rainfall, higher lithiumlevels in drinking water, and a lower in iden e of mental illness as mea-sured by hospital admissions. In Psy hiatri Drugs (1983b), I exam-ined and debunked the study and its various supporters (see Fieve,1989 [29℄; \Texas," 1971). The resear hers re ommended puttinglithium in the drinking water, mu h like drinking water has been uoridated. Perhaps this is the logi al extension of absurd laimsthat psy hiatri treatments orre t bio hemi al imbalan es withoutadversely a�e ting the brain.

8.12 Other So-Called Mood StabilizersThree antiepilepti drugs have now been FDA approved as mood sta-bilizers for the prevention of re urring episodes of mania: divalproexsodium (Depakote), extended-release arbamazepine (Equetro), andlamotrigine (Lami tal). Many of these drugs are pres ribed to hil-dren for the ontrol of epilepsy and, in reasingly, for bipolar disorder.A riti al question is their e�e t on the developing mental and emo-tional fun tion of hildren, but there is little resear h on the subje t(Loring, 2005 [61℄).

324 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERValproi a id (Depakene), sodium valproate (Depakene syrup), anddivalproex sodium (Depakote, enteri - oated ombination of the othertwo) are forms of an antiepilepti agent that has been approved by theDA for the treatment of bipolar disorder. The drug an be hepato-toxi , espe ially in hildren. From the brain-disabling perspe tive, it an ause sedation, tremor, and ataxia. More rarely, it an auseadverse hanges in mood and behavior, in luding behavioral automa-tisms, aggression, and onfusion. Somnolen e or delirium an develop,espe ially when ombined with other sedatives (Silver et al., 1994 [91℄).There may be \mild impairment of ognitive fun tion with hroni use" (Hyman et al. [42℄, 1995, p. 127). Like lithium, valproi a id auses delirium in a signi� ant per entage of older patients (Shulmanet al., 2005 [90℄). It also auses a variety of endo rine disorders andmetaboli hanges (Verrotti et al., 2005 [102℄). Clini ally, I have seenthis drug ause depression and hostility.Of as yet unknown onsequen e to the brain and nervous system,here are many studies indi ating that valproi a id promotes a vari-ety of potentially dangerous viruses (e.g., Fan et al., 2005 [27℄). Bothvalproi a id and arbamazepine ause a small in rease in the rate ofmajor ongenital malformations in infants (Wide et al., 2004 [105℄).A ute and potentially fatal pan reatitis has been reported with val-proi a id (e.g., Grauso-Eby et al., 2003 [35℄). Liver failure is a knownproblem as wel1. Valproi a id is known to ause hyperammonemiawith en ephalopathy (e.g., M Call et al., 2004 [65℄). Severe and evenlethal skin disorders an o ur with all of the antiseizure medi ationsnow used as mood stabilizers. The various adverse e�e ts of valproi a id and other mood stabilizers are not nearly s benign as physi iansbelieve in their eagerness to swit h patients from lithium.Carbamazepine (Tegretol) is losely related to the tri y li antide-pressants. In neurologi al medi ine, its prin ipal uses are as an anti- onvulsant for partial omplex seizures and in the management of ti douloureux, a fa ial pain syndrome. It auses similar brain-disabling8.12. OTHER SO-CALLED MOOD STABILIZERS 325e�e ts to the older antidepressants, in luding sedation, tremor, on-fusion, depression, psy hosis, and memory disturban es ( hapter 1).Cognitive disturban es are more ommon with on omitant use of neu-rolepti s, with preexisting brain damage, and with aging (Hyman etal., 1995 [42℄). In addition, it poses the threat of potentially lethalagranulo ytosis or aplasti anemia. Carbamazepine an ause hy-ponatremia (low serum sodium), leading to a syndrome that in ludeslethargy, onfusion or hostility, and stupor.Clonazepam (Klonopin), a benzodiazepine tranquilizer, has beenused to treat both a ute mania and as prophylaxis. It has all themany, sometimes severe, problems asso iated with the other benzo-diazepines, in luding sedation, rebound and withdrawal syndromes,addi tion, and behavioral abnormalities ( hapter 7). Neurolepti s re-main the mainstay for ontrolling a ute mani rea tions.Verapamil (Calan and others) is a al ium hannel blo ker used forthe treatment of ardia disorders that has also been used o�-label asmood leveler. It an produ e a variety of ardiovas ular side e�e ts.Clonidine, an antihypertensive drug, also has been used in the treat-ment of mania. Sudden withdrawal an produ e a rebound hyper-tensive risis. Consistent with the brain-disabling prin iples, it anprodu e a variety of psy hiatri symptoms, in luding sedation, vividdreams or nightmares, insomnia, restlessness, anxiety, and depression.More rarely, it an ause hallu inations. Unfortunately, this drug istoo ommonly used as so- alled mood stabilizer in hildren. Whenmistakenly pres ribed with stimulants, it auses an elevated risk of ardia arrhythmia and ardia arrest in hildren.Some lini ians will add a variety of antidepressants, in luding SS-RIs like Proza , to the treatment of patients with bipolar disorder.Nearly a antidepressants an ause or worsen mania ( hapter 12).Nonetheless, Eli Lilly managed to obtain FDA approval for Symbyax,a ombination Zyprexa and Proza , for the treatment of depressive

330 BIBLIOGRAPHY[8℄ Ban haabou hi, M., de Ortiz, S., Menendez, R., Ren, K., &Maldonado-Vlaar, C. (2004). Chroni lithium de reases Nurr 1expression in the rat brain and impairs spatial dis rimination.Pharma ology, Bio hemistry and Behavior, 79, 607-621.[9℄ Beitman, B. (1978). Tardive dyskinesia reindu ed by lithium ar-bonate. Ameri an Journal of Psy hiatry, 135, 1229-1230.[10℄ Bell, E., Willson, M., Wilman, A., Dave, S., & Silverstone, P.(2005). Di�erential e�e ts of hroni lithium and valproate onbrain a tivation in healthy volunteers. Human Psy hopharma ol-ogy: Clini al and Experimental, 20, 415-424.[11℄ Beyer, J., Ku hibbada, M., Payne, M., Moo-Young, M., Cassidy,F., Ma Fall, J., et al. (2004). Hippo ampal volume measurementin older adults with bipolar disorder. Ameri an Journal of Geri-atri Psy hiatry, 12, 613-620.[12℄ Blumberg, H., Kaufman, J., Martin, A., Whiteman, R., Zhang,J., Gore, J., et al. (2003). Amygdala and hippo ampal volumes inadoles ents and adults with bipolar disorder. Ar hives of GeneralPsy hiatry, 60, 1201-1208.[13℄ Bran hey, M., Charles, J., & Simpson, G. (1976). Extrapyramidalside e�e ts in lithium maintenan e therapy. Ameri an Journal ofPsy hiatry, 133, 444-445.[14℄ Breggin, P. (1983b). Psy hiatri drugs: Hazards to the brain.New York: Springer Publishing.[15℄ Brumm, W., van Gorp, W., & Wirshing, W. (1998). Chroni neuropsy hologi al sequelae in a ase of severe lithium intoxi a-tion. Neuropsy hiatry, Neuropsy hology, and Behavioral Neurol-ogy, 11, 245-249.

8.14. CONCLUSION 327der. Instead of withdrawing the patient from the o�ending agent, thehealth are provider is likely to in rease the dose or to add anotherdrug, ultimately worsening the patient's ondition. But as the re-sear h in hapters 7 and 6 shows, many people with no past historyof mani episodes are driven into mani like states by antidepressantmedi ation.Chapter 7 will examine one of the great shames of my professionpsy hiatry: the in reasing numbers of hildren diagnosed with bipolarorder and medi ated with adult mood stabilizers and neurolepti s.

8.14 Con lusionLithium is a highly neurotoxi substan e with a generally suppressivee�e t on neuronal fun tion and mental fun tion in the ommonly pre-s ribed therapeuti range. It is poisonous to brain ells. The mu hpromoted on ept that lithium and other \mood stabilizers" are some-how \prote tive" of brain ells is fantasti al.Lithium has no spe i� therapeuti e�e t on mania or other statesof overex itement. Its brain-disabling e�e t is not spe i� for pa-tients diagnosed as mani or bipolar. Lithium will subdue or suppressthe mental and physi al fun tioning of animals, newborn infants andnursing infants of mothers who take lithium, and normal volunteers, aswell as people diagnosed with psy hiatri disorders. Lithium-treatedvolunteers su�er devastating e�e ts on their ability to relate and tofun tion intelle tually. Animals show similar taming e�e ts.Lithium is highly spellbinding. Normal volunteers fail to per eivehow impaired they have be ome, and patients given therapeuti doseseasily be ome severely toxi without per eiving their deteriorating lini al ondition. Patients treated long term with lithium typi allyfail per eive how subdued they have be ome or how impaired theirmemories have be ome.

328 CHAPTER 8. DRUGS FOR BIPOLAR DISORDERThe various alternatives to lithium have their own brain-disablinge�e ts, and none of the drugs is spe i� for mania.Although lithium possesses these suppressive properties, it is not ase�e tive in ontrolling mania as the neurolepti s, espe ially in a utemania or in severe, re urrent mania. This is partly be ause lithiumis too overwhelming in toxi ity in doses suÆ ient to subdue severelydisturbed or rebellious individuals.The laim that lithium is a disease-spe i� therapy for mania ormani -depressive (bipolar) disorder has no basis in fa t; it is a braindisabling agent. Its eÆ a y has been exaggerated, and its adversee�e ts on the brain and mind, as well as the body as a whole, havebeen too frequently minimized.

Bibliography

[1℄ Adityanjee. (1987). The syndrome of irreversible lithium e�e tu-ated neurotoxi ity. Journal of Neurology, Neurosurgery, and Psy- hiatry, 50, 1246.[2℄ Adityanjee, Munshi, K., & Thampy, A. (2005). The syndrome ofirreversible lithium-e�e tuated neurotoxi ity. Clini al Neurophar-ma ology, 28, 38-49.[3℄ Alexander, P., Van Kammen, D., & Bunney, W. (1979). Antipsy- hoti e�e ts of lithiumm in s hizophrenia. Ameri an Journal ofPsy hiatry, 136, 283-287.[4℄ Ameri an Psy hiatri Asso iation. (2000). Diagnosti and statis-ti al manual of mental disorders (4th ed., text rev.). Washington,DC: Author.[5℄ Ameri an Psy hiatri Asso iation. (1975). The urrent status oflithium therapy: Report of the APA Task For e. Ameri an Jour-nal of Psy hiatry, 132, 997-1001.[6℄ Baldessarini, R.J. (1978). Chemotherapy. In A. Ni holi (Ed.), TheHarvard guide to modern psy hiatry. Cambridge, MA: HarvardUniversity Press.[7℄ Baldessarini, R.J. (1977). S hizophrenia. New England Journal ofMedi ine, 297, 988-995. 329

334 BIBLIOGRAPHY[43℄ Je�erson, J. (1993). Mood stabilizers: A review. In D. Dunner(Ed.), Current psy hiatri therapy (pp. 246-254). Philadelphia:Saunders.[44℄ Jess, G., Smith, D., Ma Kenzie, C., &: Crawford, C. (2004). Car-bamazepine and rebound mania. Ameri an Journal of Psy hiatry,161, 2132-2133.[45℄ Johnson, G., Gershon, S., & Hekimian, L. J. (1968). Controlledevaluation of lithium hlorpromazine in treatment of mani states:An interim report. Comprehensive Psy hiatry, 9, 563-573.[46℄ Judd, L., Hubbard, B., Janowsky, D. S., Huey, L., & Attewell,P. (1977a). The e�e t of lithium arbonate on a�e t, mood, andpersonality of normal subje ts. Ar hives of General Psy hiatry,34, 346-351.[47℄ Judd, L., Hubbard, B., Janowsky, D., Huey, L., & Takahashi, K.(1977b). The e�e t of lithium arbonate on the ognitive fun tionof normal subje ts. Ar hives of General Psy hiatry, 34, 355-357.[48℄ Judd, L., Squire, L., Butters, N., Salmon, D., & Paller, K. (1987).E�e ts of psy hotropi drugs on ognition and memory in normalhumans and animals. In H. Y. Meltzer (Ed.), Psy hopharma ol-ogy: The third generation of progress (pp. 1467-1475). New York:Raven.[49℄ Judd, L. L. (1979). E�e t of lithium on mood, ognition, andpersonality fun tion in normal subje ts. Ar hives of General Psy- hiatry, 36, 860-865.[50℄ Juhl, R., Tsuang, M., & Perry, P. (1977). Con omitant admin-istration of haloperidol and lithium arbonate in a ute mania.Diseases of the Nervous System, 38, 675-676.

BIBLIOGRAPHY 331[16℄ Cade, J. F. J. (1949). Lithium salts in the treatment of psy hoti ex itement. Medi al Journal of Australia, 2, 349-352.[17℄ Cavanagh, J., Smyth, R., & Goodwin, G. (2004). Relapse intomania or depression following lithium dis ontinuation: A 7-yearfollow-up. A ta Psy hiatri a S andinavi a, 109, 91-95.[18℄ Chakrabarti, S., & Chand, P. (2002). Lithium-indu ed tardivedystonia. Neurology India, 50, 473-475.[19℄ Chen, G., Rajkowska, G., Du, F., Seraji-Bozorgzad, N., & Manji,H. (2000). Enhan ement of hippo ampal neurogenesis by lithium.Journal of Neuro hemistry, 75, 1729-1734.[20℄ Cohen, W., & Cohen, N. (1974). Lithium arbonate, haloperidol,and irreversible brain damage. Journal of the Ameri an Medi alAsso iation, 230, 1283-1287.[21℄ Cor oran, A. C., Taylor, R. D., & Page, L. H. (1949). Lithiumpoisoning from the use of salt substitutes. Journal of the Ameri- an Medi al Asso iation, 139, 685-688.[22℄ Crews, E. L., & Carpenter, A. E. (1977). Lithium-indu ed ag-gravation of tardive dyskinesia. Ameri an Journal of Psy hiatry,134,933.[23℄ Dawson, E. B., Moore, T. D., & M Ganity, W. J. (1970). Themathemati al relations of drinking water, lithium, and rainfall tomental hospital admissions. Diseases of the Nervous System, 31,811-820.[24℄ Demers, R. G., & Davis, L. S. (1971). The in uen e of prophy-la ti lithium treatment on the marital adjustment of mani -depressives and their spouses. Comprehensive Psy hiatry, 12,348-353.

332 BIBLIOGRAPHY[25℄ Dempsey, G. M., & Herbert, M. L. (1977). Lithium toxi ity: Areview. In L. Roizen, H. Shiraki, & N. Gr evi (Eds.), Neurotox-i ology. New York: Raven.[26℄ Dyson, W. L., & Mendelson, M. (1968). Re urrent depressionsand the lithium ion. Ameri an Journal of Psy hiatry, 125, 544-548.[27℄ Fan, S., Maguire, e., Ramirez, S., Bradel-Tretheway, B., Sapinoro,R., Sui, Z., et al. (2005, January 16). Valproi a id enhan es geneexpression from viral gene transfer ve tors. Journal of Virologi alMethods, 125, 23-33.[28℄ Faravelli, D., Di Bernardo, M., Ri a, V., Benvenuti, P., Bartelli,M., & Ron hi, O. (1999). E�e ts of hroni lithium treatment onthe peripheral nervous system. Journal of Clini al Psy hiatry, 60,306-310.[29℄ Fieve, R. R. (1989). Moodswing. New York: Morrow.[30℄ Friedman, M. J., Culver, C. N., & Ferrell, R. B. (1977). On thesafety of long-term treatmem with lithium. Ameri an Journal ofPsy hiatry, 134, 1123-1126.[31℄ Ghadirian, A.-M., Annable, L., Belanger, M.-C., & Chouinard,G. (1996). A ross-se tional study of Parkinsonism and tardivedyskinesia in lithium-treated a�e tive disordered patients. Jour-nal of Clini al Psy hiatry, 57, 22-28.[32℄ Gitlin, M., Swendsen, J., Heller, T., & Hammen, C. (1995). Re-lapse and impairment in bipolar disorder. Ameri an Journal ofPsy hiatry, 152, 1635-1640.[33℄ Glue, P., Nutt, D., Cowen, P., & Broadbent, D. (1987). Sele tivee�e t of lithium on ognitive performan e in man. Psy hophar-ma ology, 91, 109-111.

BIBLIOGRAPHY 333[34℄ Goodwin, F., & Jamison, K. (1990). Mani -depressive illness.New York: Oxford University Press.[35℄ Grauso-Eby, N., Goldfarb, O., Feldman-Winter, L., & M Abee,G. (2003). A ute pan reatitis in hildren from valproi a id: Caseseries and review. Pediatri Neurology, 28, 145-148.[36℄ Grignon, S., & Bruguerolle, F. (1996). Cerebellar lithium toxi -ity: A review of re ent literature and tentative pathophysiology.Th~A^A rapie, 51, 101-106.[37℄ Growe, G. A., Crayron, J. W., Klass, D. B., Evans, H., & Strizi h,M. (1979). Lithium in hroni s hizophrenia. Ameri an Journalof Psy hiatry, 136, 454-455.[38℄ Harada, H., Sugiyama, T., & Suketa, Y. (1996). Chara teri-zation of inhibition by hroni treatment with lithium ion onnerve growth fa tor-indu ed neuronal di�erentiation on frat PC12pheo hromo ytoma ells. Journal of Toxi ology and Environmen-tal Health, 49, 197-206.[39℄ Hoenig, J., & Chaulk, R. (1977). Delirium asso iated with lithiumtherapy and ele tro onvulsive therapy. Canadian Medi al Asso- iation Journal, 116, 837-838.[40℄ Hollister, L. E. (1976). Psy hiatri disorders. In G. S. Avery (Ed.),Drug treatment. Littleton, MA: Publishing S ien es.[41℄ Hollister, L. E. (1961). Medi al intelligen e: Current on eptsin therapy: Compli ations from psy hotherapeuti drugs. I. NewEngland Journal of Medi ine, 264, 291-293.[42℄ Hyman, S., Arana, G., & Rosenbaum, J. (1995). Handbook ofpsy hiatri drug therapy (3rd ed.). New York: Little, Brown.

338 BIBLIOGRAPHY[77℄ Rane, A., Tomson, G., & Bjarke, B. (1978). E�e ts ofmatemallithium therapy in a new born infant. Journal of Pedi-atri s, 93, 296-297.[78℄ Reisberg, B., & Gershon, S. (1979). Side e�e ts asso iated withlithium therapy. Ar hives of General Psy hiatry, 36, 879-887.[79℄ Remi k, R. A. (1978). A ute brain syndrome asso iated with ECTand lithium. Canadian Psy hiatri Asso iation Journal, 23, 129-130.[80℄ S hatzberg, A., & Cole, J. (1991). Manual of lini al psy hophar-ma ology (2nd ed.). Washington, DC: Ameri an Psy hiatri Press.[81℄ S hlagenhauf, G., Tupin, J., & White, R. B. (1966). The useof lithium arbonate in treatment of mani psy hoses. Ameri anJournal of Psy hiatry, 123, 201-207.[82℄ S hou, M. (1968). Lithium in psy hiatry - A review. In D. H.Efron (Ed.), Pharma ology: A review of progress 1957-1967(Publi Health Servi e Publi ation No. 1836). Washington, DC:U.S. Government Priming OÆ e.[83℄ S hou, M. (1976). Pharma ology and toxi ology of lithium. An-nual Review of Pharma ology and Toxi ology, 16, 231-243.[84℄ S hou, M., Amdisen, A., & Thomsen, K. (1968). The e�e t oflithium on the normal mind. In P. Baudis, E. Peterova, & S.V. Plzen (Eds.), De psy hiatria progrediente (Vol. 2). London:North-Holland.[85℄ S hou, M., & Baastrup, P. (1973). Personal and so ial impli a-tions of lithium maintenan e and treatment. In T. A. Ban (Ed.),Psy hopharma ology, sexual disorders and drug abuse. London:North-Holland.

BIBLIOGRAPHY 335[51℄ Kane, J., Rifkin, A., Quitkin, F., & Klein, D. (1978). Extrapyra-midal side e�e ts with lithium treatment. Ameri an Journal ofPsy hiatry, 135, 851-853.[52℄ Kroph, D., & Muller-Oerlinghausen, B. (1979). Changes in learn-ing, memory, and mood during lithium treatment. A ta Psy hi-atri a S andinavi a, 59, 97-124.[53℄ Laga e, D., & Eis h, A. (2005). Mood-stabilizing drugs: Are theirneuroprote tive aspe ts lini ally relevant? Psy hiatri Clini s ofNorth Ameri a, 28, 399-414.[54℄ Lang, E., & Davis, S. (2002). Lithium neurotoxi ity: The devel-opment of irreversible neurologi al impairment despite standardmonitoring of serum lithium levels. Journal of Clini al Neuro-s ien e, 9, 308-309.[55℄ Le amwasam, D., Synek, B., Moyles, K., & Ghose, K. (1994).Chroni lithium neurotoxi ity presenting as Parkinson's disease.International Clini al Psy hopharma ology, 8, 127-129.[56℄ Lepkifker, E., Sverdlik, A., Ian u, I., Ziv, R., Segev, S., & Kotler,M. (2004). Renal insuÆ ien y in long-term lithium treatment.Journal of Clini al Psy hiatry, 65, 850-856.[57℄ Lim, K.- Y., Yang, J.-J., Lee, D., Noh, J., Jung, M., & Chung,Y.-K. (2005). Lithium attenuates stress-indu ed impairment oflong-term potentiation indu tion. Neuroreport 16, 1605-1608. .[58℄ Linnoila, M., Saario, I., & Maki, M. (1974). E�e t of treatmentwith diazepam or lithium and al ohol on psy homotor skills re-lated to driving. European Journal of Clini al Pharma ology, 7,337-342.[59℄ Livingston, C., & Rampes, H. (2006). Lithium: A review of itsmetaboli adverse e�e ts. Journal of Psy hopharma ology, 20,347-355.

336 BIBLIOGRAPHY[60℄ Logan, J. (1976). Josh: My up and down, in and out life. NewYork: Dela orte.[61℄ Loring, D. (2005, September). Cognitive side e�e ts of antiepilep-ti drugs in hildren. Psy hiatri Times, pp. 1-10.[62℄ Mandel, M. R., Madsen, J., Miller, A. L., & Baldessarini, R. J.(1980). Intoxi ation asso iated with lithium and ECT. Ameri anJournal of Psy hiatry, 137, 1107-1109.[63℄ Marini, J. L., & Sheard, M. H. (1977). Antiaggressive e�e t oflithium ion in man. A ta Psy hiatri a S andinavi a, 55, 269-285.[64℄ May�eld, D., & Brown, R. G. (1966). The lini al and ele troen- ephalographi e�e ts of lithium. Journal of Psy hiatri Resear h,4, 207-219.[65℄ M Call, M., & Bourgeois, J. (2004). Valproi a id-indu ed hyper-ammonemia: A ase report. Journal of Clini al Psy hopharma- ology, 24, 521-526.[66℄ Meyer-Lindenberg, A., & Krausni k, B. (1997). Tardive dyskine-sia in a neurolepti naive patient with bipolar-I disorder: Persis-tent exa erbation after lithium intoxi ation. Movement Disorders,12, 1108.[67℄ Mi er, V., & Lyn h, D. M. (1974). E�e t of lithium on disturbedseverely mentally retarded patients. British Journal of Psy hiatry,125, 110.[68℄ Morrison, S., Erwin, C., Giontur o, D., & Gerber, C. (1973).E�e t of lithium on ombative behavior in humans. Diseases ofthe Nervous System, 34, 186-189.[69℄ Muller-Oerlinghausen, B., Bauer, H., Girke, W., Kanowski, S., &Gon alves, N. (1977). Impairment of vigilan e and performan eBIBLIOGRAPHY 337under lithium treatment: Studies in patients and normal volun-teers. Pharmiakopsy hiatrie Neuro-psy hopharmakologie, 10, 67-68.[70℄ Muthane, V., Prasad, B., Vasamh, A., & Satish handra, P.(2000). Tardive Parkinsonism, orofa ial dyskinesia and akathisiafollowing brief exposure to lithium arbonate. Journal of the Neu-rologi al S ien es, 176, 78-79.[71℄ National Institute of Mental Health. (1970). Lithium in thetreatment of mood disorders (National Clearinghouse for Men-tal Health Publi ation No. 5033). Ro kville, MD: Departmem ofHealth, Edu ation, and Welfare.[72℄ Pea h, M. J. (1975). Cations: Cal ium, magnesium, barium,lithium, and ammonium. In S. Goodman & A. Gilman (Eds.),The pharma ologi al basis of therapeuti s (5th ed.). New York:Ma millan.[73℄ Podskalny, G., & Fa tor, S. (1996). Chorea aused by lithiumintoxi ation: A ase report and literature review. Movement Dis-orders, 11, 733-737.[74℄ Polatin, P., & Fieve, R. R. (1971). Patient reje tion of lithium arbonate prophylaxis. Journal of the Ameri an Medi al Asso i-ation, 218, 864-866.[75℄ Prien, R. F., Ca�ey, E. M., & Klett, J. C. (1972). Comparison oflithium and hlorpromazine in the treatment of mania. Ar hivesof General Psy hiatry, 26, 146-153.[76℄ Prien, R. F., Ca�ey, E. M., & Klett, J. C. (1974). Fa tors asso- iated with treatment su ess in lithium arbonate prophylaxis.Ar hives of General Psy hiatry, 31, 189-192.

BIBLIOGRAPHY 339[86℄ S hou, M. (1957). Biology and pharma ology of the lithium ion.Pharma ology Review, 9, 17-58.[87℄ Shaw, E., Stokes, P., Mann, J., & Manevitz, A. (1987). E�e tsof lithium arbonate on the memory and motor speed of bipolaroutpatients. Journal of Abnormal Psy hology, 96, 64-69.[88℄ Sheard, M., Marini, J., Bridges, C., & Wagner, E. (1976). Thee�e ts of lithium on impulsive aggressive behavior in man. Amer-i an Journal of Psy hiatry, 133, 1409-1412.[89℄ Shopsin, B., & Gershon, S. (1975). Cogwheel rigidity related tolithium maintenan e. Ameri an Journal of Psy hiatry, 132, 536-538.[90℄ Shulman, K., Sykora, K., Gill, S., Mamdani, M., Bronskill, S.,Wod his, W., et al. (2005). In iden e of delirium in older adultsnewly pres ribed lithium or valproate: A population based ohortstudy. Journal of Clini al Psy hiatry, 66, 424-427.[91℄ Silver, J., Yudofsky, S., & Hurowitz, G. (1994). Psy hopharma- ology and ele tro onvulsive therapy. In R. Hales, S. Yudofsky,& J. Talbott (Eds.), The Ameri an Psy hiatri Press handbookof psy hiatry (2nd ed.). Washington, DC: Ameri an Psy hiatri Press.[92℄ Small, J., Kellams, J., Milstein, V., & Small, I. (1980). Compli- ations with ele tro onvulsive treatment ombined with lithium.Biologi al Psy hiatry, 15, 103-112.[93℄ Small, J., Milstein, V., Perez, H., Small, I., & Moore, D. (1972).EEG and neurophysiologi al studies of lithium in normal volun-teers. Biologi al Psy hiatry, 5, 65-77.[94℄ Smith, S., & Smith, H. (1973). The e�e t of prolonged lithiumadministration on a tivity, rea tivity, and enduran e in the rat.Psy hopharma ologia, 30, 83-88.

340 BIBLIOGRAPHY[95℄ Stip, E., Dufresne, J., Lussier, I., & Yatham, L. (2000). A double-blind, pla ebo- ontrolled study of the e�e ts of lithium on og-nition in health subje ts: Mild and sele tive e�e ts on learning.Journal of A�e tive Disorders, 60, 147-157.[96℄ Strayhorn, J., Jr., & Nash, J. (1977). Severe neurotoxi ity de-spite \therapeuti " serum lithium levels. Diseases of the NervousSystem, 38, 107-111.[97℄ Strothers, J., Wilson, D., & Royston, W. (1973). Lithium toxi ityin newborn. British Medi al Journal, 3, 233-234.[98℄ Suppes, T., Baldessarini, R., Faedda, G., & Tohen, M. (1991).Risk of re urren e following dis ontinuation of lithium treatmentin bipolar disorder. Ar hives of General Psy hiatry, 48, 1082-1088.[99℄ Swanson, C., Jr., Pri e, W., & M Evoy, J. (1995). E�e ts of on- omitant risperidone and lithium treatment. Ameri an Journal ofPsy hiatry, 152, 1096.[100℄ Swartz, M., & Jones, P. (1994). Hyperlithemia orre tion andpersistent delirium. Journal of Clini al Pharma ology, 34, 865-870.[101℄ Van Putten, T. (1975a). Why do patients with mani -depressiveillness stop their lithium? Comprehensive Psy hiatry, 16, 179-183.[102℄ Verrotti, A., Gre o, R., Latini, G., & Chiarelli, F. (2005). En-do rine and metaboli hanges in epilepti patients re eiving val-proi a id. Journal of Pediatri Endo rinology and Metabolism,18, 423-430.[103℄ Weiner, R., Whanger, A., Erwin, C., & William, W. (1980).Prolonged onfusional state and EEG seizure a tivity followingBIBLIOGRAPHY 341 on urrent ECT and lithium use. Ameri an Journal of Psy hiatry,137, 1452-1453.[104℄ Weingartner, H., Rudorfer, M., & Linnoila, M. (1985). Cognitivee�e ts of lithium treatment on normal volunteers. Psy hopharma- ology, 86, 472-474.[105℄ Wide, K., Winbladh, B., & Kallen, B. (2004). Major malfor-mations in infants exposed to antiepilepti drugs in utera, withemphasis on arbamazepine and valproi a id: A nation-widepopulation-based register study. A ta Paediatri a, 93, 174-176.[106℄ Wilson, A., S hild, H. O., & Modell, W. (1975). Applied phar-ma ology (11th ed.). New York: Chur hill Livingstone.[107℄ Yao, C.-J., Lin, C.-W., & Lin-Shiau, S.-Y. (1999). Altered intra- ellular al ium level in asso iation with neuronal death indu edby lithium hloride. Journal of Formosan Medi al Asso iation,98, 820-826.[108℄ Zetterstrom, R., Solomin, L., Jansson, L., Ho�er, B., Olson,L., & Perlmann, T. (1997). Dopamine neuron agenesis in Nurr1-de� ient mi e. S ien e, 276, 248-250.