A CASE OF TREATMENT- -RESISTANT SCHIZOAFFECTIVE DISORDER BIPOLAR TYPE AND SLEEP DISORDERED BREATHING Summary: This is a case of a treatment-resistant schi- zoaffective disorder-bipolar type (SAFO) patient with tardive dyskinesia (TO), obstructive sleep apnea (OSA), and adult onset diabetes mellitus (AOOM). This paper has been endorsed by a Director of the Harvard South Shore Residency Training Program, Harvard Medical School, Boston, MA in a competition for the 1999 APNLilly resident Research Award. Deyan Budimirovich! James Leviu? Erick Garshick 3 1 Haven Psychiatric Hospital 2 Yale University School of Medicine, Opt. of Psychiatry, New Haven, Connecticat 3 Harvard Medical School, Boston, Massachusets records available to us (table 1). He was first admitted at the age of 22. His girl- friend, towards whom he was possessive and jealous, left him shortly before this admission which led to an escalation of his drinking. He was brought into the hos- pital from a local bar in an intoxicated state because of belligerent behavior. He was agitated, hostile, paranoid, and expe- riencing auditory hallucinations. He was diagnosed as suffering from an acute schizophrenic reaction and treated with chlorpromazine (CPZ), as well as eight electrocorivulsive treatments during his six-month hospital stay. Upon discharge ! he lived with his father and stepmother. In 0' o the community, over the next couple of g years, he first worked as sales representa- tive and then off and on for about one year as a construction worker. S§ o At the age of 25, he had his second psy- chiatric admission to a state hospital for four weeks because he had threatened 127 PAST PSYCHIATRIC HISTORY Case presentation Mr. G is a 52-year-old, white, divorced ma- le who has been unemployed since age 25, and who has been living in a foster home on and off over the last three years. His main problems are mood instability, and demanding behavior superimposed on a 30-year history of chronic psychosis. For the past two years he has carried an Axis I diagnosis of SAFD-Bipolar type. He has a history of partial response to medications. Comorbid conditions for Mr. G include a history of heavy alcohol abuse starting in the service and in remission for 20 years, a history of medication abuse (especiallyben- zodiazepines), severe nicotine dependency, morbid obesity with OSA, and AODM. Overall, Mr. G had eighteen psychiatric hospitalizations, fifteen of which have been well documented by a medical
Transcript
A CASE OFTREATMENT-RESISTANTSCHIZOAFFECTIVEDISORDERBIPOLAR TYPE AND SLEEPDISORDERED BREATHING
Summary: This is a case of a treatment-resistant schizoaffective disorder-bipolar type (SAFO) patientwith tardive dyskinesia (TO), obstructive sleepapnea (OSA), and adult onset diabetes mellitus(AOOM). This paper has been endorsed by a Directorof the Harvard South Shore Residency TrainingProgram, Harvard Medical School, Boston, MA in acompetition for the 1999 APNLilly resident ResearchAward.
Deyan Budimirovich!James Leviu?Erick Garshick3
1 Haven Psychiatric Hospital
2 Yale University School of Medicine,Opt. of Psychiatry, New Haven, Connecticat
3 Harvard Medical School, Boston,Massachusets
records available to us (table 1). He wasfirst admitted at the age of 22. His girlfriend, towards whom he was possessiveand jealous, left him shortly before thisadmission which led to an escalation ofhis drinking. He was brought into the hospital from a local bar in an intoxicatedstate because of belligerent behavior. Hewas agitated, hostile, paranoid, and experiencing auditory hallucinations. He wasdiagnosed as suffering from an acuteschizophrenic reaction and treated withchlorpromazine (CPZ), as well as eightelectrocorivulsive treatments during hissix-month hospital stay. Upon discharge !he lived with his father and stepmother. In 0'
othe community, over the next couple of gyears, he first worked as sales representa- ~
tive and then off and on for about one yearas a construction worker.
S§~o
At the age of 25, he had his second psy- ~
chiatric admission to a state hospital forfour weeks because he had threatened 127
PAST PSYCHIATRIC HISTORY
Case presentation
Mr. G is a 52-year-old, white, divorced male who has been unemployed since age 25,and who has been living in a foster homeon and off over the last three years.
His main problems are mood instability,and demanding behavior superimposed ona 30-year history of chronic psychosis. Forthe past two years he has carried an Axis Idiagnosis of SAFD-Bipolar type. He has ahistory of partial response to medications.Comorbid conditions for Mr. G include ahistory of heavy alcohol abuse starting inthe service and in remission for 20 years, ahistory of medication abuse (especiallybenzodiazepines), severe nicotine dependency,morbid obesity with OSA, and AODM.
Overall, Mr. G had eighteen psychiatrichospitalizations, fifteen of which havebeen well documented by a medical
........tv00 ENGRAMI, 22 (2000) 3-4
Table 1. Mr. G's Admission Characteristics
ADMISSION YEAR AGE ALCOHOL MOOD/ AUDITORY DELUSIONS PARANOID PRESSURE BEHAVIOR TRIGGER MEDICATIONS
.9 11/88 44 sober <> no yes yes moderate yes moderate separation Fluphe. Dec., u & CBZ
10 6/90 46 sober > no yes yes severe yes severe ex-wife visit dle"li & Fluphe. abruptly
11 8/90 46 sober < no yes no mild no ? ? Fluphe. Dec. & Li
12 1992 48 sober <> no yes yes moderate yes moderate ? Fluphe. Dec.& Li
13 5/95 51 sober <> no yes no moderate yes moderate son's visit Risperidal, Li & sertaline
14 12/95 52 sober <> no yes yes moderate yes moderate ? as above plus imipramine
15 2/96 52 sober > no yes yes severe yes severe ? die li abruptly; Risperidal
Mood!Affect: < depressed; > elated; < > mixed or labile; ? : Information unknown; # interepisodes, the medications intake was often erratic;Hall. : Auditory hallucinations; • no h/o a voices keeping PPT : Precipitant psychosocial factor;up a running commentary or two more voices conversing; Paranoid ideas: non-delusional;
people with a shotgun. On admission, hebelieved everybody was persecuting himand he behaved in a belligerent and negativistic manner.
He was treated with intramuscular injections of haloperidol involuntarily for oneweek before accepting an oral medication.He was then transferred to a another hospital where he behaved in a demanding,sarcastic, suspicious, and provocativemanner. He was diagnosed with schizophrenic reaction, paranoid type, treatedwith CPZ and trifluoperazine, and thendischarged four weeks later. He started hisoutpatient treatment at the age of 26 andwas treated for suspiciousness, depressionand anxiety. He received individual,group, family, and relaxation therapy, allwith limited results. His psychopharmacological treatment was characterized bypolypharmacy. Over the course of his illness he has been treated with a combination of conventional antipsychotics (including decanoate form), antidepressants,and antianxiety agents. The medicationsimproved his depression and anxiety, andtook the edge off of his paranoia. He was,however, »never sure that the plot was notagainst me«, and he remained easily provoked and highly sensitive to slights in hisinterpersonal relationships.
Between the age of 25 and 30 his occupational functioning was poor and his socialfunctioning was marginal. His major social interactions involved patients andstaff in a Day Treatment Program. Mr. Gwould refuse to »go out« with his brothersor father. During this period he gainedweight (e.g. over 20 lbs.), used and abused alcohol, and felt he was a »failure«.Despite this, at the age of 30, he was ableto marry and began living independently.He had two sons during the first six yearsof his marriage. There was marital discordfrom the beginning. He did not work after
the age of 25 but supported his family onhis disability income.
Starting at the age of 32, Mr. G was psychiatrically hospitalized fifteen times overthe next 20 years, including 6 episodes ofclassic mania and 6 episodes of mixedmania; virtually all these episodes wereaccompanied by psychotic features. Healso had three episodes of major depression, without psychotic features. His admission clinical presentation usually wascharacterized by anxiety, depression, agitation and paranoid delusions oftenaccompanied by impulsive, demandingand threatening behavior. A typical example for the patient was his admission atthe age 34 when he presented with grandiose and persecutory delusions believ-ing that e.g. »FBI was after me my wife isinvolved in a plot against me «. and hewas treated with 1200 mg of chlorpromazine a day. A pattern has emerged wherethe patient seeks admission himself whendepressed but requires involuntary admissions when manic. Additionally, the patienttends to leave the hospital against medicaladvice or on unauthorized absence, prior tohis clinical stabilization. He also has had atendency to increase his medication dosageimpulsively in an attempt to relieve hisanxiety or depression, and inducing lithium toxicity. He has resisted decreasing hisfluphenazine dosage, thus receiving, attimes, approximately 100 mg/day combining his decanoate and oral dosage. Hedeveloped drug-induced parkinsonian
'i'symptoms and tardive dyskinesia at the ~
age of 37. In addition, he gained 80 po- gunds between the age of 25 and 37. ~
N
On admission, at 42, Mr. G was re-diag- N
nosed as having an atypical affective disor- 5@
der because of the prominence of affective ~symptoms, alternating between mania and a3depression, as well as the absence of afamily history of schizophrenia. 129
Lithium and later the combination oflithium and carbamazepine (CBZ) weretried with limited success.
At the age of 44, he had three further psychiatric admissions. In the first, he manifested delusions and hallucinations, andwas found to have a lithium level of 1.50.He was also evaluated for GSA and nocturnal oximetry revealed a decrease in hisoxygen saturation to 60 % on two occasions. His next two admissions were inthe context of his separation and, eightmonths later, divorce from his wife. During the course of their separation, Mr. G'swife took out a restraining order againsthim because of his threatening behavior.During this time he lived in multiple motels and made numerous verbal threatsagainst his wife over the telephone, whichlead to several psychiatric admissions.
He was hospitalized on the medical service six times between the age of 45 and 46for evaluation of GSA, adustment of hismedication and to rule out neurolepticand lithium toxicity. Prior to his admission at the age of 46, he had numerouschanges in his medications. His lithiumand fluphenazine were discontinued abruptly during a medical admission due to»possible neurotoxic effect and nicotinetoxicity«. On the day of his admission, hisex-wife visited him, and informed himthat she was planning to marry her thencurrent boyfriend. He became distraught,threatened to jump out of a window, andwas involuntarily admitted. He presented
~
~ with mania with psychotic features and he§' required four-point restraint as well aso2!. intramuscular haloperidol to control his
agitation. He was treated with lithium andhaloperidol and after two weeks graduallyimproved. Characteristically, however, heleft the hospital against medical advicebefore full stabilization.
130
His next psychiatric admission was at theage of 48. He was brought in by the policeafter allegedly harassing a waitress in arestaurant by trying to take her picture. Hehad also made 900 phone calls in themonth prior to this admission. On admission, he was depressed and paranoid. Heexhibited a great deal of attention seekingbehavior and had a severe tremor in bothhands. He was then taking intramuscularand oral preparations of fluphenazine andlithium. This was supplemented with sertraline which improved his depression, but,again, he left on unauthorized absence. Typically, upon discharge after his divorce, hewould return to live in his apartment byhimself, not work and have few social interactions. Soon he would request more medications from his psychiatrist, looking forthe addition of benzodiazepine and sertraline. As an outpatient, he was started on pindolol 20 mg a day, which temporarily improved his impulse control and his mood.
In 1995, at 51, he was first started on risperidone 6 mg a day, due to a history of severe extrapyramidal side effects and moderate TD, and he responded favorably. Thehusband of his ex-wife dropped off his 14year-old son to live with him which triggered his next admission. Mr. G expressedconcern to his psychiatrist that his son wasbeing neglected and a child-neglect-casewas filed.
On admission, he presented with dysphoric mood, labile affect, and non-bizarreparanoid delusions. Once admitted, hewas particularly demanding in presentinghis needs to the staff. On discharge fromthe hospital, his diagnosis was changed toSAFD-Bipolar type.
As an outpatient, he continued to complain of depression. His sertraline was discontinued and he was begun on a trial ofimipramine 200 mg a day and fluoxetine10 mg a day (in addition to risperidone 6
131
mg a day and a therapeutic lithium level)for five months with limited effect, and,thus, was switched again to sertaline.
Mr. G was next admitted a month laterbecause of erratic use of his medicationincluding increasing his sertraline dosageto 200 mg a day, on his own, and discontinuing his risperidone. Despite a lithiumlevel of 1.05 meq/liter, he presented witha mixed mood episode with psychosis(dysphoric mood, labile affect, and bizarredelusions). Once admitted, his psychosissubsided on re-instituting risperidone 6mg per day. However, after his sertralineand lorazepam (initiated to provide additional sedation) were tapered off, within aweek, he developed crying spells, irritability and increased affective lability. Hetended to become hypomanic on sertraline and more difficult to manage, thus divalproex-sodium was added to his regimen to stabilize his mood further beforere-initiating an antidepressant. However,again, he left on unauthorized absence.
A few days later because of his worseningdiabetes his outpatient psychiatrist abruptly stopped Mr. G's lithium, which hehad continuously been on for the past 8years. Two weeks later he was brought inby the police and involuntarily admittedbecause of aggressive and odd behavior,inc!uding walking barefoot in the street infreezing weather. He presented in a dysphoric-manic state with mood-incongruent, bizarre, persecutory and religious delusions. With the re-introduction of risperidone at the dosage 6 mg per day duringthe first week of his admission, his insomnia, anxiety and restlessness were dramatically exacerbated. He was described bythe staff as »the worst he has ever been«.It was felt that the worsening of his condition had to do with risperidone-associated severe behavioral activation. He wasrestarted on lithium and gradually impro-
ved after two weeks. Despite high-therapeutic levels of lithium and divalproexsodium, and with ongoing treatment withrisperidone he was still depressed and demanding. Since he tended to become hypomanic on antidepressants and more difficult to manage, his risperidone was gradually increased to 10.5 mg per day, significantly improving his depression. This, however, led to a worsening of his extrapyramidal side effects. His diagnosis remained schizoaffective disorder-bipolar type.
Follow up three years later with his primary psychiatrist, despite several changesin his living arrangement, revealed no subsequent psychiatric hospitalizations orrelapses. Mr. G was on same medication regimen except increase in risperidone doseto 11 mg per day and added benztropinbecause of his tremor and drooling.
PAST MEDICAL HISTORY
Mr. G has been diagnosed with OSA, andhas used nasal continuous positive airwaypressure (CPAP) since the age of 45,which he tolerates poorly. He continues tosmoke two packs of cigarettes per day,exhibiting severe nicotine dependence. Hehas AODM and had been insulin dependent for approximately two years. His headCT without contrast, at the age of 52, wasnegative. His neuropsychological testingat the same age showed an average intelligence' no signs of hypoxemic amnesia ordementia, but revealed evidence of impairment in executive functioning. He also !had a head CT scan and a electroencep- 8halogram study at the age of 42, both of ~
which were negative.
Mr. G did not have history of head trauma, ~seizures, cerebrovascular accidents or ~other neurological disorders. Three years ~later, his AODM was stable on oral antidiabetic and diet only.
\
PERSONAL HISTORY
Mr. G was the third of four siblings. Hisfather worked as a laborer and was an alcoholic. Mr. G described him as »very moody«, hostile and distant. Mr. G's motherwas a housewife and he described her as»depressed«. He felt she had neglected himemotionally and »teased« him though,despite this, he still felt closer to her thento his father. Mr G's developmental historywas normal without a history of any prenatal insult, early developmental delay, formally diagnosed learning disability, andattention deficit hyperactivity disorder orconduct disorder. He did, however, havereading and spelling difficulties, and repeated the third grade. In school, he wasafraid to play with other children and related poorly to his teachers.
His mother died at the age of 59 from acerebral hemorrhage when Mr. G was 14years old. Both he and his sister were profoundly affected by this loss which ledtheir father, initially, to be extremely permissive with them. Mr. G's father re-married two years later and Mr. G adjusted»reasonably well« to his stepmother, butfelt anger toward his father for this»quick« re-marriage. At the age of 17, hedescribed himself as »scared and verynervous«. He finished high school at 19.At the age of 26, to his therapist, his coreissues were feeling sadness and abandonment over losing his mother when he was14, having anger at his father for father's
l' »quick« re-marriage, and feeling of rejec~ ted and depressed following the loss of hisg first girlfriend while in the service, trig~N gering his first psychiatric treatment.N
132
Discussion
A) Differential diagnosis of chronicpsychosis/psychopathology of SAFD
Mr. G's psychiatric disturbances wereprincipally in the spheres. of mood,thought content, and behavior. He hassuffered from a combination of episodescharacterized by mood-congruent andincongruent psychosis, an affective disturbance without psychosis, and psychoticepisodes without an affective disturbance.
Mr. G's diagnosis between the age of 22and 42 was chronic schizophrenia, paranoid type. His longitudinal course wasepisodic, however, with interepisode residual non-bizarre delusions and ideas ofreference, and marginal social functioning. With stress, these ideas becamefrank delusions of persecution and ideasof reference. Even though his diagnosiswas changed to atypical bipolar disorder atthe age of 42, his non-bizarre persecutoryand referential delusions were worse inhis 40's than in his 30's, and were presentcontinuously.
In addition, after separation from his wifeat the age of 44, and especially after hisdivorce at 45, his course changed fromepisodic to deteriorating, with two uninterrupted periods of illness. The first period was between the ages of 44 and 46,during which time he had four psychiatrichospitalizations and several admissionsfor treatment of his OSA. Since the age 46,however, he used CPAp, and required nomedical admissions.
The second period was between the agesof 48 and 52, during which time he hadfour additional psychiatric admissions.During this period of time he met DSM-IVcriteria for three mixed and one manicepisode concurrent with symptoms thatmet Criterion A for schizophrenia (non-
bizarre persecutory and bizarre delusions,and disorganized behavior). During theinitial phase of his second uninterruptedperiod of illness, there have been nonbizarre persecutory and referential delusions, and disorganized behavior, for atleast two weeks in the absence of prominent mood symptoms (Criterion B). Thepatient's mood symptoms have been present for a substantial portion of the totalduration of his illness (Criterion C). Thesymptoms were not present due to directphysiological effects of a general medicalcondition (his OSA was stable) or a substance (Criterion D). His diagnosis wasthus changed to SAFD-Bipolar type at theage of 5l.
In considering Mr. G's diagnosis, his history of alcohol abuse, interepisode chronicdysphoria, a positive family history of affective disorder and negative family historyfor a chronic psychotic disorder, and along history of requiring both a mood stabilizer and anti psychotics suggest that Mr.G had an affective subtype of SAFD (Tsuang M., et al., 1986; Levitt]., Tsuang M. etal., 1988; Williams P., and McGlashan T.,1989; Levitt]., Tsuang M. et al., 1990; andTsuang M., Levitt]. et al., 1995). Mr. G'srelatively good premorbid adjustment andaffective symptomatology were clearlypresent for a substantial period of his illness. This, together with a relatively preserved capacity for establishing rapportwith others, might further suggest that hehad an affective subtype.
Therefore, even though he carried thediagnosis of paranoid schizophrenia for 20years (during 1960s and 1970s), schizophrenia in its pure form is not a strongpossibility as the diagnosis for Mr. G. Ofnote, during the 1960s and 1970s patientswith mixed schizophrenic and affectivefeatures tended to be diagnosed as schizophrenic (Pope H., et al., 1978).
Pure bipolar disorder should also be considered as a possible diagnosis for Mr. G.At the age of 42, he was re-diagnosed ashaving an atypical affective disorder, andlater on as bipolar disorder not-otherwisespecified. His bipolar disorder clearly wascomplex, meaning that in addition to medical comorbidities he had psychoticsymptoms and, he also carried an Axis IIdiagnosis of mixed personality disorderwith prominent borderline features. Mr. Gwas treated with anti psychotics for 30years (30-40% of bipolar patients remainon an antipsychotic) and during the last 8years, lithium was added. Despite thisregimen, he had continuous behavioralproblems during his admissions, andinterepisodically. Although he was able tomarry, have children, and live independently for many years, he suffered a declinein his social and occupational functioning(not characteristic of pure bipolar patients).
Overall, the outcome of SAFD has beenreported as intermediate to that of schizophrenia and affective disorder (Tsuang M.,and Marneros E., 1986; Williams P., andMcGlashan 1:, 1987; McGlashan 1:, andWilliams P., 1990), which seems mostconsistent with Mr. G's course.
B) Psychophannacological treatmentof SAFD-Bipolar type - focuson risperidone
There are no drugs approved by the FDA 1"for the treatment of SAFD, and few con- M
8trolled acute treatment studies of SAFD g
~used diagnostic criteria that resemble Cur- C'l
rent definitions of the disorder. The find- C'l
ings of these studies must, therefore, be ~considered preliminary (Keck P. et al., C-'
Z1996). However, these findings suggest u.l
typical antipsychotics and lithium produced comparable albeit incomplete bene- 133
ficial effects for SAFO-Bipolar type, manicphase, except in acutely agitated patientsfor whom CPZ produced more favorableresults. These studies also suggest thatthe combination of lithium and conventional antipsychotics might be superior toanti psychotics alone (Keck RE. et al.,1996). This indirectly supports the diagnosis of SAFO for Mr. G, as he had beenon fluphenazine for more than 20 years,and on lithium for 8 years. Although combining antipsychotic and thymoleptictreatment represents common clinicalpractice for the prophylactic treatment ofSAFO in clinical practice, the efficacy ofthis treatment has not been rigourouslystudied in controlled clinical trials, andhence, further research is warranted (SirisS.G. et al., 1993).
The empirical data supporting the efficacyof divalproex-sodium and CBZ in thetreatment of SAFO are limited.
In a review of 5 controlled studies it wasconcluded that divalproex-sodium is effective in the treatment of schizoaffectivemania and psychotic mania (McElroy SL,Keck PE, et al., 1992), however, doubleblind, controlled trials are needed to establish the efficacy of these agents beyondtheir usage in bipolar disorder to SAFO(Keck PE et al., 1996). In the case of Mr.G, divalproex-sodium did not preventrisperidone-induced severe behavioral activation despite medium-therapeutic level,however, later on it appeared to be usefulas an adjunct to lithium.
'¢ A new generation of »novel« antipsy-I
r<'l choties, which began with clozapine, andg continues with risperidone and olanzap-o~ ine, appears to be promising for the treat-NN ment of major mental disorder. McElroyet~ al. (1999) reviewed a number of con~ trolled and uncontrolled studies examinr5 ing the role of risperidone and olanzapine
in SAFD. The results seem mixed, with
134
both risperidone and olanzapine appearpromising in some patients with SAFO,but both agents may cause problems insome SAFD patients.
It has been reported that both clozapineand risperidone share similar antipsychotic effects (Heinrich K. et al., 19'94). Risperidone, a mixed 5HT2/02 receptor antagonist, has demonstrated efficacy as anantipsychotic in the treatment of schizophrenia with the additional advantage ofcausing less extrapyramidal side effectsthan conventional anti psychotics (BorisonR.L. et al., 1992; Chouinard G. et al.,1993). At higher doses, however, risperidone induces EPS, as we observed in Mr.G when he was on 8 mg, and especiallywhen he was on 10.5 mg per day. We alsoobserved that Mr. G exhibited less restlessness with a 0.5-mg per day increase indosage compared with 1 mg per day increase, possibly due to a steep dose-responsecurve in the high dose range t> 7 mg perday) for akathisia in risperidone.
Overall, during a period of one year whereMr. G was on 6-mg risperidone per day, inaddition to high-therapeutic levels of lith iurn, his depressed mood did not improve.This was supported by a need for severalantidepressant trials with only limited,and temporary improvement. His depressed mood, however, significantly improved when his risperidone dose was increased to 10.5 mg per day. This was supported not only by clinical observationbut, also, by a significant decrease of hisHAM-O score, prompting Mr. G's longawaited discharge. A follow-up at 6months of outpatient care, and a follow upthree years later showed continued maintenance of Mr. G' s mood improvementwithout an antidepressant, currently being on risperidone 11 mg per day.
There have been reports in the literature(McElroy S. et al., 1996) about an antide-
pressant effect of risperidone in a doseshigher than 10 mg per day, compared tolower doses such as 4-6 mg per day,whichresulted in antipsychotic effects alone. Asmall number of recent reports suggestthat risperidone's receptor blocking properties may exert antidepressant effects inpatients with SAFD. The preliminary findings from the three recent studies in thetreatment of patients with SAFD suggestthat the thymoleptic effect of risperidonemay differ from those of clozapine in thatrisperidone may possess unidirectionalantidepressant rather than anti manic ormood-stabilizing properties (Dwight M.M. et al., 1994; Ceskova E. et al., 1993;Hillen A. et al., 1992).
Recently, Muller-Siecheneder comparedthe efficacy of combination haloperidol!amitriptyline therapy with risperidonemonotherapy, in a prospective study. Inthe SAFD subgroup, the data has showeda similar degree of improvement of psychotic and depressive symptoms in bothgroups. The existing data are, at least,suggestive that risperidone exerts someantidepressant effect, which may be dueto its antagonism of 5HT2 and alpha-receptors (Keck P.E., 1998). The above findings indicate the need for short- and longterm controlled trials of risperidone, andquite possibly olanzapin (Tollefson GD etal., 1998), regarding their's antidepressant profile.
On the other hand, there was a study ofmood stabilizer resistant bipolar patients,with psychotic features, who responded tothe addition of risperidone (Tohen M. etal., 1994). The patients in this study, however, were also either on lithium, or ananticonvulsant. This fits in with the observation that patients with SAFD-Bipolartype, were more likely to respond to risperidone in combination with thymoleptics than to resperidone alone (Keck PE etal., 1994). Therefore, some authors (e.g.,
Keck PE, 1998), consider the use of risperidone for manic symptoms controversial, in part due to lack of controlled clinical trials establishing its efficacy for thisindication although several controlled clinical trials examining the effect of risperidone on mood are currently in progress.
Consistent with the posited unidirectional antidepressant effect of risperidone area number of studies which suggest thatmanic symptoms may be exacerbated orinduced by risperidone (Dwight M. et al.,1994; Byerly M.J. et al., 1995; Koek R.J.,1996; Diaz S.F., 1996; Schnierow B.J.,1996; Sajatovic et al., 1996). Additionally,it was recently reported mood stabilizers,including lithium and divalproex-sodium,in patients receiving documented therapeutic blood levels, failed to preventrisperidone-induced mania (Barkin J. etal., 1997). Mr. G had his last two mixedpsychotic episodes despite treatment wihdocumented high-normal therapeutic levels of lithium. Mr. G also exhibited severebehavioral activation of his psychoticmania, during the first week of the secondof these two episodes, when risperidone 6mg per day was re-instituted. The resulting behavioral activation was more severeand qualitatively different than his priorepisodes of akathisia and was manifestedby significant worsening in his insomnia,anxiety, and restlessness. The presence ofmedium-normal therapeutic level of divalproex-sodium did not prevent the behavioral activation. Mr. G gradually improvedtwo weeks only after lithium was added to
'fhis regimen. r<")
8The observed behavioral activation might g
~be, at least in part, explained via several N
preclinical findings. First, the most specif- N
ic high affinity SHT2 receptor antagonist ~ritanserin increased both burst firing and o
zthe firing rate of midbrain dopamine neu- U.l
rons in a dose-dependent manner (UgedoL. et al., 1989). These findings suggest 135
that serotonin may exert inhibitory control of midbrain dopamine cell activity via5HT2 receptors. The 5HT2 blockade-induced stimulation of midbrain dopamineactivity might promote switching to orworsening of mania. The same mechanism may be responsible for a desirableimprovement in drive, motivation, andmood observed in SAFD-Depressed typepatients (Dwight M. et al., 1994).
Second, increased activity of the frontallobe in mania has been implicated. Dopamine (DA) axons innervate the medialprefrontal cortex (PFC), where they synapse with both pyramidal cells and someGABAergic interneurons (Deutch A.,1998). 5HT axons also terminate in thePFC and appear to form synapses predominantly with interneurons. The 5HT2areceptor was shown to be localized predominantly to the apical dendrites of pyramidal cells and also to a subset of interneurons (Ibid.). The data suggest that OA,acting predominantly through a 02-likereceptor, and serotonin, acting through a5HT2 receptor subtype, may coordinatelyregulate interneurons in the PFC, andthus regulate both cortical outflow andlocal circuitry.
Third, stabilization of sleep is a paramountfactor in the treatment and prophylaxis ofmania. The activity of 5HT neurons is lowest during the slow wave sleep (SWS orNREM phases 3 and 4), and highest duringwaking (Lemoine P., 1996). 5HT antagonist ritanserin provoked insomnia, and cle-
<:t~ arly and rapidly increases SWS. Ritanserin§' may increase an arousal and SWS from theo2!- very first day (Ibid). Risperidone has a sim-i=j ilar 5HT profile as ritanserin, and appears~. to exhibit similar effects on sleep and aro~ usal. Further, risperidone may indirectly~ have an additional manicogenic effect by
decreasing sleep.
136
As mentioned above, risperidone mightinduce mania, and this manicogenic effectof risperidone may have been a factorresponsible for the induction of Mr. G'smanic episode(s). Other possible contributing factors include his history of: tricyclic antidepressant exposure (e.g. imipramine) (Wehr and Goodwin, 1987)4 theuse of selective reuptake inhibitors (SSRI)fluoxetine (Hon and Prescorn, 1989) orsertraline (Henry et al., 1992; Heiman S.,March ]., 1996), the abrupt discontinuation of lithium (Trisha S. et al., 1991), andthe natural course of Mr. G's illness. Someauthors have suggested, regarding SSRIs,that they have diverse effects on severalneurotransmitter systems (Stahl S., 1998).For example, sertraline appears to havemodest effects on dopamine and norepinephrine reuptake. It remains difficult todisentangle and point out one of the abovepossible factors in the case of Mr. G. Forexample, in his first, mixed episode at theage 0 51, he was also on 6-mg risperidoneand 50 mg sertraline prior to admission.Six months later, in his second mixedepisode, imipramine was discontinuedfour weeks prior to admission, and at thetime of admission he was also on 6-mgrisperidone and 200 mg sertraline. Hislast admission was an episode of psychotic mania, after lithium was abruptlydiscontinued two weeks prior to admission.Simultaneously, he was continued on 6-mgof risperidone, a low therapeutic level ofdivalproex-sodium, and 50 mg of sertraline. This episode is similar to one at theage of 46, after his lithium and fluphenazine were abruptly discontinued.
On a follow-up three years later, Mr. Gremains relapse-free, and continues to bemaintained on risperidone, lithium, anddivalproex-sodium.
C) Comorbidity of sleepdisordered breathing
Based on clinical evaluation and nocturnaloximetry tracings, Mr. G likely has GSA.He was first evaluated for the possibilityof GSA at the age of 44. At that time heweighed 283 pounds, and was noted tohave periods of both apnea and »dyspnea«at night, accompanied by thrashing. As hispsychiatric illness worsened he gainedweight steadily. At the age of 25 he hadweighed 170 pounds, and at the age of 41he weighed 260 pounds. Screening nocturnal oximetry revealed a cyclic patternof oxygen saturation with numerous episodes of desaturation from the mid 90%range to a low saturation of 60%. The cyclic pattern of the oxygen saturation isconsistent with GSA. At the age of 45,repeat nocturnal oximetry revealed cyclicrepetitive desaturation from a baseline of94% to oxygen saturation below 70%.
On a follow up study the following evening when nasal CPAP at 10 ern waterpressure was worn for 1 hour cyclic desaturation was not noted. At the age of 49,with 3 hours ofCPAP at 10 em water pressure, the saturation remained above 90%,with similar findings at the age of 50. Hedescribed a pattern of fragmented sleepeach night, taking daily naps, and wakingup coughing and choking.
At the age of 51, he underwent polysomnography (PSG). He was able to spendonly 2 hours and 13 minutes in bed, sleptfor only 61 minutes and reached sleepstages 1 and 2. He wore CPAPat 5-cm water pressure, and had no obstructive apneas. He said he felt closed in during thestudy, and got up several times for water.He has declined additional attempts atPSG because of his inability to stay in thesleep laboratory for more than severalhours, and his continued drive to smoke
cigarettes. Pulmonary function testingresulted in normal spirometry at the ages44, 48, and 49.
Discussion: Mr. G is markedly obese, hashad nocturnal choking, and has had daytime sleepiness, clinical features that sug.gest the diagnosis of GSA (KrygerM.H.,1992). Loud snoring is an additionalfeature commonly noted in GSA, but Mr.G is unsure whether he snores. Based onreports obtained during his psychiatricadmissions, snoring has been noted. Hispsychiatric condition has prevented himfrom undergoing comprehensive diagnosis and treatment of his underlying GSA.As a result of agitation and anxiety, andthe urge to smokes cigarettes chronically,he was unable to stay in bed more than 2to 3 hours to undergo either a full nightoximetry study or PSG. The advantage ofPSG is the recording of EEG data to document sleep stage. Airflow from the noseand mouth is recorded, together withchest and abdominal motion, and oxygensaturation information. An obstructiveapnea is defined by the absence of airflowwith the continuation of respiratoryefforts. During the periods where airflowis absent or decreased, the oxygen saturation can fall, and then rise in a cyclic fashion once the obstruction is broken as thepatient experiences an arousal.
By demonstrating a cyclic change in oxygen saturation the recording of oximetrycan suggest the diagnosis of GSA (CooperB.G. et al., 1991; Serier et al., 1993). ~
8Because of the failure of Mr. G to undergo gthe full sleep study, a definitive diagnosis ~of GSA is not possible. It has been an C'l
experience that with severely ill psychotic ~patient, such as Mr. G, full compliance 0
zwith the diagnostic tests is often incom- LU
plete, which further complicate the management of such patient. In this case, his 137
clinical presentation and oximetry tracingdone without the use of nasal CPAPstrongly suggest the diagnosis of GSA. Hehas been asked to use nasal CPAP duringall naps. With nasal CPAP air is blowninto the upper airway to act as a pneumatic splint for the upper airway. The oximetry recordings suggest that nasal CPAP isbeneficial in Mr. G, although the extentthat Mr. G slept during the CPAP trials isnot known.
The daytime sleepiness, whether due tosleep fragmentation as a result of obstructive apneas or inability to initiate andmaintain sleep as a result of his psychiatric illness, will lead to worsening of mania, impaired cognitive functioning, andmotor performance. Medication that canresult in excess sedation may make GSAworse. In the case of Mr. G, recent neuropsychological testing revealed intactbasic and sustained attention span, language, spatial and visual memory, andlikely intellectual functioning. In contrast,his executive function (e.g. working memory, abstraction, complex attention,organization, verbal fluency) were moderately to severely impaired, with greaterimpairment on more complex tasks. Hismemory testing revealed a borderlineimmediate and delayed verbal free recall,but normal immediate and delayed visualfree recall, with significant improvementfrom cueing. Overall, the pattern was suggestive of frontal lobe, and adacent limbicsystem structures dysfunction, with someevidence of left hemisphere dysfunction.
'<t There was no evidence of a degenerativeI
r<') cognitive or neurologic process, and noO'g clear evidence of hypoxic amnestic disor-~ der. The pattern of mild memory impairi':J ment WIth moderate to severe impairment~. in executive functions was consistent with~ SAFD, but it is unclear what was the con~ tribution of Mr. G's sleep-disordered
breathing and medication.
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Nonetheless, abnormalities of attention,concentration, as well as performance andmood have been associated with GSA(Strohl KP. and Redline S., 1996). In agroup of individuals with GSA, the profileof Mood State questionnaire was completed before and after treatment with" nasalCPAP (Derderian SS et al., 1988). PostCPAP treatment there was a significantimprovement in depression and fatiguescores, and in the Total Mood Disturbancescale. Depression, as defined using theZung Self-Rating Depression Scale, wasfound in 45% of a series of 55 patientswho underwent PSG and were found tohave GSA (Millman RP et al., 1989). ThusGSA is associated with significant neuropsychiatric symptoms, even in theabsence of an overt affective disorder. Inthe case of Mr. G, it could have been oneof the contributing factors to his longstanding complaints of depression.
Mr G. gained total 140 pounds since theage of 25, during the course of chronicantipsychotic treatment, where he gaineda 50 lbs since the age of 42 when lithiumwas initiated. The possible mechanisms ofweight gain in antipsychotics with DA and5HT antagonism are 5HT2c-receptor blockade, impaired satiety etc. (Perkins D.,1998).
Obesity is a well-known risk factor for several medical comorbidities, including type II diabetes and sleep disordered breathing, both developed in the case of Mr. G.An important factor responsible for longstanding difficulty in providing effectivetreatment for his sleep is his sleep disordered breathing. Since Mr. G has bipolartype of SAFD, sufficient sleep is a paramount factor in the stability of his moodand behavior. In GSA, sleep is fragmentedand thus GSA could contribute to his treatment resistance. For example, OSA wasreported to be responsible in cases of
treatment-resistant mania (Strakowski S.et al., 1991). In addition, in a study ofhospitalized patients with schizophrenia andSAFD, who were on antipsychotics andthyrnoleptics, up to 30% were found tohave OSA (Winkelman J., 1996).
Weight loss is associated with improvement in the extent of obstructive apneas,therefore the weight gain promoters (including medications) should be avoided.Regarding severity of weight gain associated with new and conventional antipsychotics, clozapine is reported to be high,olanzapine high to moderate, risperidoneand quetiapine are moderate, and haloperidol and molindone are low in severity ofweight gain (Perkins D., 1998). Clozapinemight have been a good choice for Mr G.since high doses of risperidone worsenedhis extrapyramidal symptoms (e.g. restingtremor) and TO, and could help his residual non-bizarre delusions. The risk ofsevere weight gain was the factor against,and similar assessment would apply forolanzapine. Mr. G's current medications(lithium, divalproex-sodium, and risperidone) are significant weight gain promoters too, and if on clozapine or olanzapinehe would not need lithium and dival-
proex-sodium the benefit might have outweigh the risk. However, despite furtherweight gain of 15 lb., his medications were not changed over the course of threeyears due to maintained clinical stability.With an assistance of community servicesin regulating Mr. G's diet and medicationcompliance he lost 15 lb. To illustrate current improvement, his insulin was alsomanaged to be discontinued. He continued using CPAp, and his OSA remained stable. Only in the last 10 years was Mr. G'sOSA recognized and treated. Even thoughhe tended not to use his CPAP properly,he put importance on having it all the time, for example, upon admission hewould ask, that CPAP to be brought to theward.
In conclusion, this case suggests the importance of the early recognition, diagnosis, and adequate treatment of OSA in patients with a schizoaffective disorder-bipolar type. It should be emphasized thatweight gain remains a significant problemin such patients who often require combination of chronic antipsychotics and moodstabilizing agents use, which promoteweight gain, which is a risk factor for several medical co-morbidities.
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PRIKAZ SLUCAJATRETMANREZISTENTNOGSHIZOAFEKTIVNOGPOREMECAJABIPOLARNI TIP PRACENOGOBSTRUKTIVNOM APNEOMUSNU
Dejan Budimirovic!James Levitt?Erick Garshick»
1 Medicinski fakultet na ,Psihijatrijskoodeljenje, Novi Haven, Konektikat
2 Medicinski fakultet na Harvardu,Psihijatrijsko odeljenje, Boston, Masacusets
3 Medicinski fakultet na Harvardu,Medicinsko odeljenje, Boston, Masacusets
Kratak sadria]: Ovo je prikaz slucaja pacijenta, kojiboluje od tretman - rezistentnog shizoafektivnogporemecaja - bipolarni tip (SAOF) sa tardivnom diskinezijom (TO), obstruktivom apneom pri spavanju(OSA) i pocetnim diabetes melitusom kod starijih(AOOM). Ovaj rad je bio podrzan od Oirektora Harvard South Shore, jednog od programa za specijalizaciju iz opste psihijatrije, Medicinski Fakultet na Harvardu, Boston, i konkurisao je za nagradu od Americke Psihijatrijske Asocijacije/Lilly Kompanije u1999. godini.
Prikaz sluiaja
G. je star 52 godine, belac, razveden, nezaposlen je od svoje 25-te godine, zivi u domu za nezbrinute u zadnje tri godine.
Glavne tegobe su nestabilno raspolozenje, izahtevno ponasanje praceno 3D-to godisnjom istorijom hronicne psihoze. U zadnjedye godine na AXIS I (osovini 1) je postavljena dijagnoza SADF-bipolarni tipa.Prisutan je podatak delimicne rezistencijena terapiju. Komorbiditet G. ukljucuje: tes-
'<I' ku zloupotrebu alkohola (apstinira2D god.),I
("() zloupotrebu lekova (specijalno benzodiaze0'g pina), tesku nikotinsku zavisnost, znacajnu~ gojaznost sa OSA-om i AODM-om.NN
140
PRETHODNI PSIHIjATRIJSKITRETMAN I SADASNJA BOLEST
Sveobuhvatno, G. je osamnaest puta psihijatrijski hospitalizovan. Petnaest hospitalizacija je veoma dobro dokumentovano ibile su nam dostupne iz medicinskih izvora (tabela 1, sa strane 128). Prvi prijem jebio u 22-oj godini. Hospitalizaciji je prethodio raskid emotivne veze, devojka, prerna kojoj je bio ljubomoran i posesivan, gaje napustila sto je izrokovalo eskalacijuopijanja. Doveden je u bolnicu u intoksiciranom stanju i pri tome je bio ratoboran.Bio je agitiran, hostilan, paranoidan, slusne halucinacije su bile takode prisutne.Postavljena je dg. akutna shizofrena reakcija. a primenjen je u pocetku hlorpromazin (CPZ), a kasnije i osam elektro-konvulzivnih tretmana tokom sestomesecnoglecenja. Po otpustu ziveo je sa ocem i ma-
cehom u zajednici. Nekoliko sledecih godina, je radio kao predstavnik prodaje, azatim i kao radnik na gradevini.
U 25-oj godini je drugi put psihijatrijskihospitalizovan tokom cetiri nedelje, zatosto je pretio ljudima lovackom puckorn.Pri prijemu, je verovao je da ga svi progone, bio je ratoboran i negativistican.
Tretiran je haloperidolam (i.m. inj.) nedelju dana pre nego sto je pristao na oralnuterapiju. Tada je premesten u drugu bolnicu, gde je ispoljio zahtevno ponasanje usarksaticnorn, sumnjicavom i provokativnom maniru. Postavljena je dg. Shizofrenareakcija, paranoidnog tipa, i tretiran je saCPZ i trifluoperazinom, i nakon cetiri nedelje je bio otpusten. U 26-oj godini zapoceo je vanbolnicki tretman zbog sumnjicavosti, depresivnosti i anksioznosti. Primenjena je individualna grupna porodicnai relaksaciona terapija. Sve pristupi su ostvarili ograniceni uspeh. Psihofarrnakoloskije tretiran je kombinacijom konvencionalnih antipsihotika (ukljucujuci depo), antidepresivima i anksioliticima. Lekovi supovoljno uticali na depresiju i anksioznost, i »srnanjili su stepen njegove paranoje«. On ipak »nikad nije bio siguran dapostoji zavera protiv njega«, i ostao je ustanju lake provokacije, bio je jako osetljivdo nivoa ornalovazavanja u interpersonalnim relacijama. ad 25. do 30. god.,slabo poslovno funkcionise dok je socijalno funkcionisanje marginalno. Njegovaglavna socijalna interakcija je podrazumevala pacijente i osoblje u programu dnevnog tretmana. G. je odbijao da »izlazi« saocem i bratom. Tokom ovog perioda seugojio, koristio i zloupotrebljavao alkohol,i osecao se »promasenirn«, Uprkos tome, u30-oj godini je bio sposoban da se ozeni ipocne da zivi nezavisno. Tokom prvih sestgodina braka dobio je dva sina. Bracno neslaganje je bilo prisutno od samog pocetka. Nije radio od svoje 25-te godine, ali je
izdrzavao svoju porodicu od dodatka kojije primao, u vezi njegove mentalne bolesti.
Od 32-ge godine, tokom narednih 20 godina, G je psihijatrijski hospitalizovan 15puta ukljucujuci 6 epizoda klasicne rnani-je i 6 epizoda »mesane-manije«. Prakticnosve epizode su propracene sa psihoticnirnsadrzajima. Takode je imao tri epizode welike-depresije«, bez psihoticnih sadrzaja.Tokom hospitalizacija, karakteristike klinicke slike su anksioznost, depresivnost,agitiranost, paranoidni sadrzaji cesto praceni impulsivnim, zahtevnim i pretecimponasanjem. Tipican primer, je prijem u34-oj godini kada su bili prisutni grandiozni, persekturni sadrzaji »FBI me juri...moja zena je umesana u zaveru protivmene«. Lecen je sa 1200 mg hlorpromazina na dan. U tom periodu ispoljava sledeci obrazac ponasanja: samoinicijativnotrazi prijem sam kada je depresivan, a zahteva otpust kada je manican. Povremeno,pacijent pokusava da napusti lecenje, uprkos medicinskim savetima iii nedozvoljeno odsustvuje, a pre stabilizacije na klinickom planu. Takode je prisutna tendenca da povecava doze lekova impulsivno, sanamerom da olaksa sebi stanje anksioznosti iii depresije, takvim ponasanjem je iprozrokovao trovanje litijumom. Opiraose smanjivanju flufenazina, povremeno jeprimae 100 mgldnevno (kombinujuci depo i per os preparat). U 37-oj godini semanifestuju parkinsonizam i tardivne diskinezije. Pored toga, ugojio se oko 80 funti r
(vise od 40 kg) izmedu 25. i 37. godine.
PriIikom prijema u 42-oj godini G je redijagnostikovan kao atipican afektivni porernecaj, prvenstveno zbog prisustva naglasenih afektivnih simptoma, od manicnih do depresivnih, a dodatni razlog postavljanja ove dg. je bio nedostatak porodicnog morbiditeta za shizofreniju.
Tretiran je litijumom, a kasnije kombinacijom litijuma + karbamazepina (CBZ),medutim sve je to bilo sa delimicnimuspehom.
Tokom njegove 44.-te godine bila su tripsihijatrijska lecenja. Prilikog prvog, manifestovao je halucinacije i sumanutosti,iako je nivo litijuma bio 1,50. Takode jeposumnjano na prisustvo GSA-e, tako stoje nocna oksimetrija otkrila smanjenje zasicenosti kiseonikom od 60 % u dva maha.Sledeca dva prijema bila su u kontekstuseparacije, a osam meseci kasnije se razvodi od zene.
Tokom razvoda je uslovljen sudskom zabranom, da ne prilazi supruzi a zbog pretnji koje joj je upucivao. U tom periodu jeziveo u motelima, i u vise navrata verbalnopretio zeni preko telefonanakon cega je unekoliko navrata psihijatrijski tretiran.
Hospitalizovan je sest puta izmedu 45. i46 godine radi procene GSA-e, kao i radiprilagodavanja medikacije i regulacije nezeljenih efekata neuroleptika i litijuma.Hospitalnom tretmanu u 46.-oj godini, jeprethodio period sa vise farmakoterapijskih promena. Litijum i flufenazin su obustavljeni naglo zbog »mogucih neurotoksicnih efekata i zbog nikotinske intoksikacije«, Na dan prijema, njegova bivsasupruga ga je posetila, i obavestila da namerava da se ponovo uda. Postao je uzrujan, pretio da ce skociti kroz prozor, paje prinudno hospitalizovan. Na prijemu jebio rnanican sa psihoticnim sadrzajima.Da bi se kontrolisao nemir bio je fiksiran itretiran haloperidolom (i.m.), kasnije je
0' tretiran litijumom i haloperidolom, da biog se nakon dye nedelje stanje postepeno po-
boljsalo. Napustio je bolnicu, uprkos medicinskim savetima da to ne cini do potpune stabilizacije.
Sledeca psihijatrijska hospitalizacija je bilau njegovoj 48-oj godini. Doveden je od
142
strane policije nakon sto je navodno uznemiravao konobaricu u restoranu pokusavajuci da je fotografise. Pre ovog prijematokom sarno jednog meseca je napravio900 telefonskih poziva. Pri prijemu je biodepresivan i paranoidan. Bio je zahtevan itrazio je paznju. Izrazen tremor gornjihekstremiteta je bio prisutan. Lecen je flufeanzinom (per os i i.m.) i litijumom. Dodatno je primenjen sertralin, sto je dovelodo poboljasnja raspolozenja, kada je opetneovlasceno napustio lecenje. Zivi sam,nezaposlen je, socijalno restriktivan. Ukratkim intervalima bi od svojih psihijatara zahtevao jos lekova, narocito benzodiajazepina i sertralina. U dispanzerskimuslovima je primenjen pindolol (20 mg nadan), sto je vremenom poboljsalo kontrolu impulsa i raspolozenje.
1995. godine-oj, u 51-oj godini po prvi putje primenjen risperidon, 6mg dnevno,zbog ekstrapiramidnih nus-efekata i pojave umerene TD. Terapijski odgovor je biopovoljan. Muz njegove bivse zene izbacujenjegovog 14-eg sina, koji pocinje da zivi sanjim, sto je prethodilo sledecoj hospitalizaciji. Tad gdin G. izrazava brigu za sina itrazi pornoc za njega. Pri prijemu se notira disforicno raspolozenje, labilan afekat ine-bizarni paranoidni sadrzaji. Takode poprijemu, narocito biva zahtevan u izrazavanju svojih potreba osoblju. Prilikomotpusta iz bolnice, njegova dijagnoza jepromenjena u SADF-bipolarni tip.
Nakon otpusta nastavlja da se zali na depresiju. Sertralin je obustavljen, i zamenjen imipraminom (200 mg dnevno) i fluoksetinom 10 mg dnevno, uz risperidon(6 mg dnevno) i litijum (na terapijskomnivou). Protokol je primenjen 5 meseci saogranicenim uspehom, te je imipraminopet zamenjenin sertralinom.
Naredenog meseca biva ponovo primljenna bolnicko lecenje, a zbog pogresnog uzi-
143
RANIJE BOLESTI
OSA je dijagnostikovana zbog cega jekoristio nazalni kontinualni pozitivni vazdusnipristisak (CPAP) od 45 godine, koji je losetolerisao. Nastavio je da pusi dye pakle cigareta dnevno, uz izrazenu nikotinsku zavisnost. Zbog dijabetes melitusa je tretiraninuslinom vee dye godine. CT endokranijuma glave bez kontrasta u 52.-oj godini jebio negativan. Neuropsiholosko testiranjeu istom dobu ukazuje na prosecnu inteligenciju, bez znakova hipoksernicne amnezije ili demencije, ali i otkriva ostecenje izvrsnih funkcija. CT glave i EEG u dobi od42 godine su bili bez osobenosti.
Gdin G. nije povredivao glavu, niti gubiosvest, nije imao konvulzije, cerebrovaskularne akcidente ili druge neuroloske poremecaje. Tri godine kasnije njegov AODMje stabilizovan - oralnim antidijabeticima idijetom.
mg pro die, a sto je prouzrokovalo povoljan uticaj na raspolozenje, ali je, pogorasavalo ekstrapiramidalne nezeljene efekteo Dijagnoza je ostala shizoafektivni poremecaj-bipolarni tip.
Sledece tri godine je bio na tretrnanu kodregionalnog psihijatra i uprkos promenarna u njegovom zivotnom aranzmanu, ustabilnoj je remisiji.
Gdin G. je bio na istoj terapiji i dalje saizuzetkom korekcije doze risperidona na11 mg dnevno i dodatkom benzotrapina.
~
Trece od cetvoro dece iz braka raditelja. ~Otac je bio radnik. Alkoholicar, G ga opi- ~suje kao »promenljivog raspolozenja«, hostilnog i udaljenog. Majka je bila domacica
LICNA I PORODICNAANAMNEZA
manja lekova, ukljucujuci povecanje dozesertralina na 200 mg dnevno po sopstvenom nahodenju, i samoobustavljanju risperidona. Uprkos nivou litijuma od 1. 05meq/litru, dolazi do mesane afektivne epizode pracene psihoticnoscu (disforican,labilan afekt i bizarni sumanuti sadrzaji).Psihoticnost se povukla na dozi risperidona od 6 mg na dan. Po postepenom smanjivanju doze sertralina i lorazepama (uveden radi dodatne sedacije), za sarno nedelju dana dolazi do ispoljavanja placljivosti,iritabilnosti i povecane afaktivne labilnosti. Obzirom na sklonost ka hipomaniji nasertralinu i tezern farmakoterapijskom tretmanu uveden je valproat sa ciljem da stabilizuje njegovo raspolozenje, pre ponovnoguvodenja antidepresiva. Ipak, opet, napustalecenje samoinicijativno.
Par dana kasnije zbog pogorsanja diabetesa njegov vanbolnicki psihijatar obustavljanaglo litijum, na kome je konstantno bio 8godina. Dve nedelje kasnije doveden je odstrane policije i prisilno je primljen na lecenje zbog agresivnog i cudnog ponasanja,ukljucujuci i to sto je bos setae po veomahladnom vremenu. Prilikom prijema je biou disforicno-manicnom stanju, pracenimne kongruentnim bizarnim, perskutornimi religioznim sumanutim idejama. Sa ponovnim uvodenjem risperidona (6 mgdnevno) prve nedelje po prijemu, insomnija, anksioznost i nemir se dramaticnopogorsavaju. Opisan je od strane osobljakao »najgori do sada«. Pogorsanje stanja jedovedno u vezu sa aktivirajucom komponentom risperidona. Ponovo je ukljucenlitijum, stanje se postepeno smirivalotokom naredne dye nedelje. Uprkos visokom terapijskom nivou litijuma i valproata kao i tretmanu sa risperidonom josuvek je bio zahtevan i depresivan. Obzirom da je primecena tendenca ka hipomanicnosti po uvodenju antidepresiva, risperidon je postepeno povecavan do 10,5
NN
i G. je opisuje kao »depresivnu«. Oseca daga je zanemarila emocionalno i da ga je»zadirkivala«, ipak i pored toga, oseca dajoj je blizi bio nego oeu.
Rani psihomotorni razvoj je bio normalan.Na vreme je posao u osnovnu skolu. Ipak,imao je problema pri citanju i spelovanju,ponavljao je treci razred. U skoli je izbegavao da se igra sa drugom deeom, bio jeuplasen. Sa uciteljima je takode imaopovrsan odnos.
Majka je preminula u 59.-oj godini od eerebralne hemoragije kada je G. imao 14godina. On i sestre su bili duboko pogodeni ovim gubitkom, sto je dovelo do togada se njihov otac ponasao ekstremno popustljivo. Otae se ponovo ozenio dye godine kasnije i G. se prihvatljivo prilagodiomacehi, ali je osecao bes spram oea zbog»brzog- stupanja u novi brak. U 17.-ojgodini opisuje sebe kao »uplasenog i vrlonervoznog«. U 19.-oj godini zavrsava srednju skolu. U 26-.oj godini, po recima njegovog terapeuta problemi su mu bili tugai osecaj napustenosti zbog gubitka majkekada je imao 14 godina, bes prema oeuzbog brzog ponovnog braka, i osecanja odbacenosti i depresije posle napustanjaprve devojke dok je bio na sluzenju vojnogroka, a sto je bio i povod za njegov prvipsihijatrijski tretman.
Diskusija
A) Diferencijalna dijagnoza hroniinepsihoze/psihopatologije SAFD
Dominantne izmene pacijenta G. su bile u§' sferi raspolozenja, misljenja, i ponasanja.o~ Observirale su se kombinacije psihoticnih
epizoda praceni kongruentnim i nekon52 gruentnim raspolozenjern, afektivnim po~ rernecajima ali bez prisustva psihoticnosti~ kao i psihoticnih epizoda koje nisu bile
pracene tezim porernecajern raspolozenja.
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G. je dobi izmedu 22. i 42. godine dijagnostikovan i lecen pod dijagnozom hronicne shizofrenije, paranodni tip. Longitudinalni 10k bolesti je bio epizodican, doksu u interkriticnirn periodima bile prisutni rezidualni simptomi povisena interpretativna spremnost, povremeno do nivoauticaja, a sto je pracenom marginalnimsocijalnim funkcionisanjem. Prilikom stresnih situacija dolazilo bi do psihoticnihdekompenzacija sa jasno ispoljenim sumanutim idejama persekcije i uticaja. U dobiod 42. godine dijagnoza se menja u atipicni bipolarni poremecaj. Ne-bizarne sumanute ideje proganjanja kao i utieaja subile u vecoj meri prisutne u njegovim 40tim nego u 3D-tim godinama.
Nakon rastavljanja od supruge (44 god.) apogotovo nakon razvoda (45. god) 10kbolesti od epizodicnog dobija deteriorajucitok, sa dva neprekidna perioda bolesti.
Prvi period je od 44. do 46., tokom koga jeu cetiri navrata psihijatrijski hospitalizovan i u nekoliko navrata priman u bolnicuradi tretmana OSA. Nakon 46 god, upotrebljavao je CPAp, i nije bilo potrebe zaprijemom na hospitalni tretman.
Drugi period je izmedu 48-52. godine zivota, kada je ponovo u cetiri navrata psihijatrijski tretiran. Tokom ovog perioda pacijent je ispunio DSM-IV kriterijume za trimesane i jednu manicnu epizodu, koje suse preklapale sa simptomima koji su ispunjavale kriterijum A za shizofreniju (nebizarne persekutorne i bizarne sumanutosti, i dezorganizovano ponasanje). Tokominicijalne faze drugog perioda bile su prisutne ne-bizarne persekutorne sumanuto-
li sti i sindrom uticaja kao i dezorganizovano ponasanje, tokom 2 nedelje u odsustvuprimetnih afektivnih simptoma (kriterijum B). Afektivni simptomi su bili prisutni znacajni deo vremena bolesti (kriterijum C). Simptomi nisu posledica direkt-
nih fizioloskih efekata opsteg medicinskogstanja (OSA nije bila aktivna) ili zloupotrebe substance (kriterijum D). Stoga jediagnoza preomenjena u SAFD-bipolarnitip u 51. godini zivota pacijenta.
Prilikom razmatranja i postavljanja dijagnoze uzeta je u obzir: istorija zlopotrebealkohola, interepizodicna hronicna disforija, pozitivna porodicna anamneza za afektivne poremecaje a negativna za hronicnipsihoticni porernecaj, potom podatak 0
potrebi za prolongiranom upotrebom stabilizatora raspolozenja i antipsihotika susugerisali postavljanje dijagnoze afektivnog podtipa SAFD (Tsuang M., et al.,1986; Levitt J., Tsuang M. et al., 1988;Williams P., and McGlashan T., 1989; Levitt J., Tsuang M. et al., 1990; and TsuangM., Levitt J. et al., 1995). Dobro premorbidno funkcionisanje kao i afektivna simptomatologija su bili jasno prisutni znatanperiod vremena. Sto sa observacijom da jetokom bolesti imao relativno ocuvan kapacitet za uspostavljanje bliskosti za drugima, dodatno upucuju na postavljanje dijagnoze sa afektivnom podkomponentom.
lake je postavljena diagnoza paranoidneshizofrenije, tokom njegovih 20-ih godina(tokom 60-tih i 70-tih), ne postoje jakidokazi da se radilo 0 shizofrenji. Treba primetiti cinjenicu na koju je ukazao Poup sasaradnicima, a to je da su tokom 60-tih70-tih pacijenti sa mesanim afektivnim ishizofrenim karakteristikama pre dijagnostikovani kao shizofreni (Pope H., et al.,1978).
Bipolarni porernecaj, sam po sebi, takodedolazi u diferencijalno dijagnosticko razmatranje. U prilog tome idu podaci da jekod pacijenta G. u dobi od 42 god, ponovopostavljena dijagnoza atipicnog afektivnogporernecaja kao i da je kasnije postavljenadijagnoza bipolarnog porernecaja koji nijedrugde specifikovan. Bipolarni poremecaj
pacijenta G. je po osobenostima kompleksan, kao dopuna medicinskom komorbiditetu, prisutni su psihoticni simptomi,takode i na osovini II (Axis II) se dijagnostikuje mesani poremecaj licnosti saprominentnim borderline crtama. Gdin G.je lecen antipsihoticima tokom svojih 30tih godina (30-40% bipolarnih pacijenataostaju na antipsihotiku) a tokom poslednjih 8 godina pridodat je litijum. Uprokosopisanom farmakoterapijskom protokolu,bihejvioralni problemi su bili prisutni kako tokom prijema na lecenje tako i interepizodicno. I mada se ozenio, dobio decu,ziveo nezavisno niz godina, doslo je do deterioracije u socijalnom i radnom okruzenju (sto nije karakteristika »zistih« bipolarnih pacijenata).
Sveobuhvatno ishod kod SAFD se opisujekao intermedijarni izmedu shizofrenije iafektivnog poremecaja (Tsuang M., andMarneros E., 1986; Williams P., and MeGlashan I, 1987; McGlashan T., and Williams P., 1990), sto deluje najkonzistentnije sa tokom bolesti gospodina G.
B) Psihofarmakoloski tretmanSAFD-bipolni tip - poseban osvrtna risperidon
Za sada nijedan lek nije odobren od straneFDA za tretman SAFD, a nekoliko kontrolisanih studije SAFD su koristile dijagnosticke kriterijume koji podsecaju na sadasnju definiciju ovog poremecaja. Stogase nalazi ovih studija moraju smatrati pre- ,..liminarnim (Keck P. et al., 1996). Ipak M
0'nalazi studija ukazuju da su tipicni anti- 8psihotici i litijum prouzrokovali uporedive ~
ali ne u punoj meri pozitivne efekte za N
SAFD-bipolarni tip tokom manicne faze, S§izuzev kod akutno agitiranih pacijenata ~kod kojih je hlorpromazin (CPZ) prouzro- a1kovao povoljniji terapijski efekat, Pome-nute studije takode sugerisu da kombi- 145
nacija litijum + konvencionaIni antipsihotik moze biti superiorna u odnosu na protokol sarno sa antipsihotikom (Keck RE. etal., 1996). Ovo indirektno podrzava dijagnozu SAFD, G. je tretiran flufenazinom,duze od 20 godina, dok je litijumom tretiran 8 godina. I mada je kombinacija antipsihotika i timoleptika uobicajena u klinickoj praksi sa ciljem profilakse SAFDefikasnost ovog protokola i dalje je potrebno istrazivati (Siris S.G. et al., 1993).
Empirijski podaci koji govore 0 efikasnosti natrijum valproata i kabamazepinakod SAFD su ograniceni. Pet kontrolisanihstudija nalazi da su valproati efikasni utretmanu shizo-rnanije i psihoticne manije (McElroy SL, Keck PE, et al., 1992),buduca ispitivanja efikasnosti psihostabilizatora i sedativnih neuroleptika u spektru afektivnih poremecaja od bipolarnogdo SAFD (Keck PE et al., 1996). U slucajuG., natrijum valproat, nije preveniraorisperidonom indukovanu tesku bihejvioralnu aktivaciju uprkos srednjem terapijskom nivou, ali se pokazao kao uspesandodatak litijumu.
Nova generacija antipsihotika, pocev odklozapina, preko risperidona i olanzapina,nudi nadu farakoterapijskog pristupa itretmana mentalnih porernecaja. Mek EIroj i sar. (McElroy et al., 1999) su pratiliefikasnost risperidona i olanzapina u nekoliko kontrolisanih i nekontrolisanihstudija kod SAFD. Rezulati su mesoviti, irisperidon i olanzapin mogu biti od koristinekim obolelim od SAFD, dok kod nekih
l' drugih mogu biti uzrok problema.r<)
g Hajnrih i sar. nalaze da klozapin i risperi-o2!- don poseduju slicno antipsihoticno dejst-~ vo (Heinrich K. et al., 1994). Risperidon,~ mesani 5HT2/D2 receptorski antagonist,~ se pokazao kao efikasan antipsihotik ur5 treatmanu shizofrenije sa dodatnom pred-
noscu nad konvencionalnim antipsihotici-
146
rna, zbog manjeg ispoljavanja nezeljenihekstrapiramidnih efekata (Borison R.L. etaI., 1992; Chouinard G. et aI., 1993). Savecim dozama, risperidon uzrokuje ekstrapiramidnu simptomatologiju, a sto jeobservirano i kod pacijenta G. kada je biona dozi od 8 mg a pogotovo na 10.5 mgdnevno. Primetili smo sa postepenim povecanjem risperidona od po 0.5 mg pro dieakatiziju u manjoj meri u odnosu akatizijisa povecanjern od 1 mg pro die.
Tokom [ednogodisnjeg pracenja gdin. G jelecen sa dozom od 6-mg risperidona nadana, uz dodatak litijuma, ali bez povoljnog efekta na depresivno raspolozenje.Nekoliko terapijskih protokola sa razlicitim antidepresivima je dovelo sarno do povremenih i ogranicenih poboljsanja. Depresivno raspolozenje se popravilo znacajno, sa povecanjern doze risperidona na10.5 mg na dan. Ovo nije podrzano sarnoputem klinicke observacije vee i na osnovuznacajnog pada na HAM-D skoru, a sto jenajavilo skori otpust. Van bolnicko pracenje tokom sest meseci a potom tokomtri godine je pokazalo stabilnost na afektivnom planu, na dozi odrzavanja od 11mg risperidona pro die.
Nekoliko izvestaja ukazuje (McElroy S. etal., 1996) na antidepresivni efekat risperidona pri dozama vecim od 10 mg na dan,u odnosu na nize doze (4-6 mg pro die),kod kojih dolaze do izrazaja sarno antipsihoticni efekti. Mali broj skorijih studijasugerise da bi antidepresivno dejstvo risperidona moglo biti od koristi kod nekihpacijenata obolelih od SAFD. Preliminarninalazi tri skorije studije tretiranih SAFDpacijenata sugerisu da bi se timoleptickaakcija risperidona mogla razlikovati od akcije klozapina pre po unidirekcionalnomantidepresivnom dejstvu nego po antirnanicnom iIi stabiIizirajucem dejstvu na raspolozenje (Dwight M.M. et al., 1994; Ces-
kova E. et al., 1993; Hillert A. et al.,1992).
Prospektivna studija Miler-Siehenedera(Muller-Siecheneder) poredila je efikasnost kombinacije haloperidol/amitriptilinu odnosu na monoterapiju risperidonom.Ova studija je pokazala u slicnoj meri poboljsanje kako psihoticnih tako i depresivnih simptoma kod obe ispitivane grupe.Postojeci podaci, bar sugerisu, da risperidon ispoljava u izvesnoj meri antidepresivan efekat, sto bi mogla biti posledicaantagonizma 5HT2 i alfa-receptora (KeckPE., 1998). U svakom slucaju potrebna sudalja istrazivanja antidepresivne akcije kako risperidona, tako i olanzapina (Tollefson GD et al., 1998).
[edna studija nalazi povoljan efekat risperidona kod pacijenta obolelih od bipolarnog afektivnog porernecaja sa psihoticnimkarakteristikama - tretman rezistentnih(Tohen M. et al., 1994). Pacijenti su u ovojstudiji primali litijum iii antiepileptik.Ovakva observacija, kod obolelih odSAFD-bipolarnog tipa, upucuje na stay dabi povoljniji odgovor bio pre na terapijskip.,otokol risperidon + timoleptik, pre nego na protokol monoterapije risperidonom(Keck PE et al., 1994). Stoga neki autorisrnataju (e.g., Keck PE, 1998), upotreburisperidona kontroverznom za manicnesimptome, a sto je delom posledica i rnalog broja kontrolisanih studija.
U skladu sa postavkorn 0 unidirekcionalnom antidepresivnom dejstvu risperidonasu i studije koje nalaze egzacerbaciju iliindukciju manicnih simtoma po ukljucivanja risperidona (Dwight M. et al., 1994;Byerly M.j. et al., 1995; Koek R.j., 1996;Diaz S.F., 1996; Schnierow s.j., 1996;Sajatovic et al., 1996). Ovakav stay potkrepljuje studija Barkina i sar., u kojoj se nalazi da psihostabilizatori (litijum i valproat) , kod pacijenata sa dokumentova-
nim terapijskim nivoima u plazmi, nisuprevenirali maniju prouzrokovanu risperidonom (Barkin J. et al., 1997). Uprkos visokom-normalnorn terapijskom nivou litijuma kod pacijenta G. je u dva navrata doslo do mesane afektivne psihoticne dekompenzacije. Tokom prve nedelje prilikomdruge dekompenzacije doslo je do ispoljavanja znacajne bihejvioralne hiperaktivacije u sklopu psihoticne manije, tom prilikom je ponovo tretiran sa 6 mg risperiodna na dan. Bihejvioralna aktivacija je bila znacajno teza u odnosu na prethodneepizode akatizije, a manifestovala se znacajnim pogorsanjern insornnije, porastomanksioznosti i nemira. Prisustvo srednjihnormaInih terapijskih nivoa valproata uplazmi nije preveniralo bihejvioralnu aktivaciju, koja se postepeno kupirala tek nakon dvonedeljenog dodatnog tretmana litijumom.
Observirana bihejvioralna aktivacija bi semogla objasniti, bar delom, putem nekihpredklinickih naIaza. Visoko specifican antagonist za 5HT2 receptor ritanserin povecava kolicinu opaIjivanja dopaminskih neurona u centraInom delu mozga i dozno zavisno (Ugedo L. et al., 1989). Ovakav naIazpotkrepljuje stay da bi serotonin mogaoispoljavati inhibitornu kontrolu centralnedopaminske aktivnosti putem 5HT2 receptora. 5HT2 blokada - indukovana stimulacijom centralne dopaminske aktivnosti bimogla uticati na pogorsanje manije ili prelazak u manicnu fazu. Isti mehanizam bimogao biti odgovoran za znacajno pobolj- !sanje volje, motivacije i raspolozenja kod 8
opacijenata obolelih od SAFD-depresivni tip g(Dwight M. et al., 1994).
Drugo, povecana aktivnost frontaIne regije :;gje takode implikovana kod manije. Dopa- ~minski (DA) aksoni inervisu medialni pre- 1EfrontaIni korteks (PFC), gde se spajaju sinapse sa piramidaInim celijama i GABA- 147
ergicnim interneuronima (Deutch A.,1998). 5HT aksoni se zavrsavaju u PFC-u,a deluje i da formiraju sinapse sa interneuronima. 5HT2a receptor se predominantnolocira na apikalnim dendritima piramidalnih celija, takode 0 podgrupa interneurona(Ibid.). Navedeni podaci potkrepljuju tezuda DA, dejstvujuci predominantno putemD2-1ike receptora, i serotonin, dejstvujuciputem 5HT2 receptorskog podtipa, koordinantno uticu na interneurone u predeluPFC, i da na taj nacin regulisu i kortikalnuaktivnosti i lokalne veze.
Trece, stabiIizacija sna je kljucni faktor tretmana i profilakse manije. Aktivnost 5HTneurona je najniza tokom slow wave sna(SWS iIi NREM faze 3 i 4), a najvisa tokom budenja (Lemoine P., 1996). 5HTantagonist ritanserin provocira nastanakinsomnije, i jasno povecava SWS. Ritanserin moze povecati budnost i SWS odprvog dana primene (Ibid). Risperidon poseduje slican 5HT profil kao i ritanserin, iispoljava slicne efekte na san i budnost.Indirektno manikogeno dejstvo risperidona, se objasnjava putern porernecaja spavanja.
Kao sto je ranije u tekstu navedeno, risperidon moze indukovati maniju, te manikogeni efekat maze biti odgovoran za provociranje manicnih epizoda kod gdina G.Dodatni faktori ukljucuju: upotrebu triciklicnih antidepresiva (npr. imipramin)(Wehr and Goodwin, 1987), potom upotrebu selektivnih inhibitora preuzimanjaserotonina (SSRI) fluoksetina (Hon and
'<j" Prescorn, 1989) iIi sertralina (Henryet al.,~ 1992; Heiman S., March ]., 1996), naglog iskljucivanje litijuma (Trisha S. et al.,a~ 1991), i sam tok bolesti. Neki autori pret-NN postavljaju da antidepresivi iz grupe SSRI:E mogu delovati razlicito na neurotransmig terske sisteme (Stahl S., 1998). Tako npr.~ sertralin maze ispoljavati umeren efekat
na preuzimanje dopamina i noradrenalina.
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Sve u svemu, tesko je razmrsm 1 istacijedan ispred drugih faktora, u toku bolestipacijenta G., npr, u prvoj mesanoj epizodiu dobi od 51. godine, on je bio tretiran sa6-mg risperidona i 50 mg sertralina prodie, neposredno pred prijem. Sest mesecinakon toga, impramin je ukinut sarno cetiri nedelje pre druge mesane epizode, apred sam prijem je lecen sa 6-mg risperidona i 200 mg sertralina na dan. Razlogposlednjeg prijema na hospitalno lecenjeje bila epizoda psihoticne manije, gde jelitijum iskljucen dye nedelje pre prijema.Simultano lecenje je nastavljeno sa 6-mgof risperidona, nizom terapijskom dozomvalproata, i sa 50 mg sertralina. Ova epizoda je bila slicna epizodi, u 46. godini,koja je usledila po naglom ukidanju litijurna i flufenazina.
Tokom trogodisnjeg pracenja pune remisije G. je na terapiji odrzavanja sa risperidonom, litijumom i valproatom.
Na osnovu klinicke evaluacije i pracenja nocne oksimetrije, G. boluje i od OSA-e (nocna obstruktivna apnea). Prvi put je mogucnost prisustva OSA-e razmatrano u dobi u44-oj godine zivota pacijenta. Tada je tezio283 funte (128kg), a prirneceno je da prisustvo perioda i apnee i »dispnee« tokomnoci, pracenih hrkanjem. Intenziviranje psihijatrijske simptomatologije je praceno iporastom telesne tezine, u dobi od 25. jetezio 170 funti (77kg), da bi u 41-oj godinitezio 260 funti (117 kg). Nocno pracenje jeukazalo na ciklicni sablon saturacije kiseonika, gde su prisutne brojne epizode desaturacije od srednjeg 90% opsega do niskesaturacije od 60%, a sto je blisko sa OSAom. U 45-oj godini, ponovno merenje ukazuje na ciklicnu desaturaciju koja se ponavlja (osnovna 94% do ispod 70%).
Pri nazalnoj primeni CPAP u trajanju od 1casa ciklicna desaturacija (pri pritisku od10 mm vodenog stuba) nije primecena, Udobi od 49 god., tokom 3 casa (pri pritiskuod 10 mm vodenog stuba) primene CPAPsaturacija je ostala iznad 90%, slican nalazje bio i sledece godine. G. opisuje san kaofragmentisan, pracen cestirn budenjem uzkasalj i gusenje, Tokom dana bi cesto imaopotrebe i za dnevnim snom. U 51.-oj god.,obavljena je polisomnografija (PSG), kadaje utvrdeno da je u krevetu proveo sarno 2casa i 13 minuta, a da je spavao sarno 61minut, dostigavsi stadijume na 1 i 2. Koristio je CPAP (pri pritisku od 5 mm vodenog stuba) i nije imao obstruktivne apnee. Tokom merenja je osecao teskobu iimao potrebu da nekoliko puta ustanezbog zedi. U nekoliko navrata je odbio ponovnu PSG zbog nernogucnosti boravka ulaboratoriji vise casova, kao i zbog potrebeza cigaretama. Plucno pracenje je pokaza10 normalan spirometrijski nalaza u 44-oj,48-oj i 49-oj godini.
Diskusija: Cinjcnice da je G. izuzetno gojazan, da je nocu imao epizode gusenja, apreko dana da je bio dremljiv, su klinickekarakteristike koje upucuju na postavljanje dijagnoze nocne opstruktivne apneje(Kryger M.H., 1992). Hrkanje je takode karateristika OSE sto je prirneceno tokomklinickog lecenja. Zbog psihijatrijskog stanja nije bilo moguce sprovesti sveobuhvatnu dijagnostiku OSA-e, a time nije moguce bilo ni postaviti definitvnu dijagnozu.
Razumljivo je i poznato da je tesko obaviti sve dijagnosticke procedure kod psihoticnih pacijenata. U slucaju G. uprkos nemogucnosti da se obavi kompletno dijagnostika upotreba nazalnog CPAP se pokazala da je od koristi, i uputila na postavljanje dijagnoze OSA-e.
Dnevna pospanost, bilo da je posledicafragmanrisanog sna ili obstruktivnih apnea ili pak posledica nernogucnosti usni-
vanja i odrzavanja sna u sklopu psihijatrijskog oboljenja, utice na intenziviranjemanije, pogorsanje kognitivnog funkcionisanja i motorike. Psihofarmaci sa sedativnom akcijom mogu pogorsati OSA-u.Neuropsiholosko testiranje je ukazalo naocuvanu paznju, verbalizaciju, prostornu uvizuelnu memoriju, kao i na ocuvan intelekt, dok se egzekutivne funkcije (npr. radna memorija, abstraktno misljenje, kompleksna paznja, organizacija, verbalna fluentost) bile ostecene u srednjoj/vecoj me-ri, sa znacajnijim osetecenjima pri kompleksnijim zadacima. Neuropsiholoskotestiranje je ukazalo na disfunkcionalnostfrontalne kore i obliznjih limbickih struktura, uz naznake disfunkcije leve hemisfere disfunkcije. Neuropsiholoski nalazblagog ostecenja memorije i srednje /teskog ostecenja izvrsnih funkcija je konzistentan sa SAFD, mada ostaje nejasno koliki je doprinos nocnog obstruktivnog respiratornog porernecaja, kao i medikacije.
Pored toga poremecaji pazn]e, koncentracije kao i opsteg funkcionisanja i raspolozenja mogu biti u vezi sa OSA-om(StrohlK.P. and Redline S., 1996). Grupa obolelihod OSA-e, je ispitivanja sa Mood State questionnaire, pre i nakon tretmana sa nazalnim CPAP (Derderian SS et al., 1988).Ispitivanje je pokazalo da su vrednostipost CPAP tretmena znacajno poboljsanjena skalama za depresiju i zamor, kao i naskali Total Mood Disturbance. Depresija,definisana na osnovu Zung Self-RatingDepression skale, je nadena kod 45% u ,.grupi od 55 pacijenata koji su ispitivani M
0'polisomnografski i kod koji je dijagnos- gtikovana OSA (Millman RP et al., 1989). ~
('oJ
Moze se izvuci zakljucak da je OSA po- ('oJ
vezana sa znacajnim neuropsihijatrijskim ~simptomima, cak i u odsustvu ocitog afek- CJ
ztivnog porernecaja. U slucaju G., OSA bi u.l
mogla biti jedan od dodatnih faktora nje-gove dugotrajne depresivnosti. 149
150
Tokom kontinuiranog antipishoticnog tretmana, G. je dobio na tel. tezini 140 funti(oko 95 kg) u odnosu na 25. godinu zivota, a od 42. godine od kada je uveden litijum na telesnoj tezini je dobio 50 lbs (oko22 kg) Moguci nacin povecanja tel. tezinesa antipsihoticima koji dele DA i 5HT antagonizam, je blokada 5HT2c-receptora inarusen osecaj sitosti (Perkins D., 1998).
Gojaznost, po sebi je dobro poznat faktorrizika za medicinski komorbiditet, ukljucujuci diabetes tip II kao i za poremecaj disanja u snu. Porernecaj spavanja je tesko tretirati u sl. G. bas zbog prisustva OSA-e.A obzirom da je postavljena dijagnoza shizoafektivnog porernecaja bipolarni tip, san jekljucni faktor stabilnosti raspolozenja, Jedna od karakteristika OSA-e, je da je san fragmentisan sto bi moglo doprinositi terapijskoj rezistentnosti. Tako u nekoliko slucajeva se navodi komorbiditet OSA-e i tretmanrezistentne manije (Strakowski S. et al.,1991). jedna studija nalazi znacajan komorbiditet OSA-e kod hospitalizovane populacije shizofrenih i shizoafektivnih pacijenatacak i do 30% OSA-u (Winkelman J., 1996).
Smanjenje telesne tezine je povezano saumanjenjem tegoba nastalih kao poslediceobstruktivnih apnea, stoga bi lekovi kojiuticu na povecanje telesne tezine trebalida se izbegavaju. Uporedujuci razliciteantipsihotike: sklonost klozapina je viso-
ka, olanzapina visoka-srednja, risperidonai kvetiapina srednja, haloperidola i molindona niska sto se tice rizika za porast u tel.tezini (Perkins D., 1998). Klozapin bi mogao biti lek izbor kod gdina G., obzirom dasu vece doze risperidona pogorsale ekstrapiramidalne simptome (e. g. tremor u miru) iTO, i nisu uticale na ne-bizarne sumanute ideje. Rizik od velikog povecanjatel. tezine ne bi isao u prilog ukljucivanjani klozapina niti olanzapina. I trenutna terapija pacijenta G. (litijum, valproat i risperidon) utice na povecanje telesne tezine.Uprkos tome i dodatnom povecanju tezineza 15 lb. (oko 7 kg) terapija odrzavanja jeostala ista. Sa stabilnom remisijom i prihvatanjem dijete G. je izgubio na tezini(oko 7 kg), a sto je doprinelo prekidu insulinske terapije. Kontinuirano koristiCPAP i stanje OSA-e je stabilno (OSA jeprepoznata i tretirana poslednjih 10 godina). A i sam gdin. G. je imao potrebu zaCPAP prilikom prijema.
I da zakljucimo: ovaj slucaj ukazuje na znacaj ranog prepoznavanja, postavljanja dijagnoze i pravilnog tretmana OSA-e, kodpacijenta sa shizoafaktivnom psihozom bipolarnim tipom. Od znacaja je primetiti daje povecanje telesne tezine prateci problemmozda cak i veci pri upotrebi novih »atipicnih« antipsihotika, i da ima znacaja za nekoliko stanja komorbiditeta.
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