prakash j. 2008. manajemen of negative symptom

DELHI PSYCHIATRY JOURNAL Vol. 11 No.1 APRIL 2008

Review Article

Delhi Psychiatry Journal 2008; 11:(1) Delhi Psychiatric Society32

IntroductionIn early days negative symptoms were

considered to represent the fundamental defect ofschizophrenia,1-2 but over the years, the importanceof negative symptoms is being progressivelydownplayed. Positive symptoms are beingincreasingly emphasized with renewed interest. Thealmost universal presence and relative persistenceof negative symptoms, and the fact that theyrepresent the most debilitating and refractory aspectof schizophrenic psychopathology make themdifficult to ignore and warrants intensive effort tounderstand them.3-5

Negative symptoms are though now better butstill incompletely understood, and their treatmentis still inadequate. Though one is able to managegrossly agitated person living in his own world ofaliens and enemies, not much is in store for thosesocially withdrawn and inept people confined to acorner of their room and unable to think and workconstructively. In this article we review the existingliterature and researches to look into variousmanagement options available for negativesymptoms in schizophrenia.

Negative schizophrenia as the term indicatesis the loss or deficit in other wise normal functionsand is characterized by anhedonia (loss of interestin pleasurable activity), avolition (loss of ability towill), asociality (loss of ability to interact socially),apathy (loss of feeling of feeling), alogia (poorspeech output) and attentional impairment.6

ClassificationNegative symptoms can be divided essentially

into primary and secondary negative symptoms:7

1. Primary negative symptoms: These aresymptoms integral to schizophrenic process.These can be:

(a) Premorbid negative symptoms- Negativesymptoms preceding the illness.

(b) Psychotic phase negative symptoms-Negative symptoms fluctuate with eachpsychotic episode.

(c) Deteriorative negative symptoms- Negativesymptoms intensify following eachpsychotic episode and leads to furtherdeterioration in socio-occupationalfunctioning.

2. Secondary negative symptoms: Negativesymptoms caused due to secondary factors.(a) Depressive symptomsDepressive symp-

toms simulating negative features.(b) Extrapyramidal symptomsNegative

symptoms due to effects of antipsychoticdrugs used in the treatment.

(c) Environmental deprivationPoor psycho-social support affects illness adversely andmay present as negative symptoms.

Assessment:7

Assessment parameters are clinical andparaclinical.1. Clinical

Clinical evidence of apathy, paucity of speech,blunting/incongruity of emotional response,alogia etc

2. Psychometric Scales(a) Score more than five on any BPRS negative

symptoms cluster items(b) Total BPRS negative symptoms cluster

scores more than fifteen.(c) Total score more than fourteen on

emotional blunting scale(d) Three points in negative scale of PANSS

Pharmacotherapeutic optionsVarious drugs have been used for the treatment

Management of Negative Symptoms inSchizophrenia: Looking Positively

Jyoti Prakash, A.K. MitraMilitary Hospital, Pathankot

APRIL 2008 DELHI PSYCHIATRY JOURNAL Vol. 11 No.1

Delhi Psychiatry Journal 2008; 11:(1) Delhi Psychiatric Society

of negative symptom of schizophrenia.

1. AntipsychoticsAtypical antipsychotics are more effective forboth positive and negative symptoms than eitherplacebo or typical antipsychotics.8 Atypicalantipsychotics improve negative symptoms byabout 25% as compared to 10 to 15%improvements with conventional agents.9-10

Clozapine has been found superior for bothpositive and negative symptoms than any otheratypical antipsychotics.11-12

2. BenzodiazepinesBenzodiazepines were primarily used asadjunctive therapy with antipsychotics. Therehave been five specific studies.13-17 Manystudies reported significant improvementcompared to placebo while few did not.18

Studies, which showed positive outcome,utilized diazepam, alprazolam, and estazolamwhereas the studies showing inadequateresponse used chlordiazepoxide and diazepam.Doses ranged from as low as 15 mg ofdiazepam15 to 4 mg of alprazolam { 80 mg ofdiazepam}.16 Improvement was seen both inpositive and negative symptoms. Thisimprovement can be substantiated logically onpostulates that schizophrenic patients may havedecreased GABA activity

3. LithiumThere have been few double blind, controlledcrossover tr ials, combining lithium andantipsychotics.19-20 Lithium was found superiorto placebo. 33-50% of patients showed someimprovement within four weeks. Lithiumplasma concentrations ranged from 0.8-1.2mEq/L in these studies. However lithiumaugmentation needs to be monitored closely forneurotoxicity.

4. PropanalolThere have been several double blind,controlled trials. They showed reducedpsychotic symptoms,21-22 to a modestbenefit,23-24 whereas a few25-26 found nodifference between propranolol and placebo.Various mechanisms of action were proposedlike increase in plasma concentration of

anipsychotics,27 anticonvulsant action at highdoses (4 g/d) and suppression of temporal lobeabnormalities.

5. L-DopaSeveral double-blind placebo controlled studiesfound L-dopa superior to placebo.28-30 Therewas significant improvement in motivation andsociality, seen most often in-patients withduration of illness less than five years. (L-dopa300-600 mg/day). Carbidopa also showedsignificant improvement.28 These were used incases with prominent negative symptoms andminimal positive symptoms.

6. AmphetamineAmphetamine led to improvement in floridsymptoms, nonregressive symptoms and somenegative symptoms at dosage of 30 mg whenaugmented with the neuroleptics. It improvedattention and mood, made patient relaxed, alertand confident.31

7. BiperidenThere is significant alteration of cholinergicfunction in schizophrenia and plays animportant role in the negative and cognitivesymptoms. Biperiden a centrally actinganticholinergic agent significantly lowerednegative symptoms when used in dosage of 8mg/day.32 Anticholinergics have also been usedin secondary negative symptoms.

8. CyproheptadineIt is a nonselective serotonin antagonist.Reports varied from significant improvementin a double blind, placebo-controlled33 to nosignificant effect.34 Doses in these studiesranged from 4-32 mg/day. Improvement wasprimarily seen in anergia, affective flattening,alogia however positive symptoms may getexacerbated and needs due considerations.

9. FluoxetineFluoxetine when added to Neurolepticssignificantly improved both positive andnegative psychotic symptoms as well asdepressive symptoms.35 Used generally indosage of 20 mg/day. Whether it relievesdepression, increases serum antipsychotic level,

33



downregulates serotonin receptor sites or actsby serotonin-dopamine pathway interaction themechanism remains yet unclear.

10. FluvoxamineFluvoxamine have been found better thanplacebo in negative symptoms.35-36 Though ithas more effect on alogia and affectivesymptoms, it also has some effect on anhedonia.It is effective as augmentation and in the dosageof 50-100 mg. Mechanism remains varied andunclear.

11. MoclobemideMoclobemide have been found effective inschizophrenia and schizoaffective disorders.Moclobemide augmentation amelioratesnegative, depressive and general symptoms inschizophrenia.37

12. TCAImipramine has been found effective. Mostlyit improves depressive component and to someextent improvement in negative symptoms.38

Commonly used for augmentation.

13. VasopressinIts use was based on suggested disturbance inneuropeptide function in schizophrenia.Significant improvement has been seen innegative symptoms.39 It improves attention,isolation, emotional inhibition, social interest,interpersonal communication and memory.

14. RitanserinDouble-blind, placebo-controlled trial havefound Ritanserin or other drugs blocking 5-HT2and/or 5-HT1c receptors effective in bothpositive and negative symptoms.40

15. Ondansetron5HT 3 receptor antagonist. This has been usedboth as single drug or adjunct.41 A double-blind,randomized, placebo-controlled study aneffective adjunctive agent in enhancing theeffectiveness and reducing some adverse sideeffects of antipsychotic therapy for chronic,treatment-resistant schizophrenia, particularlyfor negative and cognitive symptoms.42 It iseffective in both positive and negativeschizophrenia.

16. MethadoneIt is effective in both positive and negativesymptoms.43 Used primarily as adjunct therapyin dosage of 20-40 mg. Mechanism remainsunclear. Possibility of specific antipsychoticeffect, anxiolytic effect and synergism withneuroleptics and methadone has been pondered.

17. FamotidineFamotidine improves both positive and negativesymptoms.45-47 Increased level of histamine asevidenced by increased amount of tele-methylhistamine (a metabolite) has been suggested forits possible mode of action. It has been usedeither alone or in combination with neurolepticsin dose of 40-120 mg. Other serotoninantagonists have also been found effective.

18. Dehydroepiandrosterone (DHEA)Used in dosage of 100mg/d for 6 weeks.Placebo controlled double blind study showedsignificant improvement in negative symptoms,as well as in depressive and anxiety symptomsin individuals receiving DHEA. This effect wasespecially noted in women.48

19. Glycine and D-CycloserineGlycine is an agonist at the glycine modulatorysite of the NMDA receptor. It improves negativesymptoms and may still be able to improvethese symptoms when given with clozapine.49-50 D-cycloserine a partial agonist at the glycinemodulatory site of the NMDA receptor alsoimproves negative symptoms when added tosome drugs, but may worsen these symptomswhen given with clozapine. The action of thesemolecules points towards glutamatergicdysregulation in schizophrenia.51

20. Selegeline- A double blind placebo controlledmulticentre trial using low dose selegelineaugmentation with antipsychotics revealedsignificant improvement in negative symptomsand global improvement scores.52

21. Other agents under investigation and havebeen used sometime or the other areAzothioprine (Acts on autoimmune antibody)53

Allopurinol 54

CX 516 (selectively act on AMPA type ofglutamate receptor).55


Delhi Psychiatry Journal 2008; 11:(1) Delhi Psychiatric Society 35

Gingko biloba (Acts on free radical)56

Omega 3 fatty acid (Works on essential FattyAcid abnormality.)57

Cholecystokinin and Ceruletide (Amphibiananalogue of cholecystokinin)58-59

MDMA60

NK3 (Neurokinin antagonist)61

Estrogen62

ConclusionFrom the above it is evident that there is a

strong need for understanding the negativesymptoms of schizophrenia and treating themaggressively. Though significant numbers oftreatment options are available they have not beeneither used extensively or validated upon by moreuse or research. Some feel that the use of drugs totreat negative symptoms is a misuse/abuse of drugtherapy as these symptoms are so inherent a defectthat drugs have little or no effect on them. Use ofthese medications over this last two to three decadeshave seen the level of benefits to be varying. Mostof the drugs have been used as augmentation; somehave been used as single medication.

However more research is required to formulateappropriate interventional strategies so thatoptimism dont travel through the realm oftherapeutic cosmoplasm in leaps and bounds but ina steady manner for better care and treatmentoutcome in people with mental distress.

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