Management of Negative Symptoms in Schizophrenia: Looking Positively
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DELHI PSYCHIATRY JOURNAL Vol. 11 No.1 APRIL 2008
Review Article
Management of Negative Symptoms in
Schizophrenia: Looking Positively
Jyoti Prakash, A.K. Mitra
Military Hospital, Pathankot
Introduction (a) Premorbid negative symptoms- Negative
In early days negative symptoms were symptoms preceding the illness.
considered to represent the fundamental defect of (b) Psychotic phase negative symptoms-
schizophrenia,1-2 but over the years, the importance Negative symptoms fluctuate with each
of negative symptoms is being progressively psychotic episode.
downplayed. Positive symptoms are being (c) Deteriorative negative symptoms- Negative
increasingly emphasized with renewed interest. The symptoms intensify following each
almost universal presence and relative persistence psychotic episode and leads to further
of negative symptoms, and the fact that they deterioration in socio-occupational
represent the most debilitating and refractory aspect functioning.
of schizophrenic psychopathology make them 2. Secondary negative symptoms: Negative
difficult to ignore and warrants intensive effort to symptoms caused due to secondary factors.
understand them.
3-5 (a) Depressive symptoms–Depressive symp-
Negative symptoms are though now better but toms simulating negative features.
still incompletely understood, and their treatment (b) Extr apyramidal symptoms–Negative
is still inadequate. Though one is able to manage symptoms due to effects of antipsychotic
grossly agitated person living in his own world of drugs used in the treatment.
aliens and enemies, not much is in store for those (c) Environmental deprivation–Poor psycho-
socially withdrawn and inept people confined to a social support affects illness adversely and
corner of their room and unable to think and work may present as negative symptoms.
constructively. In this article we review the existing Assessment:
7
literature and researches to look into various
Assessment parameters are clinical and
management options available for negative
paraclinical.
symptoms in schizophrenia.
1. Clinical
Negative schizophrenia as the term indicates
Clinical evidence of apathy, paucity of speech,
is the loss or deficit in other wise normal functions
blunting/incongruity of emotional response,
and is characterized by anhedonia (loss of interest
alogia etc
in pleasurable activity), avolition (loss of ability to
2. Psychometric Scales
will), asociality (loss of ability to interact socially),
(a) Score more than five on any BPRS negative
apathy (loss of feeling of feeling), alogia (poor
symptoms cluster items
speech output) and attentional impairment.6
(b) Total BPRS negative symptoms cluster
Classification scores more than fifteen.
Negative symptoms can be divided essentially (c) Total score more than fourteen on
into primary and secondary negative symptoms:7 emotional blunting scale
1. Primary negative symptoms: These are (d) Three points in negative scale of PANSS
symptoms integral to schizophrenic process. Pharmacotherapeutic options
These can be:
Various drugs have been used for the treatment
32 Delhi Psychiatry Journal 2008; 11:(1) © Delhi Psychiatric SocietyAPRIL 2008 DELHI PSYCHIATRY JOURNAL Vol. 11 No.1
27
of negative symptom of schizophrenia. anipsychotics, anticonvulsant action at high
doses (4 g/d) and suppression of temporal lobe
1. Antipsychotics
abnormalities.
Atypical antipsychotics are more effective for
both positive and negative symptoms than either 5. L-Dopa
8
placebo or typical antipsychotics. Atypical Several double-blind placebo controlled studies
28-30
antipsychotics improve negative symptoms by found L-dopa superior to placebo. There
about 25% as compared to 10 to 15% was significant improvement in motivation and
9-10
improvements with conventional agents. sociality, seen most often in-patients with
Clozapine has been found superior for both duration of illness less than five years. (L-dopa
positive and negative symptoms than any other 300-600 mg/day). Carbidopa also showed
11-12 28
atypical antipsychotics. significant improvement. These were used in
2. Benzodiazepines cases with prominent negative symptoms and
Benzodiazepines were primarily used as minimal positive symptoms.
adjunctive therapy with antipsychotics. There 6. Amphetamine
13-17
have been five specific studies. Many
Amphetamine led to improvement in florid
studies reported significant improvement
symptoms, nonregressive symptoms and some
compared to placebo while few did not. 18
negative symptoms at dosage of 30 mg when
Studies, which showed positive outcome,
augmented with the neuroleptics. It improved
utilized diazepam, alprazolam, and estazolam
attention and mood, made patient relaxed, alert
whereas the studies showing inadequate
and confident.31
response used chlordiazepoxide and diazepam.
Doses ranged from as low as 15 mg of 7. Biperiden
diazepam15 to 4 mg of alprazolam { 80 mg of There is significant alteration of cholinergic
diazepam}. 16 Improvement was seen both in function in schizophrenia and plays an
positive and negative symptoms. This important role in the negative and cognitive
improvement can be substantiated logically on symptoms. Biperiden a centrally acting
postulates that schizophrenic patients may have anticholinergic agent significantly lowered
decreased GABA activity negative symptoms when used in dosage of 8
3. Lithium mg/day.32 Anticholinergics have also been used
in secondary negative symptoms.
There have been few double blind, controlled
crossover tr ials, combining lithium and 8. Cyproheptadine
antipsychotics.19-20 Lithium was found superior It is a nonselective serotonin antagonist.
to placebo. 33-50% of patients showed some Reports varied from significant improvement
improvement within four weeks. Lithium in a double blind, placebo-controlled33 to no
plasma concentrations ranged from 0.8-1.2 significant effect. 34 Doses in these studies
mEq/L in these studies. However lithium ranged from 4-32 mg/day. Improvement was
augmentation needs to be monitored closely for primarily seen in anergia, affective flattening,
neurotoxicity. alogia however positive symptoms may get
4. Propanalol exacerbated and needs due considerations.
Ther e have been several double blind, 9. Fluoxetine
controlled trials. They showed reduced Fluoxetine when added to Neuroleptics
21-22
psychotic symptoms, to a modest significantly improved both positive and
benefit, 23-24 whereas a few 25-26 found no negative psychotic symptoms as well as
difference between propranolol and placebo. depressive symptoms. 35 Used generally in
Various mechanisms of action were proposed dosage of 20 mg/day. Whether it relieves
like increase in plasma concentration of depression, increases serum antipsychotic level,
Delhi Psychiatry Journal 2008; 11:(1) © Delhi Psychiatric Society 33DELHI PSYCHIATRY JOURNAL Vol. 11 No.1 APRIL 2008
downregulates serotonin receptor sites or acts 16. Methadone
by serotonin-dopamine pathway interaction the
It is effective in both positive and negative
mechanism remains yet unclear.
symptoms.43 Used primarily as adjunct therapy
10. Fluvoxamine in dosage of 20-40 mg. Mechanism remains
Fluvoxamine have been found better than unclear. Possibility of specific antipsychotic
placebo in negative symptoms.
35-36
Though it effect, anxiolytic effect and synergism with
has more effect on alogia and affective neuroleptics and methadone has been pondered.
symptoms, it also has some effect on anhedonia. 17. Famotidine
It is effective as augmentation and in the dosage
Famotidine improves both positive and negative
of 50-100 mg. Mechanism remains varied and
symptoms.45-47 Increased level of histamine as
unclear.
evidenced by increased amount of tele-methyl
11. Moclobemide histamine (a metabolite) has been suggested for
Moclobemide have been found effective in its possible mode of action. It has been used
schizophrenia and schizoaffective disorders. either alone or in combination with neuroleptics
Moclobemide augmentation amelior ates in dose of 40-120 mg. Other serotonin
negative, depressive and general symptoms in antagonists have also been found effective.
schizophrenia.37 18. Dehydroepiandrosterone (DHEA)
12. TCA
Used in dosage of 100mg/d for 6 weeks.
Imipramine has been found effective. Mostly
Placebo controlled double blind study showed
it improves depressive component and to some
significant improvement in negative symptoms,
extent improvement in negative symptoms.38
as well as in depressive and anxiety symptoms
Commonly used for augmentation.
in individuals receiving DHEA. This effect was
48
13. Vasopressin especially noted in women.
Its use was based on suggested disturbance in 19. Glycine and D-Cycloserine
neur opeptide function in schizophrenia.
Glycine is an agonist at the glycine modulatory
Significant improvement has been seen in
site of the NMDA receptor. It improves negative
negative symptoms. 39 It improves attention,
symptoms and may still be able to improve
isolation, emotional inhibition, social interest, 49-
these symptoms when given with clozapine.
interpersonal communication and memory. 50
D-cycloserine a partial agonist at the glycine
14. Ritanserin modulatory site of the NMDA receptor also
Double-blind, placebo-controlled trial have improves negative symptoms when added to
found Ritanserin or other drugs blocking 5-HT2 some drugs, but may worsen these symptoms
and/or 5-HT1c receptors effective in both when given with clozapine. The action of these
positive and negative symptoms.40 molecules points towards glutamatergic
dysregulation in schizophrenia.51
15. Ondansetron 20. Selegeline- A double blind placebo controlled
5HT 3 receptor antagonist. This has been used multicentre trial using low dose selegeline
both as single drug or adjunct.41 A double-blind, augmentation with antipsychotics revealed
randomized, placebo-controlled study an significant improvement in negative symptoms
effective adjunctive agent in enhancing the and global improvement scores.52
effectiveness and reducing some adverse side 21. Other agents under investigation and have
effects of antipsychotic therapy for chronic, been used sometime or the other are
treatment-resistant schizophrenia, particularly Azothioprine (Acts on autoimmune antibody)53
for negative and cognitive symptoms. 42 It is Allopurinol 54
effective in both positive and negative CX 516 (selectively act on AMPA type of
55
schizophrenia. glutamate receptor).
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