DELHI PSYCHIATRY JOURNAL Vol. 11 No.

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Review Article

Management of Negative Symptoms in

Schizophrenia: Looking Positively
Jyoti Prakash, A.K. Mitra
Military Hospital, Pathankot

Introduction
In early days negative symptoms were
considered to represent the fundamental defect of
schizophrenia,1-2 but over the years, the importance
of negative symptoms is being progressively
downplayed. Positive symptoms are being
increasingly emphasized with renewed interest. The
almost universal presence and relative persistence
of negative symptoms, and the fact that they
represent the most debilitating and refractory aspect
of schizophrenic psychopathology make them
difficult to ignore and warrants intensive effort to
3-5
understand them.
Negative symptoms are though now better but
still incompletely understood, and their treatment
is still inadequate. Though one is able to manage
grossly agitated person living in his own world of
aliens and enemies, not much is in store for those
socially withdrawn and inept people confined to a
corner of their room and unable to think and work
constructively. In this article we review the existing
literature and researches to look into various
management options available for negative
symptoms in schizophrenia.
Negative schizophrenia as the term indicates
is the loss or deficit in other wise normal functions
and is characterized by anhedonia (loss of interest
in pleasurable activity), avolition (loss of ability to
will), asociality (loss of ability to interact socially),
apathy (loss of feeling of feeling), alogia (poor
speech output) and attentional impairment.6
Classification
Negative symptoms can be divided essentially
into primary and secondary negative symptoms:7
1. Primary negative symptoms: These are
symptoms integral to schizophrenic process.
These can be:
32

(a) Premorbid negative symptoms- Negative

symptoms preceding the illness.
(b) Psychotic phase negative symptomsNegative symptoms fluctuate with each
psychotic episode.
(c) Deteriorative negative symptoms- Negative
symptoms intensify following each
psychotic episode and leads to further
deterioration in socio-occupational
functioning.
2. Secondary negative symptoms: Negative
symptoms caused due to secondary factors.
(a) Depressive symptomsDepressive symptoms simulating negative features.
(b) Extr apyramidal symptomsNegative
symptoms due to effects of antipsychotic
drugs used in the treatment.
(c) Environmental deprivationPoor psychosocial support affects illness adversely and
may present as negative symptoms.
Assessment:

Assessment parameters are clinical and

paraclinical.
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 options
Various drugs have been used for the treatment

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of negative symptom of schizophrenia.

1. Antipsychotics
Atypical antipsychotics are more effective for
both positive and negative symptoms than either
8
placebo or typical antipsychotics. Atypical
antipsychotics improve negative symptoms by
about 25% as compared to 10 to 15%
9-10
improvements with conventional agents.
Clozapine has been found superior for both
positive and negative symptoms than any other
11-12
atypical antipsychotics.
2. Benzodiazepines
Benzodiazepines were primarily used as
adjunctive therapy with antipsychotics. There
13-17
have been five specific studies.
Many
studies reported significant improvement
compared to placebo while few did not. 18
Studies, which showed positive outcome,
utilized diazepam, alprazolam, and estazolam
whereas the studies showing inadequate
response used chlordiazepoxide and diazepam.
Doses ranged from as low as 15 mg of
diazepam15 to 4 mg of alprazolam { 80 mg of
diazepam}. 16 Improvement was seen both in
positive and negative symptoms. This
improvement can be substantiated logically on
postulates that schizophrenic patients may have
decreased GABA activity
3. Lithium
There have been few double blind, controlled
crossover tr ials, combining lithium and
antipsychotics.19-20 Lithium was found superior
to placebo. 33-50% of patients showed some
improvement within four weeks. Lithium
plasma concentrations ranged from 0.8-1.2
mEq/L in these studies. However lithium
augmentation needs to be monitored closely for
neurotoxicity.
4. Propanalol
Ther e have been several double blind,
controlled trials. They showed reduced
21-22
psychotic symptoms,
to a modest
benefit, 23-24 whereas a few 25-26 found no
difference between propranolol and placebo.
Various mechanisms of action were proposed
like increase in plasma concentration of

27

anipsychotics, anticonvulsant action at high

doses (4 g/d) and suppression of temporal lobe
abnormalities.
5. L-Dopa
Several double-blind placebo controlled studies
28-30
found L-dopa superior to placebo.
There
was significant improvement in motivation and
sociality, seen most often in-patients with
duration of illness less than five years. (L-dopa
300-600 mg/day). Carbidopa also showed
28
significant improvement. These were used in
cases with prominent negative symptoms and
minimal positive symptoms.
6. Amphetamine
Amphetamine led to improvement in florid
symptoms, nonregressive symptoms and some
negative symptoms at dosage of 30 mg when
augmented with the neuroleptics. It improved
attention and mood, made patient relaxed, alert
and confident.31
7. Biperiden
There is significant alteration of cholinergic
function in schizophrenia and plays an
important role in the negative and cognitive
symptoms. Biperiden a centrally acting
anticholinergic agent significantly lowered
negative symptoms when used in dosage of 8
mg/day.32 Anticholinergics have also been used
in secondary negative symptoms.
8. Cyproheptadine
It is a nonselective serotonin antagonist.
Reports varied from significant improvement
in a double blind, placebo-controlled33 to no
significant effect. 34 Doses in these studies
ranged from 4-32 mg/day. Improvement was
primarily seen in anergia, affective flattening,
alogia however positive symptoms may get
exacerbated and needs due considerations.
9. Fluoxetine
Fluoxetine when added to Neuroleptics
significantly improved both positive and
negative psychotic symptoms as well as
depressive symptoms. 35 Used generally in
dosage of 20 mg/day. Whether it relieves
depression, increases serum antipsychotic level,

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DELHI PSYCHIATRY JOURNAL Vol. 11 No.1

downregulates serotonin receptor sites or acts

by serotonin-dopamine pathway interaction the
mechanism remains yet unclear.
10. Fluvoxamine
Fluvoxamine have been found better than
35-36
placebo in negative symptoms.
Though it
has more effect on alogia and affective
symptoms, it also has some effect on anhedonia.
It is effective as augmentation and in the dosage
of 50-100 mg. Mechanism remains varied and
unclear.
11. Moclobemide
Moclobemide have been found effective in
schizophrenia and schizoaffective disorders.
Moclobemide augmentation amelior ates
negative, depressive and general symptoms in
schizophrenia.37
12. TCA
Imipramine has been found effective. Mostly
it improves depressive component and to some
extent improvement in negative symptoms.38
Commonly used for augmentation.
13. Vasopressin
Its use was based on suggested disturbance in
neur opeptide function in schizophrenia.
Significant improvement has been seen in
negative symptoms. 39 It improves attention,
isolation, emotional inhibition, social interest,
interpersonal communication and memory.
14. Ritanserin
Double-blind, placebo-controlled trial have
found Ritanserin or other drugs blocking 5-HT2
and/or 5-HT1c receptors effective in both
positive and negative symptoms.40
15. Ondansetron
5HT 3 receptor antagonist. This has been used
both as single drug or adjunct.41 A double-blind,
randomized, placebo-controlled study an
effective adjunctive agent in enhancing the
effectiveness and reducing some adverse side
effects of antipsychotic therapy for chronic,
treatment-resistant schizophrenia, particularly
for negative and cognitive symptoms. 42 It is
effective in both positive and negative
schizophrenia.
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16. Methadone
It is effective in both positive and negative
symptoms.43 Used primarily as adjunct therapy
in dosage of 20-40 mg. Mechanism remains
unclear. Possibility of specific antipsychotic
effect, anxiolytic effect and synergism with
neuroleptics and methadone has been pondered.
17. Famotidine
Famotidine improves both positive and negative
symptoms.45-47 Increased level of histamine as
evidenced by increased amount of tele-methyl
histamine (a metabolite) has been suggested for
its possible mode of action. It has been used
either alone or in combination with neuroleptics
in dose of 40-120 mg. Other serotonin
antagonists have also been found effective.
18. Dehydroepiandrosterone (DHEA)
Used in dosage of 100mg/d for 6 weeks.
Placebo controlled double blind study showed
significant improvement in negative symptoms,
as well as in depressive and anxiety symptoms
in individuals receiving DHEA. This effect was
48
especially noted in women.
19. Glycine and D-Cycloserine
Glycine is an agonist at the glycine modulatory
site of the NMDA receptor. It improves negative
symptoms and may still be able to improve
49these symptoms when given with clozapine.
50
D-cycloserine a partial agonist at the glycine
modulatory site of the NMDA receptor also
improves negative symptoms when added to
some drugs, but may worsen these symptoms
when given with clozapine. The action of these
molecules points towards glutamatergic
dysregulation in schizophrenia.51
20. Selegeline- A double blind placebo controlled
multicentre trial using low dose selegeline
augmentation with antipsychotics revealed
significant improvement in negative symptoms
and global improvement scores.52
21. Other agents under investigation and have
been used sometime or the other are
Azothioprine (Acts on autoimmune antibody)53
Allopurinol 54
CX 516 (selectively act on AMPA type of
55
glutamate receptor).

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DELHI PSYCHIATRY JOURNAL Vol. 11 No.1

Gingko biloba (Acts on free radical)56

Omega 3 fatty acid (Works on essential Fatty
Acid abnormality.)57
Cholecystokinin and Ceruletide (Amphibian
analogue of cholecystokinin)58-59
MDMA60
NK3 (Neurokinin antagonist)61
Estrogen62

7.

8.
9.

Conclusion
From the above it is evident that there is a
strong need for understanding the negative
symptoms of schizophrenia and treating them
aggressively. Though significant numbers of
treatment options are available they have not been
either used extensively or validated upon by more
use or research. Some feel that the use of drugs to
treat negative symptoms is a misuse/abuse of drug
therapy as these symptoms are so inherent a defect
that drugs have little or no effect on them. Use of
these medications over this last two to three decades
have seen the level of benefits to be varying. Most
of the drugs have been used as augmentation; some
have been used as single medication.
However more research is required to formulate
appropriate interventional strategies so that
optimism dont travel through the realm of
therapeutic cosmoplasm in leaps and bounds but in
a steady manner for better care and treatment
outcome in people with mental distress.
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