Schizophrenia exacerbations

Disulfiram produces a variety of adverse effects, which commonly include drowsiness, lethargy, and fatigue (Chick 1999). Other more serious adverse effects, such as optic neuritis, peripheral neuropathy, and hepatotoxicity, are rare. Psychiatric effects of disulfiram are also uncommon. They probably occur only at higher dosages of the drug and may result from the inhibition by disulfiram of a variety of enzymes in addition to ALDH. Included among the enzymes inhibited by disulfiram is dopamine P-hydroxylase, inhibition of which increases dopamine levels, which in turn can exacerbate psychotic symptoms in patients with schizophrenia and occasionally may result in psychotic or depressive symptoms in patients without schizophrenia. 

Phencyclidine (PCP), a dissociative anesthetic agent, which is subject to abuse, produces behavioral effects in man that frequently resemble schizophrenia (Luisada 1978). Manifestations of persistent psychopathology frequently remain after the acute effects of PCP have diminished. With PCP, subjects may display autistic and delusional thinking typical of schizophrenics (Luby et al. 1959). A more striking link between schizophrenia and PCP comes from observations of cases in which PCP was given to hospitalized schizophrenics (Luisada 1978). After receiving PCP, these patients showed extreme exacerbation of their psychoses the reaction persisted for up to 6 weeks. By contrast, LSD produced no more severe effects in schizophrenics than in normal subjects. 

Nonetheless, the amphetamine-1ike actions of PCP are of considerable interest for the following reasons. Malfunction of the dopaminergic system has been implicated as having considerable importance in schizophrenia. PCP s interactions with this system may be responsible in large measure for its schizophreniform manifestations in humans. Like amphetamines, PCP would be expected to exacerbate schizophrenia, and users with this or related disorders, or with latent psychiatric diseases, may be at... 

The typical antipsychotic drugs, which for 50 years have been the mainstay of treatment of schizophrenia, as well as of psychosis that occurs secondary to bipolar disorder and major depressive disorder, affect primarily the positive symptoms[10]. The behavioral symptoms, such as agitation or profound withdrawal, that accompany psychosis, respond to the antipsychotic drugs within a period of hours to days after the initiation of treatment. The cognitive aspects of psychosis, such as the delusions and hallucinations, however, tend to resolve more slowly. In fact, for many patients the hallucinations and delusions may persist but lose their emotional salience and intrusiveness. The positive symptoms tend to wax and wane over time, are exacerbated by stress, and generally become less prominent as the patient becomes older. 

The onset of schizophrenic symptoms also may be associated with the menopause, and it has been suggest that estrogen protects women from schizophrenia (Hafner, et al., 1993 Seeman, 1996). Schizophrenia may be exacerbated by the menopause and during other periods when estrogens are low, such as the postpartum period. 

Finally, the natural course of illness can help to distinguish BPAD from schizophrenia. Many patients with BPAD resume normal functioning between episodes of illness, although those with severe variants of BPAD not uncommonly become chronically ill. Most patients with schizophrenia, in contrast, are unable to achieve their premorbid functional level between exacerbations of illness and many experience a gradually declining course. 

Subsequent Acute Exacerbations. When a patient with schizophrenia experiences another acute phase of illness, two questions must be answered. First, is hospitalization needed Second, why has this happened ... 

In the residual phase, the patient is unlikely to have an acute exacerbation even if (s)he stops taking an antipsychotic. Nevertheless, (s)he may still require treatment for residual symptoms. If medications are continued during a residual phase of schizophrenia, an atypical antipsychotic is preferred. Because positive symptoms are no longer a prominent aspect of the illness, there is usually little justification for using a typical antipsychotic and thereby exposing a patient to the risk of tardive dyskinesia. Moreover, atypical antipsychotics likely better treat the remaining negative symptoms of residnal schizophrenia. 

Chlorpromazine is an aliphatic phenothiazine antipsychotic used in schizophrenia and which may exacerbate parkinsonism. Co-careldopa is a combination of levodopa and the peripheral dopa-decarboxylase inhibitor, carbidopa. Co-careldopa, amantadine, entacapone and bromocriptine are all indicated in the management of parkinsonism. 

Psychotic disorders Cautiously treat patients suffering from psychotic disorders, schizophrenia, or confusional states and keep under careful surveillance because exacerbations of these conditions have been observed with oral administration. Autonomic dysreflexia Use with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal may cause an autonomic dysreflexic episode. 

The transmethylation hypothesis depended on the psychosis of mescaline as an example of how methylated compounds similar in structure to the monoamine neurotransmitters could be psychotogenic, and demonstrated how methionine, the precursor of the methyl donor S-adenosylmethionine, could exacerbate the psychotic symptoms of schizophrenia in patients. This theory was fed by studies of the now notorious pink spot, an amine found in paper chromatography of urine extracts from schizophrenics and thought to be 3,4-dimethoxyphenylethylamine (i.e., O-methylated dopamine). Subsequent studies eventually identified this as another compound or compounds, primarily of dietary origin. Another methylated derivative erroneously proposed to be found in higher quantities in schizophrenia was dimethyltryptamine. This compound is similar in structure to LSD, the hallucinogenic nature of which was the key to the serotonin deficiency hypothesis, which proposed that the known antagonism of serotonin (5-HT) by LSD indicated that psychotic disorders such as schizophrenia may result from a hypofunction of 5-HT. 

Several lines of evidence have implicated NMDA receptor hypofunction in the pathophysiology of schizophrenia. The administration of certain, but not all, uncompetitive NMDA receptor antagonists exacerbates psychotic symptoms in schizophrenics and mimics schizophrenia in non-psychotic subjects (Coyle et al. 2003 Konradi and Heckers 2003). 

Glutamate was initially implicated in schizophrenia by studies of the behavioral effects of N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., PCP, ketamine), which produce psychotic symptoms and cognitive dysfunction in healthy subjects and exacerbate psychotic, negative, and cognitive symptoms in patients with schizophrenia. Studies show that acute administration of NMDA antagonists causes NMDA receptor dysfunction, resulting in decreased inhibition of subcortical dopamine neurons and consequent increased mesolimbic dopamine release. Chronic administration produces decreased release, or hypoactivity, of dopamine in the prefrontal cortex (Davis and Lieberman, 2000). 

Arvanitis LA, Miller BG Multiple fixed doses of Seroquel (quetiapine) in patients with acute exacerbation of schizophrenia a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry 42 233-246, 1997... 

Patients with this condition manifest the symptoms of an acute exacerbation of schizophrenia, with symptoms lasting at least one month, but they make a complete recovery, with the prodromal, active, and residual phases remitting in less than 6 months. 

Arvanitis and Miller (129) reported a multiple fixed-dose, placebo-controlled, double-blind study of quetiapine in comparison with haloperidol and placebo in acutely exacerbated patients with chronic schizophrenia. Quetiapine was administered in five doses 75, 150, 300, 600, and 750 mg/day haloperidol was given at 12 mg/day. The study design had slightly more than 50 patients in each group. The 75-mg dose of quetiapine was clearly less efficacious than the higher doses. Doses of 150 to 750 mg/day were superior to placebo and comparable with haloperidol in reducing positive symptoms and 300 mg/day was superior to placebo and comparable with haloperidol for negative symptoms. 

Sedation, ataxia, and cognitive impairment occur more frequently with high BZD dosages. Other adverse effects reported when BZDs were used to treat schizophrenia include behavioral disinhibition, exacerbation of psychosis, and increase in anxiety and depression ( 163, 188, 189,190, 191,192, 193,194 and 195, 351). Concomitant use of a BZD and the atypical antipsychotic clozapine may increase the risk of sedation, dizziness and collapse with loss of consciousness ( 196). Respiratory compromise has also been reported with this combination (395, 396). 

Daniel DG, Zimbroff DL, Potkin SG, et al. Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsychopharmacology 1999 20 491-505. 

Lane HY, Chiu WC, Chou JC, et al. Risperidone in acutely exacerbated schizophrenia dosing strategies and plasma levels. J Clin Psychiatry 2000 61 209-214. 

Falloon IRH, Boyd JL, McGill CW, et al. Family management in the prevention of exacerbations of schizophrenia. A controlled study. N EnglJ Med 1982 306 1437-1440. 

Schizophrenia-related disorders, such as schizophreniform disorder, can closely mimic an acute exacerbation of mania. Attention to premorbid personal and family history may help differentiate them from mood disorders. A definitive diagnosis may not be possible, however, until the course of the illness is followed for a period of time. Clinical clues include the propensity of bipolar manics (in contrast to schizophrenics) to demonstrate pressured speech, flight of ideas, grandiosity, and overinclusive thinking. Hallucinations are less common than delusions in both mania and depression, with delusions normally taking on the qualities of expansivity, hyperreligiosity, or grandiosity. Delusions are also relatively less fixed than in schizophrenia. 

Blood pressure and heart rate should be monitored at each visit during the dose titration phase to permit early detection of adverse effects. To minimize the risk of development of movement disorders or psychotic symptoms, psychostimulants should be used cautiously in any patient with a history of tics or psychotic symptoms, or with a family history of Tourette s syndrome or schizophrenia. Nevertheless, studies have shown that psychostimulants are effective in treating ADHD in patients with co-morbid Tourette s syndrome and that they do not exacerbate tics in the majority of such patients ( 88, 89). Furthermore, no evidence indicates that psychostimulants can lower the seizure threshold or cause seizures. 

Lane H-Y, Chang Y-C, Cheng Y-C, Liu G-C, Lin X-R, Chang W-H. Effects of patient demographics, risperidone dosage, and clinical outcome on body weight in acutely exacerbated schizophrenia. J Clin Psychiatry 2003 64 316-20. 

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