Rapid tranquilization with olanzapine in acute psychosis: a case series.

Acute, high-dose loading strategies (rapid neuroleptization) with the first-generation antipsychotics administered orally or parenterally, alone or combined with benzodiazepines, have been a commonly used treatment paradigm for controlling acutely agitated psychotic patients. The rationale was to achieve high plasma levels of drug within a shorter time period, resulting in rapid symptom mitigation. However, studies have shown that rapid neuroleptization with first-generation antipsychotics is associated with a greater incidence of side effects. To our knowledge, loading strategies with second-generation antipsychotics have not been investigated, primarily owing to a need for dose titration. Olanzapine, a second-generation antipsychotic, is well tolerated in doses ranging from 5 to 20 mg. The objective of this report was to determine experience with the use of up to 20 mg of an oral loading dose of olanzapine administered within 4 hours in the treatment of patients early in an acute psychotic phase of their illness. In the reported case series of 57 patients, olanzapine initiated at 15 to 20 mg/day was a safe and effective medication for rapidly calming the agitation of acutely agitated psychotic patients (rapid tranquilization). Furthermore, dose reduction over 2 to 3 weeks was achieved in a number of patients without appreciable loss of efficacy.

Effective resolution with olanzapine of acute presentation of behavioral agitation and positive psychotic symptoms in schizophrenia.

Behavioral agitation and prominent positive psychotic symptoms often characterize the acute presentation of schizophrenia. The clinical treatment goal is a rapid control of these symptoms. The relative efficacy of olanzapine, a novel antipsychotic drug, was compared with that of the conventional antipsychotic drug haloperidol. A post hoc analysis conducted on a large multicenter, double-blind, 6-week study of acute-phase patients with DSM-III-R schizophrenia or schizophreniform or schizoaffective disorders treated with olanzapine (5-20 mg/day) or haloperidol (5-20 mg/day) assessed the treatment effects on agitation (Brief Psychiatric Rating Scale [BPRS] agitation score) and positive symptoms (BPRS positive symptom score). Overall, olanzapine-treated patients experienced significantly greater improvement in behavioral agitation than did haloperidol-treated patients (last observation carried forward [LOCF]; p < .0002). Both groups showed similar reductions in agitation scores during the first 3 weeks of therapy; olanzapine was associated with significantly greater improvements at weeks 4, 5, and 6 (observed cases [OC]). Similarly, patients with predominantly positive psychotic symptoms experienced significantly greater improvement in BPRS positive symptom scores with olanzapine compared with haloperidol (LOCF; p = .013). In olanzapine-treated patients, improvement in BPRS agitation and positive symptom scores was significantly greater at weeks 4, 5, and 6 (agitation scores, p < or = .01; positive symptom scores, p < .05) (OC). These data suggest that olanzapine may be considered a first-line treatment for the patient in an acute episode of schizophrenia.

Reflex-related activation of putative pain facilitating neurons in rostral ventromedial medulla requires excitatory amino acid transmission.

Although the importance of the rostral ventromedial medulla in pain modulation is generally accepted, the recognition that it can exert both pain facilitating and pain inhibiting influences, and that its constituent neuronal population is physiologically and pharmacologically heterogeneous, is relatively recent. A class of neuron which may be a source of facilitating influences from the rostral ventromedial medulla has been identified in electrophysiological experiments. These neurons, termed "on-cells," are characterized by a sudden burst of activity beginning just before nocifensive reflexes. This burst of firing is thought to be a significant factor in brainstem control of nociceptive transmission under physiological conditions. The aim of the present study was to determine whether an excitatory amino acid is involved in generation of the reflex-related burst that defines on-cells, and more generally, to examine the role of excitatory amino acid neurotransmitters within the rostral ventromedial medulla of the rat. Iontophoretic application of the broad-spectrum excitatory amino acid receptor antagonist kynurenate significantly reduced the reflex-related on-cell burst, whereas ongoing firing was unaffected. Spontaneous activity of other medullary neurons was unchanged. These data demonstrate that release of an endogenous excitatory amino acid neurotransmitter is necessary for the activation of on-cells that is associated with nocifensive reflexes. In contrast, these receptors evidently play a much less significant role in maintaining the ongoing activity of any cell class in the rostral ventromedial medulla in lightly anaesthetized rats.

Effects of iontophoretically applied serotonin on three classes of physiologically characterized putative pain modulating neurons in the rostral ventromedial medulla of lightly anesthetized rats.

The importance of the rostral ventromedial medulla (RVM) in nociceptive modulation is well documented, and several lines of evidence point to a role for serotonin (5HT) in regulating the activity of pain modulating neurons in this region. The aim of the present study was to examine the effect of iontophoretically applied 5HT upon the firing of three physiologically defined classes of RVM neurons with distinct roles in pain modulation. The predominant effect across all classes was a facilitation of ongoing or evoked activity. A minority of cells within each class were inhibited by 5HT itself, but agonists at 5HT1 receptor types inhibited the majority of cells tested. The results thus indicate that the behavioral effects of manipulating 5HT within the RVM cannot be attributed to a selective influence on a particular cell class.

Endogenous opioids acting at a medullary mu-opioid receptor contribute to the behavioral antinociception produced by GABA antagonism in the midbrain periaqueductal gray.

This study examined the contribution of endogenous opioids to the antinociception produced by microinjection of the GABAA receptor antagonist, bicuculline, into the rat midbrain ventrolateral periaqueductal gray region. Microinjection of bicuculline (40 ng/0.4 microliter) into the periaqueductal gray produced robust antinociception as measured by the tail-flick latency to noxious heat. This antinociception was partially reversed by intravenous administration of the non-selective opioid antagonist naloxone hydrochloride (1 and 5 mg/kg), indicating that endogenous opioid release is necessary for this effect. To determine whether opioid release in the rostral ventromedial medulla, a major projection target of the periaqueductal gray, contributes to this effect, we microinjected another opioid antagonist, naltrexone, into the rostral ventromedial medulla. Naltrexone in the rostral ventromedial medulla (5 and 10 micrograms/microliter) significantly attenuated bicuculline antinociception elicited from the periaqueductal gray. Cys2, tyr3, orn5, pen7-amide (26.5 nmol), a selective mu-opioid receptor antagonist, also reversed the antinociception when microinjected into the rostral ventromedial medulla. Microinjections of naltrexone (10 micrograms/microliter) or cys2, tyr3, orn5, pen7-amide at sites in the medulla dorsal to the rostral ventromedial medulla were ineffective. None of the antagonists altered baseline tail-flick latencies. These results support the hypothesis that a population of periaqueductal gray neurons produces antinociception through a mu-opioid receptor-mediated action of endogenous opioids in the rostral ventromedial medulla. Thus, two opioid-sensitive pain-modulating brainstem sites are linked by an endogenous opioid synapse in the rostral ventromedial medulla.