Хлорфенамин как антидепрессант

Chlorpheniramine, selective serotonin-reuptake inhibitors (SSRIs) and over-the-counter (OTC) treatment

Антидепрессанты сравнение рецепторных свойств

Compound	SERT	NET	DAT	H1	M1-5	α1	α2	5-HT1A	5-HT2	D2
Agomelatine	?	?	?	?	?	?	?	?	270	?
Amitriptyline	4.3	35	3250	0.95	9.6	24	690	450	18	1460
Amoxapine	58	16	4310	25	1000	50	2600	?	?	?
Atomoxetine	8.9	2.03	1080	5500	2060	3800	8800	10900	940	35000+
Bupropion	45026	1389	2784	11800	35000+	4200	35000+	35000+	35000+	35000+
Buspirone	?	?	?	?	?	138	?	5.7	174	362
Butriptyline	1360	5100	3940	?	?	?	?	?	?	?
Citalopram	1.16	4070	28100	?	?	?	?	?	?	?
Clomipramine	0.28	38	2190	31	37	38	3200	?	?	?
Desipramine	17.6	0.83	3190	60	66	100	5500	6400	350	3500
Dosulepin	8.6	46	5310	?	?	?	?	?	?	?
Doxepin	68	29.5	12100	0.17	23	23.5	1270	276	27	360
Duloxetine	0.8	7.5	240	?	?	?	?	?	?	?
Etoperidone	890	20000	52000	3100	35000+	38	570	85	36	2300
Femoxetine	11	760	2050	4200	184	650	1970	2285	130	590
Fluoxetine	0.81	240	3600	5400	590	3800	13900	32400	280	12000
Fluvoxamine	0.81	240	3600	?	?	?	?	?	?	?
Imipramine	1.4	37	8500	37	46	32	3100	5800	150	620
Lofepramine	70	5.4	18000	360	67	100	2700	4600	200	2000
Maprotiline	5800	11.1	1000	2	570	90	9400	?	?	?
Mazindol	100	1.4	11	?	?	?	?	?	?	?
Mianserin	4000	71	9400	?	?	?	?	?	?	?
Milnacipran	123	200	10000+	?	?	?	?	?	?	?
Mirtazapine	1500+	1250~	1500+	1~	1000~	500~	100~	1500+	10~	1500+
Nefazodone	200	360	360	24000	11000	48	640	80	26	910
Nisoxetine	383	5.1	477	?	?	?	?	?	?	?
Nomifensine	1010	15.6	56	?	?	?	?	?	?	?
Nortriptyline	18	4.37	1140	6.3	37	55	2030	294	41	2570
Oxaprotiline	3900	4.9	4340	?	?	?	?	?	?	?
Paroxetine	0.13	40	490	22000	108	4600	17000	35000+	19000	32000
Protriptyline	19.6	1.41	2100	25	25	130	6600	?	?	?
Reboxetine	720	11	10000+	?	?	?	?	?	?	?
Sertraline	0.29	420	25	24000	630	380	4100	35000+	9900	10700
Trazodone	160	8500	7400	1100	35000+	42	320	96	25.0	35000+
Trimipramine	149	2450	3780	0.27	58	24	680	?	?	?
Venlafaxine	82	2480	7647	35000+	35000+	35000+	35000+	35000+	35000+	35000+
Viloxazine	17300	155	100000+	?	?	?	?	?	?	?
Zimelidine	152	9400	11700	?	?	?	?	?	?	?

SERT, NET, and DAT correspond to the abilities of the compounds to inhibit the reuptake of serotonin, norepinephrine, and dopamine, respectively. The other values correspond to their affinity for various receptors.

http://en.wikipedia.org/wiki/Antidepressant

Аспирин при шизофрении

"Aspirin given as [an adjunct treatment] to regular antipsychotic treatment reduces the symptoms of schizophrenia spectrum disorders. The reduction is more pronounced in those with the more altered immune function. Inflammation may constitute a potential new target for antipsychotic drug development."

Aspirin for Schizophrenia?

Зипрасидон (зелдокс, геодон)

Focus on Ziprasidone

Потенциирование трийодтиронином при недостаточном ответе на терапию ТЦА

"The exact mechanism of action of T3 augmentation remains largely unknown. In depressed patients, the circulating plasma levels of free T4 appear to be normal,
but levels of free T3 may be decreased. Approximately one third of depressed patients show blunting of the TSH response to thyrotropin releasing hormone.
Approximately 15% of depressed patients have elevated basal TSH levels, probably indicating subclinical hypothyroidism, and thyroid autoantibodies
are found in a similar percentage of patients.11
Thyroid abnormalities are found at a higher frequency among TCA nonresponders and this may link with the underlying mechanism of T3 augmentation.In most case reports, patients had normal thyroid function, as in our second case. There seems to be no
relationship between thyroid state and the efficacy of T3 augmentation. In the first case, the patient had sick euthyroid syndrome, which is sometimes seen in
depressed patients. In this condition, peripheral deiodination of T4 to T3 is reduced, although the TSH level is normal.
One proposed mechanism of T3 augmentation is that T3 may raise peripheral thyroid hormone concentrations in patients with covert or borderline hypothyroidism. Other authorities believe that there is no difference in the thyroid state of the
responders and nonresponders to T3 augmentation. 12 L-triiodothyronine may act in euthyroid patients through augmentation of the β-adrenergic system.13 Alternatively, T3 may also affect thyroid utilisation and local neuronal deiodination in the brain."

"The usual dose of T3 in augmentation therapy is 25 µg/d to 50 µg/d. A starting dose of 20 µg increasing to 40 µg was given to the patients in this study. Initial improvement in mood is usually apparent within several days. Goodwin et al reported that there was improvement in all aspects of the depressive syndrome within 1 to 3 days. For the two patients in this study,initial responses were noted after 3 and 7 days. An adequate trial of T3 augmentation should last for 7 to 14 days to reach its full effect. If T3 augmentation is effective, most studies recommend a maintenance
period of 2 months before gradually reducing the dose at the rate of 10 µg every 3 to 7 days."

Triiodothyronine augmentation for the treatment of depression in substance misusers unresponsive to tricyclic antidepressants.

Омега-3, омега-6 и витамин D в предупреждении возникновения психотических симптомов

"Our findings raise a possibility that adult women with a high intake of fish, omega-3 or omega-6 PUFA and vitamin D have a lower rate of psychotic-like symptoms."

Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33 000 women from the general population

Фармакотерапия социофобии

Pharmacotherapy for Social Anxiety Disorder: An Update

Анксиолитический эффект сока черноплодной рябины у крыс

"The main biologically active constituents of Aronia melanocarpa fruit juice (AMFJ) are polyphenolics, amongst them flavonoids, mainly anthocyanins. The aim of the present study was to investigate the effects of AMFJ (5 and 10 mL/kg) on anxiety using the social interaction test, on locomotor activity in the open field test and on working memory in the object recognition test in rats. AMFJ showed an anxiolytic-like effect which was demonstrated by a dose-dependent increase in the time of active social contacts between the test partners. The effects of both AMFJ doses were comparable to the effect of diazepam (1 mg/kg). AMFJ neither changed significantly horizontal and vertical locomotor activity, nor did it adversely affect working memory. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved."

Anxiolytic-like effect of Aronia melanocarpa fruit juice in rats.

Прегабалин при ГТР

"These results indicate that pregabalin is an effective, rapidly acting, and safe treatment for generalized anxiety disorder. In short-term treatment, pregabalin does not appear to have the withdrawal symptoms associated with the benzodiazepines."

Pregabalin in Generalized Anxiety Disorder: A Placebo-Controlled Trial

"The dose of 150 mg pregabalin over the four weeks of the trials was found insufficient for the treatment of GAD. In the dose range of 200-450 mg daily, a clinically significant effect was obtained, although with a plateau-like curve which was not increased for the maximum dose of 600 mg daily."

Dose-response relationship of pregabalin in patients with generalized anxiety disorder. A pooled analysis of four placebo-controlled trials.

"The efficacy of pregabalin in treating GAD is not surprising as a number of other antiepileptic drugs have also been shown to have anxiolytic properties and to be effective in treating patients with anxiety disorders. Valproate has been shown to have efficacy in the treatment of panic disorder (Primeau et al 1990; Woodman and Noyes 1994; Baetz and Bowen 1998) and blocks lactate-induced panic attacks (Keck et al 1993). The antiepileptic drug carbamazepine has efficacy in the treatment of panic disorder (Tondo et al 1989), post-traumatic stress disorder (PTSD) (Lipper et al 1986), and obsessive compulsive disorder (OCD) (Joffe and Swinson 1987). Lamotrigine is potentially effective in the treatment of PTSD (Hertzberg et al 1999) and may have an adjunctive role in the treatment of refractive OCD (Kumar and Khanna 2000). Topiramate has been shown to be efficacious in open-label trials for PTSD (Berlant and van Kammen 2002; Berlant 2004), social phobia disorder (Van Ameringen et al 2004) and may have an adjunctive role in treatment-resistant OCD (Van Ameringen et al 2006). However, unlike previous antiepileptic drugs which primarily block sodium and potassium channels or increase cerebral GABA concentrations, pregabalin decreases presynaptic calcium currents and in doing so decreases the release of several neurotransmitters, including glutamate (Dooley et al 2000a), substance P (Fehenbacher et al 2003), calcitonin-gene-related peptide (Fehenbacher et al 2003), and norepinephrine (Dooley et al 2002). Interestingly, many of these neurotransmitters have been implicated in the pathogenesis GAD or other anxiety disorders (Erikkson et al 1991; Geracioti et al 2001; Olsson et al 2004; Geracioti et al 2006). As might be expected, agents that pharmacologically dampen these systems have therapeutic roles in a number of anxiety disorders (Peet and Ali 1986; Furmark et al 2005; Strawn and Geracioti 2006). Also, decreases in the activity of these or related “fear circuits” that underlie the pathophysiology of certain anxiety disorders (Stahl 2004) could explain the efficacy of pregabalin in patients with GAD. It will be of interest to examine the effects of pregabalin in other anxiety disorders such as PTSD, panic disorder, or even meal-related anxiety in anorexia nervosa (wherein additional benefit may be conferred by pregabalin-associated weight gain)."

The treatment of generalized anxiety disorder with pregabalin, an atypical anxiolytic

Антиконвульсанты в терапии поведенческих и психологических симптомов деменции

"INTRODUCTION: Dementia, besides the dominant cognitive disorders that define it, is associated with behavioral disturbances, the consequences of which are, on various levels, a determining factor for the handling of these patients. The treatment of behavioral and psychological symptoms is essential and although, to date, no therapeutic solution is satisfactory, it is necessary to look for an alternative to the neuroleptics usually employed, which raise real problems of tolerance in this geriatric population. BACKGROUND: For several years, anticonvulsants, among which some have shown mood stabilizing activity, have been the object of research in this indication. The purpose of this review of the literature is to assess the interest and the limits of anticonvulsant mood stabilizers (carbamazepine, valproic acid, gabapentin, lamotrigine, topiramate, oxcarbazepine) in the treatment of the so-called "noncognitive" symptoms of dementia. Their mechanism of action in mood disorders is not well known, but it would appear to be via the modulation of glutamate-mediated excitatory synaptic transmission and gamma-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission that anticonvulsants might reduce behavioral symptoms in demented patients. METHODS: The method employed in this work was a systematic bibliographic review, in which only the double-blind placebo-controlled studies or the clinically detailed enough open-labelled studies using validated scales were retained. RESULTS: Among these medications, only carbamazepine demonstrated its efficacy in behavioral and psychological symptoms of dementia (BPSD) in controlled studies, notably that of Tariot et al. [J Am Geriatr Soc 42 (1994) 1160-1166 and Am J Psychiatry 155 (1998) 54-61] and Olin et al. [Am J Geriatr Psychiatry 9 (2001) 400-405], but with significant adverse events (sedation, hyponatremia, cardiac toxicity), particularly in the elderly and, being a strong enzymatic inducer, with a high likelihood of drug-drug interactions. Valproic acid showed some interesting results in BPSD within a large number of open studies and case reports. However, among the five controlled studies that have been published [Curr Ther Res 62 (2001) 51-67; Am J Geriatr Psychiatry 9 (2001) 58-66; Int J Geriatr Psychiatry 17 (2002) 579-585; Curr Alzheimer Res 2 (2005) 553-558 and Am J Geraitr Psychiatry 13 (2005) 942-945], none confirmed its efficacy on these symptoms. Regarding its tolerability in the geriatric population, no notable major side effect was reported (haematologic and hepatic effects are not more frequent than in the general population), except possible excessive sedation. Moreover, it appears that valproic acid could have neuroprotective effects, even if the contrary has been observed in a recent study. More studies need to be (and are being) conducted, notably on the interest of valproic acid in prophylaxis of BPSD. Gabapentin seems to be worthwhile and well tolerated in this indication, but no controlled study has been conducted to prove its efficacy, even if a quite important number of case reports and open studies have shown encouraging results. Concerning lamotrigine, which may potentially induce severe cutaneous side effects when administered with valproic acid, this drug has shown its efficacy in bipolar disorders and two recent case reports seem to indicate some interest in BPSD. Furthermore, lamotrigine appears to have neuroprotective effects. Although topiramate has shown interesting results in one open study in BPSD, its use in demented patients cannot be recommended because of its deleterious effect on cognitive functions. Oxcarbazepine, theoretically, could be an alternative to carbamazepine, which is, as aforesaid, the only anticonvulsant that proved its interest in BPSD. However, no clinical study has yet been published to support this hypothesis. This drug is better tolerated than carbamazepine, but induces severe and more frequent hyponatremia. DISCUSSION AND CONCLUSION: Finally, although we all know that antipsychotics should no longer be prescribed in the elderly, the treatment of behavioral and psychological symptoms of dementia remains a difficult problem, considering the lack of a real alternative to these medications. Anticonvulsant mood stabilizers are an interesting solution but none of them, other than carbamazepine, which did, but which is not better tolerated than the usual drugs in this population - was able to prove its efficacy in this indication. Among these medications, valproic acid, gabapentin and lamotrigine should be studied further, and the neuroprotective effect of some of them is an interesting route for research."

Anticonvulsant mood stabilizers in the treatment of behavioral and psychological symptoms of dementia (BPSD)

Влияние современных антиконвульсантов на когнитивные функции

"BACKGROUND: Antiepileptic drugs (AEDs) can be associated with neurotoxic side effects including cognitive dysfunction, a problem of considerable importance given the usual long-term course of treatment. Pregabalin is a relatively new AED widely used for the treatment of seizures and some types of chronic pain including fibromyalgia. We measured the cognitive effects of 12 weeks of pregabalin in healthy volunteers. METHODS: Thirty-two healthy volunteers were randomized in a double-blind parallel study to receive pregabalin or placebo (1:1). Pregabalin was titrated over 8 weeks to 600 mg/d. At baseline, and after 12 weeks of treatment, all subjects underwent cognitive testing. Test-retest changes in all cognitive and subjective measures were Z scored against test-retest regressions previously developed from 90 healthy volunteers. Z scores from the placebo and pregabalin groups were compared using Wilcoxon tests. RESULTS: Thirty subjects completed the study (94%). Three of 6 target cognitive measures (Digit Symbol, Stroop, Controlled Oral Word Association) revealed significant test-retest differences between the pregabalin and placebo groups, all showing negative effects with pregabalin (p < 0.05). These cognitive effects were paralleled by complaints on the Portland Neurotoxicity Scale, a subjective measure of neurotoxicity (p < 0.01). CONCLUSION: At conventional doses and titration, pregabalin induced mild negative cognitive effects and neurotoxicity complaints in healthy volunteers. These effects are one factor to be considered in the selection and monitoring of chronic AED therapy. Class of Evidence: This study provides Class I evidence that pregabalin 300 mg BID negatively impacts cognition on some tasks in healthy volunteers."

Cognitive effects of pregabalin in healthy volunteers: a double-blind, placebo-controlled trial.

"OBJECTIVE: To evaluate the cognitive effects of topiramate (TPM) and gabapentin (GBP). METHODS: Forty healthy volunteers were randomized to a 12-week course of TPM, GBP, or placebo. Doses were gradually escalated over 10 weeks to a maximum of 400 mg/day of TPM or 3,600 mg/day of GBP or to the highest tolerated dose. Subjects were interviewed and examined biweekly. Cognitive testing was performed prior to initiating the drug and again 12 weeks later, at least 2 weeks after achieving plateau dosing. For each subject and cognitive measure, test-retest Z scores were calculated based on regression equations derived from 73 healthy volunteers. Group comparisons utilized the Wilcoxon test. RESULTS: There were significant TPM vs GBP and TPM vs placebo differences in test-retest Z scores for four of six target cognitive measures (Digit Symbol, Story Recall, Selective Reminding, Controlled Oral Word Association), always indicating worse retest performance for subjects receiving TPM. Overall, 12 of 24 cognitive measures were similarly affected. TPM effects were large, and several target measures averaged >2 SD of negative change. One measure was significantly affected by GBP. CONCLUSIONS: Topiramate (TPM) impaired cognitive test performance, whereas gabapentin had minimal effects. The effects of TPM were of sufficient magnitude potentially to affect daily and occupational function."

Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers.

Кветиапин: эффективность и переносимость доз

"Quetiapine has a wide clinical dose range that extends up to 750mg/day (up to 800 mg/day in the USA and Canada).[21,22] Although administration is usually twice-daily,[23] a pilot study in patients with schizophrenia or schizoaffective disorder found similar levels of clinical efficacy in patients administered quetiapine on a once-or twice-daily basis.[24] Moreover, our clinical experience has suggested that a more rapid initiation schedule than that described in current prescribing information (300 mg/day by Day 4; 300-400 mg/day by Day 4 in the USA and Canada),[21] with a higher target dose, may be more appropriate in hospitalised adult and adolescent patients with an acute exacerbation of schizophrenia in order to achieve rapid control of symptoms. Some evidence supporting this assertion can be found in a poster that described a randomised, multicentre, double-blind, pilot study of hospitalised patients with acute schizophrenia who had their doses of quetiapine (twice-daily oral administration) titrated to 400 mg by Days 2, 3 or 5, without any increased risk of adverse events compared with classic initiation.[25] The overall frequency of adverse events was similar among the three initiation groups and somnolence was experienced by fewer than 15% of patients in each initiation group; indeed, the lowest incidence of somnolence (8%) was observed in the group of patients using the fastest initiation scheme (400 mg by Day 2). Throughout the study, patient vital signs and laboratory values were similar among the three initiation groups. The somnolence observed in these quetiapine-treated patients is likely to be a result of histamine H1 antagonism to which tolerance usually develops over time. Experience has shown that somnolence with quetiapine is not dose-related, most cases are mild and transient (usually dissipating after approximately 2 weeks), and that the incidence of somnolence does not increase over time. These data support our clinical experience of initiating quetiapine at 200mg/day in the inpatient setting and increasing the dose in increments of 200 mg/day."

Dosing of quetiapine and Clinical Global Improvement scores in a small study of patients with schizophrenia, schizoaffective disorder or other psychotic disorders.

Managing Acute Exacerbations of Schizophrenia: Focus on: Influence of Tolerability on Treatment Selection

Рецепторный профиль анитипсихотиков второго поколения и галоперидола

Receptor Binding Profile of Aripiprazole and Reference Antipsychotics^a

Receptor	Aripiprazole	Olanzapine	Risperidone	Quetiapine	Ziprasidone	Clozapine	Haloperidol
D1	265b	31	430	455	525	85	210
D2	0.34b	11	4	160	5	126	0.7
D3	0.8b	49	10	340	7	473	2
D4	44b	27	9	1600	32	35	3
5-HT1A	1.7b	>10,000	210	2800	3	875	1100
5-HT2A	3.4b	4	0.5	295	0.4	16	45
5-HT2C	15b	23	25	1500	1	16	>10,000
a1	57	19	0.7	7	11	7	6
H1	61b	7	15	11	50	6	440
M1	>10,000	1.9	>10,000	120	>1000	1.9	>150

Aripiprazole in the Treatment of Schizophrenia

Гэмблинг вызваный прамипексолом

BACKGROUND: Dopamine agonists (DAs), long used in treating Parkinson’s disease and effective in relieving symptoms of restless legs syndrome, have frequently been reported to induce problematic compulsive behaviors (e.g., obsessive gambling, hypersexuality) in individuals who had never had difficulties with such behaviors before. OBJECTIVE: The authors report two cases that add to a small-but-growing literature suggesting that these drugs be dispensed with appropriate caution. METHOD: The authors describe two patients seen in a psychiatric setting—one, after a suicide attempt, and one with depression—both resulting from intractable compulsive gambling. RESULTS: In both instances, control of gambling was achieved: in one, when pramipexole was discontinued, and in the other, after substitution of ropinirole and addition of spiritual and support-group approaches. DISCUSSION: DAs stimulate pathways that govern reward behavior, including pleasure and addiction. Other reward behaviors, such as eating and sexual activity, may also be affected by DAs. These cases demonstrate a clear temporal relationship between initiation and behavioral change; patients and their caregivers should be alerted to the possibility of such changes.

Impact of Dopamine Agonists on Compulsive Behaviors: A Case Series of Pramipexole-Induced Pathological Gambling

Психогенная пурпура

Case Report: Psychogenic Purpura

Фоноагнозия

Woman unable to recognise voices gives new insights into the human brain

Fast-Off эффект

"Mode of Action

Quetiapine binds to a number of potentially relevant neurotransmitter receptors. Quetiapine has a greater affinity for serotonin 5HT2 receptors than for dopamine D, receptors. Together with considerable activity at histamine receptors and a-adrenoceptors, that explains somnolence and orthostatic hypotension caused by it. Quetiapine has less affinity for dopamine D2 receptors than dopamine itself, as a result It is rapidly dissociated from D2 receptor which results into several beneficial effects such as absence of EPS, absence of tardive dyskinesia and no effect on serum prolactin levels. This phenomena is known as "Fast-off",

Fast – off Effect

Typical antipsychotic drugs such as haloperidol, chlorpromazine, and fluphenazine have higher affinity for D2 receptor and bind more tightly than dopamine itself to D2 receptors. Prolonged occupancy of D2 receptors by typical antipsychotic drug result into several side effects such as extrapyramidal symptoms, elevated levels of serum prolactin and after a period of time tardive dyskinesia. It has been demonstrated that haloperidol, chlorpromazine dissociate very slowly over a 30 minutes time span, while quetiapine and clozapine dissociate rapidly from D2 receptors in less than 60 seconds.¹²"

Quetiapine: A Novel Anti Schizophrenic Drug

Скорость ответа на ЭСТ

"In a recent large study carried out by the Consortium for Research in ECT (CORE), Husain and colleagues³ reported that 34% of 253 patients achieved remission (HAM-D score of 10) at or before the 6th session with ECT (within 2 weeks) and 65% achieved remission at or before the 10th session (within 3 to 4 weeks)। More than half (54%) had an initial first response (decrease of 50% in HAM-D score) by session 3. Furthermore, 19% of the seriously ill cohort in this study (baseline HAM-D score of approximately 35) experienced remission with 4 or fewer ECT sessions."

Speed of Response to ECT

"We present the case of a 74-year-old Caucasian man who developed severe and prolonged interictal ECT-induced delirium after being treated with ECT for worsening depression. His CT scan findings revealed evidence of chronic bilateral basal ganglia infarcts. Our case supports evidence that basal ganglia lesions have been implicated as one of the risk factors for ECT-induced delirium।"

A Case of Prolonged Interictal ECT-Induced Delirium

Руководство по взаимодействию лекарств в психиатрии

2006 Guide to Psychiatric Drug Interactions

Сравнительная таблица: дулоксетин и венлафаксин

"Venlafaxine (Effexor, Effexor XR) has the flexibility of being an SSRI at lower doses (75 mg/day), affecting the reuptake of serotonin, and an SNRI at higher doses (150-225 mg/day). It also very weakly blocks the reuptake of dopamine at very high doses (above 350 mg/day).

Duloxetine (Cymbalta) is a strong, balanced inhibitor of both norepinephrine and serotonin reuptake.

Duloxetine differs from venlafaxine in that it is comparatively more noradrenergic। Venlafaxine has a 30-fold higher affinity for serotonin than for norepinephrine while duloxetine has a 10-fold selectivity for serotonin6. Approximate potency ratios (5-HT:NE) are 1:10 for duloxetine, and 1:30 for venlafaxine."

Brief comparison table

	Venlafaxine (Effexor)	Duloxetine (Cymbalta)
Generic name	Venlafaxine hydrochloride	Duloxetine hydrochloride
Brand name/Manufacturer	Wyeth	Eli Lilly
FDA approval date	1993	2004
Active Metabolite	O-Desmethylvenlafaxine	5-hydroxy-duloxetine 6-methoxy-duloxetine
Half-life	4 (11 for O-desmethylvenlafaxine)	12 hours (range 8 to 17 hours)
Time to steady-state	3 days	3 days
Bioavailability, %	45	50
Potential for interactions	Has one of the most favorable drug-interaction profiles4 Weak or negligible inhibitor of CYP isozymes (CYP2D6, CYP1A2, CYP2C19, and CYP3A4)	Moderate inhibitor of CYP2D6, has the potential to interact with other drugs that are also metabolized by this cytochrome P450 system
Generic avalability	Yes	No
FDA Pregnancy Category	C	C
Most common side effects	nausea headache somnolence dizziness insomnia nervousness dry mouth anorexia sweating abnormal ejaculation constipation impotence	nausea somnolence headache dry mouth dizziness insomnia fatigue constipation diarrhea decreased appetite vomiting erectile dysfunction
Mode of action	Serotonergic at lower doses, modest noradrenergic effects at higher doses (> 250 mg/day)	Strong, balanced inhibitor of both norepinephrine and serotonin reuptake

Antidepressants Comparison: Effexor versus Cymbalta

"

In a study by Bymaster and colleagues it was found that duloxetine inhibited binding to the human norephinepherine (NE) and serotonin (5-HT) transporters with K(i) values of 7.5 and 0.8 nM, respectively, and with a K(i) ratio of 9. Venlafaxine inhibited binding to the human NE and 5-HT transporters with K(i) values of 2480 and 82 nM, respectively, and with a K(i) ratio of 30. Duloxetine inhibited ex vivo binding to rat 5-HT transporters and NE transporters with ED(50) values of 0.03 and 0.7 mg/kg, respectively, whereas venlafaxine had ED(50) values of 2 and 54 mg/kg, respectively.

Thus, duloxetine more potently blocks serotonin and norephinepherine transporters in vitro and in vivo than venlafaxine,^[23] arguably making it the most potent of all commercially available SNRIs. Duloxetine and venlafaxine have not been measured against milnacipran."

Duloxetine

Атипичные антипсихотики: сон, седация и эффективность

"In general, the high-milligram, low-potency antipsychotics, such as chlorpromazine and mesoridazine, produce more sedation than the low-milligram, high-potency antipsychotics such as haloperidol and fluphenazine (Table 1).6 This principle tends to hold true for the atypical antipsychotics as well. For example, the high-potency, low-dose atypical antipsychotic risperidone is less sedating than the lower-potency, high-dose atypical antipsychotics quetiapine and clozapine. However, dose does not always determine sedation. Olanzapine, which has a common dose range of 15 to 30 mg/day, is more sedating than ziprasidone, which has a common dose range of 80 to 160 mg/day. Studies have indicated that sedation may also be related to the affinity of the medication for the histamine H1 receptors. The antipsychotics vary in their ability to block these receptors.4,7 A study by Richelson and Souder7 of the binding profiles of antipsychotic medications found that olanzapine has the highest affinity for the histamine H1 receptors, followed by clozapine (Figure 1Figure 1.). This may explain why olanzapine has a relatively large sedative effect even though it is a high-potency medication. Of the antipsychotics studied, haloperidol had the lowest affinity for the histamine H1 receptors. Quetiapine and risperidone had the lowest affinity of the atypical antipsychotics. Although both dosage and affinity for histamine H1 receptors play a part in the sedative effect of a medication, what ultimately determines sedative effect is the amount of the drug reaching the histamine H1 receptors in the central nervous system. For example, quetiapine, which has little affinity for the histamine H1 receptors, is a less potent antipsychotic medication and requires many more milligrams to be effective than do higher-potency medications such as risperidone and ziprasidone. Because of this, quetiapine has a greater sedative effect on patients in clinical use than do risperidone and ziprasidone."

"If sedation is bothersome to patients taking antipsychotic medications, physicians can take steps to minimize it. According to the 1999 Expert Consensus Guidelines on the treatment of schizophrenia,15 physicians should consider eliminating other sedating agents from the patient's list of medications. This includes antidepressants, such as the tricyclics and mirtazapine, and mood-stabilizing medications such as valproic acid. Instructing the patient to take his or her medication at bedtime can also reduce daytime sedation. If the entire dose cannot be given at bedtime, then the majority of the dose should be taken at night. If necessary, the physician should consider reducing the dose of the antipsychotic medication, but this should be done slowly and cautiously. The physician could also consider switching the patient to a less sedating antipsychotic. Also, the physician might consider checking the patient for hypothyroidism, which can cause individuals to feel sedated. If these efforts do not work, caffeine or bupropion might help the patient feel more alert. Many patients taking antipsychotic medications drink several cups of coffee every morning to feel less sedated.
The 1999 guidelines recommended prescribing stimulants for patients who were persistently sedated, but this has become highly controversial. Generally, I do not recommend prescribing stimulants for psychotic patients because sedation can usually be controlled using other means and the physician may be held liable for the patient's actions while medicated with stimulants.
A medication that has recently emerged as an option to treat drug-induced sedation is modafinil. The treatment mechanism of modafinil is unknown, and although it is a schedule IV controlled substance, it is not a stimulant. It has been used successfully in clinical settings to combat sedation, but there is concern that it may worsen psychotic symptoms. Modafinil was reported to have exacerbated psychosis in 1 patient who was taking a dose of 200 mg 4 times daily,16 but no adverse effects were reported in 3 patients who were taking 200 mg/day along with antipsychotic medications.17"

Atypical Antipsychotics: Sleep, Sedation, and Efficacy

Амантадин для коррекции набора веса при терапии оланзапином

OBJECTIVE: This study sought to determine if amantadine affects weight gain in psychiatric patients taking olanzapine. METHOD: Twenty-one adults who had gained at least 5 lb with olanzapine were randomly assigned to receive amantadine (N=12) or placebo (N=9) in addition to olanzapine. The length of time taking olanzapine ranged from 1 to 44 months. Body mass index, psychiatric status, and fasting blood levels were assessed at baseline and 12 weeks. RESULTS: Significantly fewer subjects taking amantadine gained weight, with a mean change in body mass index of –0.07 kg/m2 for the amantadine group and 1.24 kg/m2 for the placebo group. This effect remained significant when the authors controlled for baseline body mass index and length of olanzapine treatment. No changes in fasting glucose, insulin, leptin, prolactin, and lipid levels were seen. Positive and Negative Syndrome Scale scores remained stable. CONCLUSIONS: Amantadine induced weight stabilization in subjects taking olanzapine and was well tolerated.
Double-Blind, Placebo-Controlled Investigation of Amantadine for Weight Loss in Subjects Who Gained Weight With Olanzapine

Повышение уровня ГАМК может исправить когнитивный дефект при шизофрении

Raising GABA Levels Might Undo Cognitive Defect in Schizophrenia

Вызывают ли бета-блокаторы депрессию

"Studies show no significant difference in incidence of depression between patients who received beta blockers and those who did not"

Do beta blockers cause depression?

Комбинированная психофармакотерапия

"Unipolar depression. Blier et al1 demonstrated a remarkable superiority of 3 different combinations of 2 antidepressants compared with fluoxetine monotherapy. The remission rate with combination therapy (46% to 58%) was double that of fluoxetine alone (25%). When 1 of the 2 antidepressants was blindly discontinued in high responders, 40% relapsed. Tolerability to the combination was the same as to monotherapy. Recent FDA approval of 2 atypical antipsychotics—aripiprazole2 and quetiapine3—as adjuncts to antidepressants to increase the remission rates further supports the case for combination therapy.

Bipolar disorder. Psychiatrists know that combining a mood stabilizer with an antipsychotic exerts more efficacy that either drug alone.4 But what about combining 2 mood stabilizers? A recent study5 confirmed the superiority of combining lithium plus valproate compared with either 1 alone. Score another victory for polypharmacy in bipolar disorder, where FDA studies of combination therapy are more common than in any other psychiatric disorder.

Schizophrenia. It is highly unrealistic to expect 1 drug (such as a dopamine antagonist) to show efficacy for schizophrenia’s disparate symptoms, including positive symptoms, negative symptoms, cognitive impairment, mood dysregulation, and substance use. Yet antipsychotic monotherapy remains the standard of care in schizophrenia, and there are no FDA combination trials of antipsychotics. However, in the United States, more than one-third of persons with chronic schizophrenia receive ≥2 antipsychotics because their psychiatrist found that combinations exerted more efficacy compared with just 1 antipsychotic agent. A combination of 2 atypical antipsychotics may be superior to monotherapy, but controlled studies have not been conducted.

In addition, patients receiving clozapine for refractory schizophrenia experienced significant improvement with the addition of lamotrigine.6 Another anticonvulsant, valproate, also was shown to accelerate response to an antipsychotic.7 Clinical trials are being conducted for new agents that enhance memory8 and negative symptoms.9 If the results are positive, the future of schizophrenia pharmacotherapy will shift decisively to polytherapy of 3 or even 4 drugs targeting positive, negative, cognitive, and mood symptoms.10

Anxiety. Recent studies confirm the benefits of combining small doses of atypical antipsychotics to an antidepressant/anxiolytic regimen.11 Most Patients with anxiety receive benzodiazepines as well.

OCD. Most patients with OCD do not achieve a remission with a selective serotonin reuptake inhibitor. Many studies have indicated additional improvement from adding an atypical antipsychotic.12 Other studies have added the glutamate modulating agent memantine with reported benefit."

Combination therapy is here to stay

Половые различия в ответе на терапию антидепрессантами

Sex differences in antidepressant response

Class	Response: Male vs female
Monoamine oxidase inhibitors	M<F
Serotonin-norepinephrine reuptake inhibitors	M=F
Selective serotonin reuptake inhibitors	Age <50: M< F Age ≥50: M=F
Tricyclic antidepressants	M=F
References 1-12

"Medical literature has documented gender differences in antidepressant absorption, distribution, metabolism, and elimination.a-c Compared with men, women—especially premenopausal women—have slower gastric emptyingd and small bowel and colonic transit times.e,f Also, because antidepressants generally are lipophilic,a,g a lower ratio of lean muscle to adipose tissue in women compared with men may result in a greater volume of drug distribution (Vd).

Sex differences also have been reported in hepatic enzyme activity and may affect clinical response. Most medications, including antidepressants, undergo phase I metabolism, commonly via the cytochrome P450 (CYP450) pathway, and/or phase II conjugation reactions. Generally, phase I oxidative metabolism appears to be greater in women than in men; in contrast, phase II conjugation activity appears to be greater in men than in women.h

Lower CYP1A2 activity in womeni along with gonadal steroid inhibition of CYP1A2j,k may explain why clomipramine metabolic clearance is reduced in young womenl and mean steady state plasma levels of fluvoxamine are almost double in women than in men for the same dose.m In theory, greater CYP3A4 activity in womeni has the potential to accelerate metabolism and/or decrease plasma levels of some commonly used antidepressants metabolized via CYP3A4, such as nefazodone and (to some extent) sertraline and citalopram. In contrast, CYP2D6 and CYP2C9 do not show sex differences in metabolism.

Differences in antidepressant blood levels, however, are difficult to base solely on CYP metabolic route differences. Sex differences in plasma antidepressant levels likely reflect a summation of several sex-associated pharmacokinetic processes and may impact one of many factors that contribute to the small observed difference in antidepressant efficacy between men and women."

"Sexual dimorphisms in the localization and concentration of endogenous neurotransmitters such as serotonin and dopamine and their degradative enzymes and transporters have the potential to clinically affect antidepressant pharmacodynamics (eg, drug-receptor interactions).

Recent investigations report sex differences in some key monoaminergic enzymes in the brain, notably monoamine oxidase-A (MAO)a,b and catechol-O-methyltransferase (COMT).c-e

For example, estrogen has been found to inhibit MAO,f which is potentially clinically relevant in light of the finding that women respond better than men to MAO inhibitors. COMT—which is responsible for metabolism of norepinephrine, epinephrine, and dopamine—is down regulated by estradiole,g likely accounting for some sex effects. Recently, the sexually dimorphic effect of a COMT polymorphism was associated with a poorer fluoxetine response in men treated for major depression.h"

"Hormone-related changes associated with the menstrual cycle may affect antidepressant absorption and distribution"

"Dose increases are necessary in two-thirds of pregnant women on antidepressant monotherapy"

"Studies have shown better SSRI response in postmenopausal women receiving estrogen therapy compared with placebo"

"Human sexual dimorphism of the serotonergic system has been described for many years,a,b including estrogen’s sexually dimorphic effects on the brain.c Sex steroid receptors are found in mood-processing brain regions in men and womend and may influence sex differences in antidepressant response.

Estrogen has been found to augment serotonergic activitye by increasing serotonin synthesis and decreasing serotonin reuptakef as well as increasing serotonin 5-HT2A binding sites.g Estrogen therapy has been shown to increase the number of sites available for active transport of 5-HT into brain cells.h"

Sex-related differences in antidepressant response: When to adjust treatment

Антидепрессанты при БАР

"Although some might argue that the precise relative risk of antidepressant-induced mania or hypomania is unknown (eg, considering intervening factors such as the natural illness course), recent literature suggests that the emergence of mania or hypomania can be reasonably attributed to antidepressant use in no more than 10% to 25% of patients with bipolar disorder"

"One large randomized trial showed comparable antidepressant efficacy with a mood stabilizer plus adjunctive venlafaxine (43%) vs sertraline (55%) vs bupropion (49%) over 10 weeks,14 but the lack of a mood stabilizer monotherapy comparison group limits the ability to anticipate whether adjunctive antidepressants increase response or remission rates more than mood stabilizers alone. Adjunctive imipramine,13 paroxetine,12,13,15 and bupropion12 yield no greater improvement in depressive symptoms than is seen with optimally dosed mood stabilizers alone."

"The largest dataset on this topic—the randomized controlled data from Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)12—found that the risk for treatment-emergent manic switch with paroxetine or bupropion was almost identical (about 10%) with or without an FDA-approved antimanic agent.

In a retrospective study, Henry et al6 found that cotherapy with lithium but not divalproex or carbamazepine protects against antidepressant-induced mania, and that switch rates to mania were the same whether or not an antidepressant was taken with an anticonvulsant. In a naturalistic retrospective study (n=158), Bottlender et al24 revealed that mood stabilizers (lithium, carbamazepine, or divalproex) prevented switches from depression to mania during treatment with TCAs but not SSRIs or MAOIs.

I favor incorporating lithium or other antimanic agents in the regimens of patients with bipolar depression not primarily to guard against antidepressant-induced mania but more for pharmacodynamic synergy—complementary mechanisms of action that collectively may produce more substantial antidepressant effects—especially when the patient’s illness course has included manic or hypomanic features in the preceding year."

"Wehr et al25 reported that antidepressants may accelerate cycling frequency (ie, inter-episode durations become shorter) in a small subgroup (N=10) of patients. By contrast, use of TCAs was not more likely in the weeks preceding shifts from depression to mania or hypomania in a 14-year follow-up study of bipolar rapid cycling from the NIMH Collaborative Depression Study.26 In fact, rapid-cycling patients spent more weeks depressed when taking lithium without a TCA than with."

Antidepressants in bipolar disorder: 7 myths and realities

Успешное возобновление клозапина у пациентки с нейтропенией вызванной клозапином

S.P. was a 56-year-old African American man with a 30-year history of paranoid schizophrenia. He had sufficiently tolerated a clozapine rechallenge in 2007, 2 years after developing clozapine-induced neutropenia. Following a period of relative stability after the rechallenge, he discontinued treatment with clozapine because of complaints of dizziness and an unwitnessed syncopal episode, which were not clearly attributed to the drug. Shortly afterward, he suffered functional decline and required inpatient stabilization. He was initially titrated to haloperidol (20 mg/twice daily), olanzapine (20 mg/day), and divalproex sodium (750 mg/twice daily). Unfortunately, this regimen was ineffective, and he continued to exhibit bizarre behavior, severe paranoid delusions, social isolation, and an inability to conduct activities of daily living. In light of his improvement after the 2007 clozapine rechallenge, S.P. and his treatment team elected to initiate clozapine treatment again.

Clozapine Rechallenge in Refractory Schizophrenia

Медицинская марихуана и повышенный риск психоза

"Mr. Z" was a 24-year-old man who was first hospitalized for insomnia, irritability, and aggressiveness 2 years after military service. On admission, he displayed heightened religiosity and mild suspiciousness. Urine toxicology screening revealed cannabinoids, supporting the patient's endorsed semi-daily cannabis use via water pipe for the past 18 months, without other substance abuse. He was started on quetiapine (100 mg/day), with rapid resolution of symptoms, and discharged after 10 days.

The patient subsequently discontinued quetiapine and was lost to follow-up. Four months later, he presented to a marijuana clinic complaining of chronic pain, insomnia, and anxiety and was given a diagnosis of posttraumatic stress disorder (PTSD) and pain, along with a medical recommendation for cannabis. No psychotic symptoms were elicited. He later explained that he switched from "street" marijuana to medical marijuana in order to obtain a more potent product as well as to avoid illegal activity and getting "ripped off" by drug dealers. He also increased the frequency of his daily use from approximately once to twice daily.

Six months later, Mr. Z was rehospitalized with new-onset auditory hallucinations (multiple voices speaking to each other and urging violence) and delusions (believing that people were tampering with his windows and eavesdropping on his conversations and that he was Jesus Christ). Aripiprazole (15 mg/day) was prescribed, with gradual symptomatic improvement, and then tapered to a lower dose (7.5 mg/day) due to tremor. The patient reported that he believed smoking cannabis helped his chronic pain but that it worsened his psychotic symptoms, such that he wanted help to stop smoking the drug. After 4 weeks, he was discharged to residential substance abuse treatment with only mild, residual psychotic symptoms and a discharge diagnosis of psychotic disorder not otherwise specified, PTSD, and cannabis dependence. At a 3-month follow-up evaluation, while still taking aripiprazole, Mr. Z remained off cannabis and free of psychotic symptoms.

Psychosis Associated With Medical Marijuana: Risk vs. Benefits of Medicinal Cannabis Use