(British Approved Name, US Adopted Name, rINN)

INNs in other languages (French, Latin, and Spanish):

Paroxetine Hydrochloride

Drug Approvals

(British Approved Name Modified, rINNM)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Pharmacopoeias. In Europe and US, which permit the anhydrous and hemihydrate forms.

European Pharmacopoeia, 6th ed. (Paroxetine Hydrochlonde, Anhydrous). A white or almost white, hygroscopic, crystalline powder. It exhibits polymorphism. Slightly soluble in water sparingly soluble in dehydrated alcohol and in dichloromethane freely soluble in methyl alcohol. Store in airtight containers at a temperature not exceeding 25°.

European Pharmacopoeia, 6th ed. (Paroxetine Hydrochloride Hemihydrate). A white or almost white, crystalline powder. It exhibits pseudopolymor-phism. Slightly soluble in water sparingly soluble in alcohol and in dichloromethane freely soluble in methyl alcohol. Protect from light.

The United States Pharmacopeia 31, 2008 (Paroxetine Hydrochloride). It is anhydrous or contains one-half molecule of water of hydration. A white to off-white solid. Slightly soluble in water soluble in alcohol and in methyl alcohol. Store the anhydrous form in airtight containers.

Paroxetine Mesilate

Drug Approvals

(British Approved Name Modified, rINNM)

INNs in main languages (French, Latin, and Spanish):

Adverse Effects, Treatment, and Precautions

As for SSRIs in general (see Fluoxetine). Extrapyramidal reactions (including orofacial dystonias) and withdrawal symptoms associated with paroxetine have been reported to the UK CSM more commonly than with other SSRIs. For further details, see

Extrapyramidal Effects under Adverse Effects of Fluoxetine and Withdrawal under Precautions.

Breast feeding. For comments on the use of SSRIs in breast feeding patients, see under Precautions for Fluoxetine.

Children. SSRIs are associated with an increased risk of potentially suicidal behaviour when used for the treatment of depression in children and adolescents under 18 years old for further details, see under Effects on Mental State in Fluoxetine.

Pregnancy. For discussion of the risks of SSRIs during pregnancy, and whether paroxetine is associated with a greater tera-togenic risk than other SSRIs, see under Fluoxetine.

Interactions

For interactions associated with SSRIs, see Fluoxetine.

Pharmacokinetics

Paroxetine is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring within about 5 hours of ingestion. It undergoes extensive first-pass metabolism in the liver. The main metabolic pathway is oxidation followed by methylation and formation of glucuronide and sulfate conjugates. The cytochrome P450 isoenzyme CYP2D6 is partly responsible for the metabolism of paroxetine. Paroxetine is widely distributed throughout body tissues and is about 95% bound to plasma proteins. The elimination half-life of paroxetine is reported to be about 21 hours. Excretion is via the urine (about 64%) and the faeces (about 36%), mainly as metabolites in both cases. Paroxetine is distributed into breast milk (see Breast Feeding under Precautions in Fluoxetine).

Uses and Administration

Paroxetine, a phenylpiperidine derivative, is an SSRI with actions and uses similar to those of fluoxetine. It is given orally usually as paroxetine hydrochloride, as a single dose in the morning it is also given as the mesilate. Doses are expressed in terms of the base paroxetine hydrochloride 22.8 mg or paroxetine mesilate 25.8 mg are each equivalent to about 20 mg of paroxetine. The doses given below refer to preparations containing paroxetine hydrochloride similar doses are also used when paroxetine is given as the mesilate.

In the treatment of depression, the usual dose of paroxetine is 20 mg daily, increased gradually, if necessary, in weekly increments of 10 mg to a maximum of 50 mg daily (but see Administration, below). In the treatment of generalised anxiety disorder, the initial dose is 20 mg daily further increases in increments of 10 mg at intervals of at least one week to a maximum of 50 mg have been given (but see Administration, below).

The initial dose in obsessive-compulsive disorder is 20 mg daily increased weekly in 10-mg increments to a usual maintenance dose of 40 mg daily some patients may require up to 60 mg daily (but see Administration, below).

In the treatment of panic disorder with or without agoraphobia, the initial dose is 10 mg daily increased weekly in 10-mg increments according to response the usual recommended maintenance dose is 40 mg daily, although some patients may benefit from 60 mg daily (but see Administration, below).

The recommended starting dose for the treatment of post-traumatic stress disorder is 20 mg daily. If necessary this may be increased in increments of 10 mg at intervals of at least one week to a maximum of 50 mg daily (but see Administration, below). The initial dose for the treatment of social anxiety disorder is 20 mg daily increased after several weeks, if necessary, by increments of 10 mg to a maximum of 50 or 60 mg daily (but see Administration, below).

A suggested maximum daily dose in elderly or debilitated patients is 40 mg US licensed product information also recommends a starting dose of 10 mg daily in such patients. Reduced doses should be given to patients with hepatic or renal impairment, see below.

A modified-release preparation (as the hydrochloride) is also available in the USA for the treatment of depression, panic disorder, and social anxiety disorder the maximum doses with this preparation may be slightly greater than those recommended with the immediate-release preparation. The modified-release preparation may also be used in the treatment of premenstrual dysphoric disorder. The initial dose is 12.5 mg once daily, usually in the morning, which may be increased to 25 mg once daily, if necessary, after an interval of at least one week. Treatment may be given throughout the menstrual cycle or limited to the luteal phase.

Paroxetine should be withdrawn gradually to reduce the risk of withdrawal symptoms. For further details, see Withdrawal under Precautions of Fluoxetine.

Administration. Although paroxetine is licensed in the UK at higher doses the UK CSM considers that there is a lack of evidence from clinical trials of additional efficacy with paroxetine when given above the following daily doses:

• depression, generalised anxiety disorder, social anxiety disorder, post-traumatic stress disorder: 20 mg

• obsessive-compulsive disorder, panic disorder: 40 mg

Administration in hepatic or renal impairment. In the USA the recommended initial oral dose of paroxetine in patients with severe renal or hepatic impairment is the equivalent of 10 mg daily, increased to a maximum of 40 mg daily as necessary. UK licensed drug information recommends that doses in such patients are limited to the lower end of the range.

Anxiety disorders. Paroxetine is used in anxiety disorders including generalised anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social anxiety disorder (see under Phobic Disorders). It has also been tried for adult night terrors (see under Sleep-associated Movement Disorders).

Depression. As discussed on site, there is very little difference in efficacy between the different groups of antidepressant drugs, and choice is often made on the basis of adverse effect profile. SSRIs such as paroxetine are widely used as an alternative to the older tricyclics as they have fewer adverse effects and are safer in overdosage.

Hot flushes. Some SSRIs, including paroxetine, have been tried in the treatment of hot flushes for further details see under Fluoxetine.

Hypochondriasis. For mention of the use of SSRIs, including paroxetine, in hypochondriasis, see under Fluoxetine.

Premenstrual syndrome. Paroxetine (as a modified-release preparation) is used to control both the psychological and somatic symptoms of premenstrual syndrome.

Pruritus. Paroxetine has produced some benefit in the relief of non-dermatological pruritus.

Sexual dysfunction. Impotence or ejaculatory problems have been reported as adverse effects of SSRIs for the potential use of these effects in the management of premature ejaculation see Fluoxetine.

Preparations

British Pharmacopoeia 2008: Paroxetine Tablets

The United States Pharmacopeia 31, 2008: Paroxetine Tablets.

Proprietary Preparations

Argentina: Afenexil Aropax Datevan Meplar Neurotrox Olane Pamoxet Paxil Psicoasten Sicopax Sicotral Sostel Tiarix Xilanic

Australia: Aropax Extine Oxetine Paxtine

Austria: Allenopar Aparo Ennos Glaxopar Paluxetil † Parocetan Paroglax Paroxat Seroxat

Belgium: Aropax Seroxat

Brazil: Aropax Benepax Cebrilin Parox Paxtrat Pondera Roxetin

Canada: Paxil

Chile: Aroxat Bectam Pamax Posivyl Seretran Traviata

Czech Republic: Apo-Parox Arketis Parolex Remood Seroxat

Denmark: Oxetine Serodur Seroxat

Finland: Optipar Seroxat

France: Deroxat Divarius

Germany: Euplix Oxetf ParoLich Paroxat Paroxedura Seroxat Tagonis

Greece: Noprilex Seroxat Taberil

Hong Kong: Seroxat

Hungary: Apodepi Paretin Parogen Paroxat Rexetin Seroxat

India: Pari Parotin Xet

Indonesia: Seroxat

Ireland: Meloxat Paroser Parox Paxt Seroxat

Israel: Paxxet Seroxat

Italy: Daparox Dropaxin Eutimil Serestill Sereupin Seroxat Stiliden

Japan: Paxil

Malaysia: Seroxat

Mexico: Apo-Oxpar Aropax Paxil

The Netherlands: Seroxat

Norway: Seroxat

New Zealand: Aropax Loxamine

Philippines: Seroxat

Poland: Deprozel Paromerck Paxeratio Paxtin Rexetin Seroxat Xetanor

Portugal: Denerval Oxepar † Paxetil Seroxat

Russia: Paxil Rexetin

South Africa: Aropax Deparoc Parax Paxil Sedarin Serrapress Xet

Singapore: Seroxat

Spain: Casbol Frosinor Motivan Paratonina Parotur Seroxat Xetin

Sweden: Euplix Paroxiflex Seroxat

Switzerland: Deroxat; Dexantol; Parexat; Paronex; Paroxetop

Thailand: Seroxat

Turkey: Paxil Seroxat

UK: Seroxat

USA: Paxil; Pexeva

Venezuela: Paxil.

The evidence of the effect of paroxetine (Paxil) on anxiety symptoms within depression comes from several sources including meta-analysis of studies in depression, from a large study in patients with depression and anxiety symptoms, and from investigation of the effect of paroxetine (Paxil) on coexistent symptoms of anxiety in studies of depressed patients.

Meta-analyses have been conducted on paroxetine (Paxil) data similar to those reported on fluoxetine (Prozac). Dunbar and Fuell (1992) compared a database of 2963 paroxetine (Paxil)-treated patients with 554 who received placebo and 1151 given a comparison antidepressant (most often a tricyclic antidepressant). Paroxetine (Paxil) and active control both reduced baseline psychic anxiety more effectively than placebo. Both pharmacological treatments were effective in treating somatic anxiety with paroxetine (Paxil), demonstrating an earlier onset of activity. Neither paroxetine (Paxil) nor active control induced new anxiety symptoms. Paroxetine (Paxil) was superior to placebo in the treatment of agitation at weeks 4 and 6 and to active control at week 4 only. Both paroxetine (Paxil) and active control were more protective against new-onset agitation than placebo. Finally, there was no difference between the three groups in the incidence of spontaneously reported adverse events indicative of anxiety.

Two large reference controlled studies have been carried out in patients with anxiety and depression. Ravindran and colleagues (1996) conducted a 12-week, double-blind, parallel-group comparison of paroxetine (Paxil) 20-40 mg/day with clomipramine 75-150 mg/day. This was a large study that included 1002 patients. Inclusion criteria were drafted so as to recruit patients with moderate levels of both anxiety and depression as defined by the Montgomery-Asberg Depression Rating Scale (MADRS) score and Clinical Anxiety Score (CAS). Both paroxetine (Paxil) and clomipramine reduced the MADRS and CAS ratings at 2, 6 and 12 weeks and at endpoint, with no significant differences between treatment groups at any time point. The Clinical Global Improvement (CGI) severity of illness score and CGI improvement ratings were also similar throughout the trial. However, there was a statistically significant difference in the CGI efficacy index at 6 weeks and at endpoint, which favoured paroxetine (Paxil). There were also significantly fewer adverse events and study dropouts due to adverse effects among paroxetine (Paxil)-treated patients.

Paroxetine (Paxil) has also been compared to amitriptyline in patients with a diagnosis of depression with anxiety in an 8-week comparison that included 505 patients. Both treatments showed similar reduction in mean total MADRS, CAS and CGI scores during the study. However, paroxetine (Paxil) was better tolerated and significantly more anticholinergic events were reported in the amitriptyline group than in patients treated with paroxetine (Paxil) (30% vs. 17%).

In addition to these studies designed to select patients with depression and anxiety, further evidence of the efficacy of paroxetine (Paxil) on the anxiety symptoms in depression comes from a large comparison of paroxetine (Paxil), imipramine (Tofranil), and placebo in outpatients. A significantly better effect was reported with paroxetine (Paxil) than imipramine (Tofranil) at week 2 on the anxiety somatization factor of the Hamilton Depression Rating Scale. This early improvement of the anxiety symptoms with paroxetine (Paxil) was also registered on the Covi scale as early as the second week of treatment, whereas imipramine (Tofranil) was effective only at the end of treatment. Meta-analysis of the large paroxetine (Paxil) comparator and placebo database confirmed this finding with paroxetine (Paxil), showing a significant advantage over the comparators in treating the psychic anxiety, measured on the Hamilton Depression Scale, at weeks 2, 4 and 6. A similar result was seen in a separate analysis of the US data (where a five-point scale was used for the agitation item) with an advantage for paroxetine (Paxil) on the agitation scores compared with comparators antidepressants at weeks 2, 4 and 6.

There have been very few studies comparing individual SSRIs, so that it is difficult to draw conclusions on possible differences between them. Paroxetine (Paxil) has been compared with fluoxetine (Prozac) in two comparator studies, both relatively small. In one, 90 patients suffering from moderate to severe depression were treated with either paroxetine (Paxil) 20 mg/day or fluoxetine (Prozac) 20 mg/day, increasing to paroxetine (Paxil) 30 mg/day or fluoxetine (Prozac) 40 mg/day after a week and then flexible dosing according to efficacy and tolerability. In this study there were no significant differences between the two treatments at any time points. The anxiety scores measured on the Hamilton Anxiety Scale were significantly reduced in both treatment groups during the study. The study of de Wilde and colleagues (1993) compared paroxetine (Paxil) and fluoxetine (Prozac) in a 6-week double-blind trial of 100 patients. There were no significant differences between treatment groups in reduction of either depression or anxiety scores. However, both depression and anxiety were significantly reduced in the paroxetine (Paxil) group earlier (week 3) than among patients treated with fluoxetine (Prozac).

The large epidemiological studies that have been carried out in recent years have drawn attention to the high rates of comorbidity of psychiatric disorders in the general community. Major depression is known to have a high comorbidity with separate anxiety disorders and a problem can arise in attributing certain anxiety symptoms as part of either the depression or the anxiety disorder. The overlap of major depression and an anxiety disorder where both conditions satisfy the full diagnostic criteria is perceived as comorbidity. In this case separate diagnoses may be considered. The overlap of major depression and anxiety disorders, where neither disorder satisfies the full criteria, has come to be known as mixed anxiety depression (MAD). This chapter attempts to address the degree of overlap which is so confusing for the clinician and to assess the data relating the role of selective serotonin reuptake inhibitors (SSRIs) in treatment.

Anxious depression or comorbid anxiety and depression

Mixed anxiety depression is a common but poorly defined condition with multiple possible aetiologies. Both anxiety and depression may occur as a symptom of or reaction to a primary psychiatric or medical disorder. The concept of major depression includes a variety of subgroups, including the more severe (psychotic features, melancholia) and chronic subtypes. Anxiety disorders are classified according to whether and how the anxiety is limited to particular situations (phobias, compulsions), thoughts (obsessions) or times (panic attacks). Generalized anxiety disorder (GAD) may be thought of as chronic anxiety which is not limited to any of these dimensions. Some basic researchers believe that anxiety and depression exist on a continuum and that depression may represent under-activity of serotonergic pathways while anxiety results from over-activity in serotonergic neurones.

There are two general meanings for mixed anxiety depression. One is the depressed patient who has signs or symptoms of an anxiety disorder which does not meet the threshold for a separate diagnosis, such as the patient with panic attacks which do not occur often enough or with the requisite number of symptoms to be diagnosed as panic disorder. The other is the patient with generalized anxiety disorder who intermittently fulfils criteria for major depression. Mixed anxiety depression also appears as an experimental diagnosis in DSM-IV (Table: Research criteria for mixed anxiety depressive disorder (DSM-IV)). Its anxiety symptom criteria are very similar, and in some cases identical, to those for GAD. However, DSM-IV requires that the disorder does not meet, and never has met, criteria for generalized anxiety disorder, major depression, dysthymic disorder and/or panic disorder. This is a problem, especially because the symptom threshold for dysthymic disorder is so low (requiring only two symptoms) that chronically depressed and anxious patients will almost never meet criteria for mixed anxiety depression. One might summarize this by saying that mixed anxiety depression (MAD), as it is currently regarded, is an admixture of a subsyndromal depressive disorder with a subsyndromal anxiety disorder. In a sense it is a testament to the importance of MAD that it has received as much research attention as it has despite this lack of satisfactory diagnostic criteria.

Table: Research criteria for mixed anxiety depressive disorder (DSM-IV)

Anxiety symptoms in depression

The scales employed for rating the severity of depression reflect the nature of these anxiety symptoms as integral to the depression. The scores on these anxiety items are seen to reduce as the depression improves and the items have good face validity in depression. For example, the Hamilton Scale for Depression (Hamilton, 1960) includes items to measure agitation, somatic anxiety and psychic anxiety. Three items that measure sleep disturbance and an item to assess the phenomenon of depersonalization feelings also form part of the scale. Moreover, it can be argued that the items for assessing obsessional symptoms and hypochondriasis also register anxiety symptoms. Most studies of the efficacy of various treatments for depression have shown that the symptoms measured by these anxiety items in the scales improve at the same rate as other symptoms of depression.

Some of the items in the Hamilton Rating Scale are more sensitive to treatment change than others and Hamilton himself recognized that the depersonalization and obsessional items, which are less sensitive, should be used more appropriately for diagnostic purposes only.

SSRI in the Treatment of Anxiety Symptoms Within Depression

Some treatments are acknowledged to be more effective than others in treating particular anxiety symptoms that occur with depression. The items that measure disturbed sleep improve more rapidly in response to sedative antidepressants with marked histaminergic receptor properties such as the sedative tricyclic antidepressants or mianserin. This has been shown in a number of comparisons with non-sedative antidepressants such as the selective serotonin reuptake inhibitors. However, the advantage seen with the sedative antidepressants, which is more evident at the start of treatment, tends to diminish as the sleep improves as part of the general improvement of the depression in response to SSRIs. By the end of the acute treatment period, the advantage of the sedative antidepressants on sleep is no longer evident. On the other hand, the negative effects on psychomotor function of the histaminergic activity become apparent with daytime drowsiness and the need to desist from driving cars or operating heavy machinery.

The early effect of anxiolytic drugs on disturbed sleep and certain other anxiety, symptoms in depression has been reported but an antidepressant effect cannot be attributed to these drugs merely on these grounds. The studies of benzodiazepines in the treatment of depression show their effects on improving the sleep items and anxiety but also show that they are less effective, or not effective at all, in improving other features of depression, and it is for this reason that, independently of the associated long-term problems of tolerance and dependence, benzodiazepines are not licensed or recommended for the treatment of major depression. Some studies have reported an increase in paradoxical aggression with benzodiazepines, possibly mediated by a mechanism involving disinhibition, and this characteristic makes these drugs unsuitable for depression, where there is an elevated risk of suicide attempts.

The selective advantages of selective serotonin reuptake inhibitors (SSRIs) in treating the anxiety symptoms of depression compared with sedative tricyclic antidepressants came as a surprise. Zimelidime, an early non-sedative SSRI that was withdrawn from the market, was found to be more effective than amitriptyline in treating the anxiety symptoms of depression in a 6-week treatment study. This finding raised the possibility that serotonin reuptake might have a special beneficial effect on the symptoms of anxiety within depression. Subsequent analysis for paroxetine (Paxil) and fluvoxamine (Luvox) have confirmed this hypothesis, with a differential advantage in treating anxiety symptoms in depression reported for the SSRIs compared with reference tricyclic antidepressants. These observations led to the hypothesis that SSRIs might have particular advantages in treating separate anxiety disorders, such as panic disorder and social phobia.

The first generation of antidepressant medication included tricyclics (TCAs) and monoamine oxidase inhibitors. A number of investigators have shown these drugs to be helpful in the treatment of anxious depression. Several trials have also shown TCAs to be equivalent or even superior to benzodiazepines in the treatment of this syndrome. SSRIs improved over tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) in two main areas: tolerability and safety. However, anxiety and agitation have been reported as occasional side effects with all selective serotonin reuptake inhibitors, which might lead to reluctance to use these agents in anxious depression. A review of the available data concerning the use of SSRIs in anxious depression, especially relating to whether baseline anxiety is a poor prognostic sign, is therefore timely.

The first line of evidence is indirect. It stems from the observation that patients with anxiety disorders often have concomitant depressive symptoms. There is considerable direct evidence of the efficacy of the SSRIs in anxiety disorders. All four SSRIs approved for marketing in the USA have shown sufficient efficacy to garner an official indication for at least one anxiety disorder, obsessive-compulsive disorder (OCD). Paroxetine (Paxil) and sertraline (Zoloft) are also indicated for the treatment of panic disorder (PD). While patients with bona-fide major depression are usually excluded from trials of an antidepressant in an anxiety disorder, it is likely that a substantial number of the subjects in OCD and PD trials had clinically significant depressive symptoms.

Filteau and colleagues analysed data from 10 studies of SSRIs (sertraline (Zoloft); zimelidine; fluvoxamine (Luvox); fluoxetine (Prozac)); selective noradrenergic uptake inhibitors — desipramine, maprotiline, oxaprotiline; mixed uptake inhibitors — amitriptyline, imipramine (Tofranil); and partial 5-HT2 antagonists — ritanserin, trazodone (Desyrel), nefazodone. The data showed no differences between the efficacy of these classes in agitated or retarded depression. In a subsequent analysis the same investigators found that SSRI responders tended to be initially more anxious and agitated than non-responders.

Answer. I admire your tenacity, after all these complications with your treatment. So, let’s go through each of your questions and see if it leads to some treatment options to discuss with your doctor. First, I think buspirone augmentation can be helpful, particularly if there is an anxiety component to the depression. In fact, there are studies showing that buspirone alone, and in high doses (at least 50 mg/day) has antidepressant properties. Pindolol studies have yielded mixed results, and this may vary from SSRI to SSRI, but I think the risks are so minimal that it might be worth trying in your case. Other medications to consider as augmenters to SSRIs would include methylphenidate (Ritalin), which works well, in my experience, but could be overstimulating to you (if it were used, I’d start with 2.5 mg per day and hold it there for a week). Alternatively, you (with your doctor’s approval, of course) could try stopping the tyrosine for a week or two, then re-starting it. Sometimes this strategy works with the SSRIs as well, though some patients may experience mild-to-moderate withdrawal symptoms (flu-like symptoms) when a short-acting SSRI (Paxil, Zoloft) is suddenly stopped–so a tapering period might be better, followed by 1-2 weeks off, then a restart.

Another option would be to add a dopamine agonist, such as pergolide. I have seen this help in one case of very resistant depression. Here, too, I’d start low, and go slow with the dose. The combination of the MAO-B inhibitor selegiline (L-deprenyl) in combination with phenylalanine (another amino acid precursor) has been reported helpful. To use L-deprenyl, you must be off Zoloft for at least two weeks. You did not mention Serzone…if you haven’t tried this, it could be used in low doses in combination with the Zoloft, or as a single agent in much higher doses. Or, Serzone could be used in combination with most of the other agents mentioned above, except an MAOI. I don’t know if you’d consider treatment in Canada, but they do have a unique MAOI up there–moclobemide–that is not available in the States. It might work for you, even though two previous MAOIs did not. Moclobemide can usually be obtained via a cooperative arrangement between your doctor and one up in Canada. Then, there’s always St. John’s Wort, but we know so little about how well this works, or if it can be combined safely with standard antidepressants, that I can’t really recommend it.

Since you have been through the pharmacologic ringer, I think you should at least consider something that we know does work, and that is ECT. This is a safe and very effective treatment for major depression, and can be used on a maintenance basis.

As to the mechanism of “poop-out” – the undignified name says a lot about our state of knowledge. It doesn’t really fit the usual definition of tolerance since dosage increases may or may not help (with tolerance, an increase in dose virtually always – by definition – brings about a renewed response). Dopamine depletion from the SSRI is plausible, and goes along with the observation that some patients who experience this fading out of SSRI effects also experience a sort of emotional flattening and decreased response to rewarding stimuli (e.g., sex, good times, etc.). Since the reward system is mediated in large part by dopamine, this all hangs together. That may be why methylphenidate (Ritalin), which has dopamine enhancing properties, sometimes restores the SSRI response. On the other hand, the apparent success of pindolol – which basically unlocks the valve on the neuron that produces serotonin – suggests that serotonin slow down may underlie this loss of SSRI effect. I don’t think it is a pharmacokinetic effect in most cases. I do wish you and your doctor the best in dealing with your problem, and don’t give up!

Researchers from the University of Oregon Health Sciences Center conducted a study of 10,000 people, 5,000 with Type II diabetes and 5,000 without it. The two groups were similar in other ways such as age and gender. The team hoped to answer three questions:

· Are diabetics more likely to be depressed than those who don’t have diabetes?
· What types of medications are depressed diabetic people likely to be taking?
· What are the costs of treating a person with diabetes, depression, or both?

They found that 62 percent of diabetics are more likely to be depressed than people without the disease. Among diabetics, those who are depressed are more likely to be taking insulin than managing their diabetes through diet and oral medications.

Diabetics are less likely to be taking antidepressant drugs. Of those who are being treated, most are on the same medications as any depressed patient—serotonin re-uptake inhibitors, such as Prozac, Zoloft, or Paxil. They also were taking more tricyclic antidepressants, such as Elavil. However, the researchers were uncertain if they were taking the antidepressants at the higher doses needed to treat depression or at the lower doses used to treat peripheral neuropathy, a common complication of diabetes.

As for costs, depressed people use more services and spend more money than average, whether or not they also have diabetes. In fact, it costs about the same amount to treat a diabetic without depression as it does to treat a depressed person without diabetes. Having both diseases increases costs considerably.

Treating the depression was shown to increase an individual’s adherence to his or her treatment plan, improve blood glucose control, as well as improve the individual’s psychological outlook.

From any perspective, untreated depression in Type II diabetes carries a high cost, financially, physically, and mentally.

Panic disorders respond well to psychotherapy, drug treatment and a combination of the two, according to one of the largest studies of the condition.

Panic disorder affects several million Americans, crippling them with recurrent bouts of profound anxiety and physical symptoms that can include chest pain and pounding, as well as rapid heartbeats and shortness of breath. Many people also feel that, in the midst of an attack, they’re in danger of dying.

Perhaps it’s understandable, then, that people with this condition often feel there’s no hope of treatment. Fortunately for them, they’re wrong.

This conclusion won’t come as a surprise to specialists, who’ve been treating the condition with drugs and psychotherapy for many years. But, the researchers say, it should reinforce the message that panic disorder is a real diagnosis, and one that can be brought under control. Their findings appear in this week’s issue of the Journal of the American Medical Association.

Boston University researcher David Barlow and colleagues at three other clinics treated 312 patients from 1991 to 1998. Participants received one of five treatments: up to 300 milligrams a day of the antidepressant imipramine; a combination of imipramine and cognitive-behavioral therapy [CBT]; CBT alone; CBT plus a placebo; or a placebo alone.

Cognitive-behavioral therapy [CBT] tries to give people more control over their runaway fears by helping them recognize and stave off impending attacks through breathing exercises, desensitization techniques and other devices.

Participants received treatment once a week for three months. If they showed improvement, their treatment was eased back to once a month over a six-month maintenance period. They then were observed for an additional six months.

Using one psychiatric yardstick, known as the Panic Disorder Severity Scale, both the drug and psychotherapy treatments scored better than no treatment at reducing symptoms of panic disorder during the first phase of the study. However, neither bested the placebo when measured on another yardstick, the Clinical Global Impression Scale.

Among the people who improved during the first three months, both treatments were definitively better on each scale than the placebo during the maintenance stage. And the combination of the two was more effective than either treatment alone.

The researchers note, however, that more participants abandoned imipramine than psychotherapy because of the drug’s unpleasant side effects, which include dry mouth and dizziness.

“Our results demonstrate that both imipramine and cognitive-behavioral therapy [CBT] are better than pill placebo for treatment” of panic disorder, the researchers write in the journal report. “Imipramine produced a superior quality of response, but CBT was more durable and was somewhat better tolerated.”

Dr. Richard Glass, a Chicago psychiatrist and deputy editor of the Journal of the American Medical Association, says the study emphasizes the importance of viewing panic disorder as a treatable, chronic illness. “It hasn’t been as widely known as it should be,” says Glass, who wrote an editorial accompanying the journal article.

Panic attacks, which occur about twice as commonly in women as men, can mimic some of the symptoms of heart attack. As a result, many doctors may overlook the emotional disorder as a cause of chest symptoms and do nothing about it when they find that a patient isn’t having a heart episode, Glass says.

Similarly, many people who have panic attacks are unaware they have a wide range of treatment options, he says.

In addition to imipramine, which has been available for some two decades, newer antidepressants like Zoloft and Paxil also have been approved for treatment of panic disorder. These drugs are as effective as imipramine, Glass says, but have the advantage of not being fatal if taken in overdose amounts.

What To Do

“We know that these treatments work, but we don’t yet know which treatments work best for which people,” says Jerilyn Ross, a Washington, D.C., social worker and president of the Anxiety Disorders Association of America.

Ross, author of Triumph Over Fear (Bantam, 1994), says the worst thing a person with panic disorder can do is neglect it because the condition can lead to depression and substance abuse if unchecked.

Nor should patients who fail one therapy lose hope and think they’ll be luckless with others, she says.

* note: social anxiety disorder is characterized by the fear of being observed or evaluated by others; sufferers report an overwhelming fear of embarrassment in social and performance situations.
* researchers at the University of Southampton conducted a 12-week, multi-centre, double-blind, placebo-controlled clinical trial to compare the efficacy of Paxil (20-50 mg daily) to placebo, in 290 patients with social anxiety disorder.
* found a statistically significant symptom improvement in patients treated with Paxil within as little as four weeks of treatment onset, as measured by the Liebowitz Social Anxiety Scale (LSAS), which provides an assessment of a patient’s level of fear and avoidance of performance and/or social situations.
* the researchers say that Paxil was associated with a definitive reduction in symptoms of social anxiety disorder, increased participation in social activity, as well as a significant improvement in overall well being.
* Paxil (paroxetine), from SmithKline Beecham Pharma Canada, has been approved in 82 countries for the treatment of depression, obsessive-compulsive disorder and panic disorder in patients over the age of 18 and is indicated for the treatment of generalized social anxiety disorder in 35 countries, including the U.S.

Answer. The short, no-frills answer to your question is that any of the major antidepressants or anxiolytics are probably safe, now that the most vulnerable period of organ-formation (the first trimester) has passed. I see no reason why Zoloft and/or Klonopin could not be restarted, if the clinical situation is severe enough to warrant the modest risks. An OB/GYN consult is always a reasonable precaution, but I would not necessarily be governed by it, if you believe your patient must be on a medication. If you care to read on, here is the more complicated story:

With respect to antidepressants (ADs) in pregnancy, most data come from studies of tricyclics and fluoxetine(Prozac); we have only a modicum of information about newer agents such as sertraline (Zoloft), paroxetine (Paxil), venlafaxine (Effexor) and nefazodone (Serzone). The tricyclics (e.g., desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor)) appear to have little potential for teratogenicity. Similarly, a recent study by Pastuszak and colleagues (1993) found no evidence of teratogenicity in 128 women taking fluoxetine during the first trimester, when compared to matched controls. While there was a trend toward higher miscarriage rates in the fluoxetine group compared to controls taking known non-teratogens, the risk was small (relative risk, 1.9) and comparable to that of tricyclics. (Interestingly, depression itself may also raise the risk of miscarriage). A recent study by Chambers et al. (New England Journal of Medicine 1996, vol. 335, pp. 1010-1015) found no significant differences between fluoxetine-treated pregnant women and controls in spontaneous pregnancy loss or major structural anomalies; however, the incidence of three or more minor anomalies was significantly higher in the fluoxetine cohort.

This study has been widely criticized, however, on a number of methodologic grounds. The more anticholinergic tricyclics (e.g., amitriptyline, doxepin) can occasionally induce fetal tachyarrythmias, urinary retention or intestinal obstruction. Clomipramine (Anafranil), a tricyclic used mainly in the treatment of obsessive-compulsive disorder, also has substantial anticholinergic effects, and would be expected to produce similar effects in the neonate. Wisner et al (1993) found that the doses of tricyclic antidepressant required to achieve remission actually increased during the second half of pregnancy, reaching 1.6 times the mean dose required when the patients were not pregnant. This was attributed, in part, to enhanced hepatic metabolism of antidepressants during pregnancy and to increased volume of distribution. Neonatal irritability, tachypnea, tremor and hypotonia may result from either tricyclic toxicity or withdrawal. It is therefore prudent to monitor maternal blood levels of tricyclics throughout pregnancy and gradually to reduce the dosage during the week before delivery.

Little is known about the excretion of antidepressants into breast milk or the effects of this on the nursing infant. Some studies indicate that several antidepressants or their metabolites can accumulate in breast milk, possibly peaking at about 4-6 hours after an oral dose. (See the review by Wisner et al. in the September 1996 issue of the American Journal of Psychiatry). It is not clear to what extent antidepressants accumulate in the blood of the nursing infant or whether significant adverse effects result from such accumulation. Wisner et al. (1996) conclude that sertraline is a good choice, with respect to breast-feeding. However, many clinicians feel that breast-feeding is best avoided when the mother is taking antidepressants postpartum.

Miller (1994) concluded that the tricyclics of choice during pregnancy are desipramine and nortriptyline, due to the comparative wealth of data about them, the ability to monitor serum levels and a favorable side effect profile. Alternatively, fluoxetine (Prozac) may be a reasonable choice for the pregnant patient with major depression, in light of the data from Pastuszak et al. Finally, the clinician should keep in mind that ECT appears to be a safe and effective alternative for the pregnant patient with severe depression.

With respect to benzodiazepines (BZDs): In the 70s and 80s, diazepam (Valium) was found to be associated with cleft lip and palate in the fetus and other benzodiazepines were suspected of this association. More recently, one Swedish group has linked maternal use of benzodiazepines during pregnancy with both impaired intrauterine growth and various dysmorphic birth defects. A recent review concluded that the available data indicate a positive association between first-trimester in utero exposure to benzodiazepines and a specific anomaly oral cleft.

Diazepam may double the risk of oral cleft, while alprazolam may increase the risk by more than 11-fold. However, most available data suggest that BZDs do not markedly increase the absolute risk of cleft palate or other congenital abnormalities in exposed fetuses. Thus, the baseline risk of cleft palate is about 6 in 10,000. With alprazolam exposure during the first trimester, the risk may rise to 7 in 1000, still less than 1%. The teratogenicity of lorazepam (Ativan) is less clear. Clonazepam (Klonopin) has not been evaluated for teratogenesis in controlled studies of human subjects; however, based on animal data, clonazepam seems to have low teratogenic potential (Altshuler et al, 1996) . The presence of alcohol and other substance abuse in pregnant women using benzodiazepines complicates interpretation of the data. Infants exposed to BZDs either in the last trimester or at the time of parturition may show muscular hypotonicity, failure to feed, impaired temperature regulation, apnea and low Apgar scores). The data on behavioral teratogenicity and developmental delay are inconclusive.

There is also some evidence that benzodiazepines may increase duration of labor and lead to prolonged withdrawal symptoms in the neonate, when mothers have been maintained on these agents throughout pregnancy. Withdrawal effects may be more likely when high doses of short-acting benzodiazepines have been used. Benzodiazepines should not be stopped suddenly during pregnancy, rather, tapered slowly as delivery approaches. The non-benzodiazepine anxiolytic buspirone (BuSpar) has been shown to increase the number of stillbirths in rats, when given in high doses; however, there are insufficient data in humans to determine the risks of buspirone during pregnancy.

While there is evidence that several benzodiazepines (e.g., diazepam, lorazepam, oxazepam) are excreted into breast milk, the actual levels of BZDs detected in breast milk seem to be fairly low and the consequent risk to the infant, quite small. Lorazepam seems to have minimal accumulation in the fetus and the percentage of the maternal dose of lorazepam to which a nursing infant is exposed is roughly 2.2%. Thus, use of low dose lorazepam in the nursing mother – particularly on a prn, or short-term basis – is probably safe for the infant. The excretion of buspirone into human breast milk has not been adequately studied.

Given the above risks, are benzodiazepines contraindicated during pregnancy? There is no absolute contraindication. Rather, the modest risks of BZD exposure must be weighed against the severity of the patient’s condition; the risks of no medication; and the risks of alternative medications. For example, inadequately treated panic attacks may themselves pose a risk to the fetus. Tricyclic antidepressants, fluoxetine and perhaps other SSRIs, may be reasonable alternatives to benzodiazepines for the treatment of panic disorder during pregnancy . Cognitive-behavioral therapy (CBT) may also be helpful in a variety of anxiety disorders and may reduce the need for psychotropics during pregnancy.

Answer. I am providing you with a list of commonly used antidepressants, as well as their usual doses:

Maintenance Dosage and Tablet Size for Non-MAOI Antidepressants

With respect to non-addictive medications for anxiety, it is first important to realize that the term addiction is defined in many ways. The medications most commonly used in the treatment of anxiety – the benzodiazepines, such as Valium, Librium, Ativan, etc. – are not highly addictive for the vast majority of people who are prescribed them for the right reasons. These agents may be abused or become habit-forming, however, in individuals with a history of alcohol and substance abuse, and, very rarely, in individuals who do not have such problems. The antianxiety agent buspirone (BuSpar) is a good alternative, and is not habit-forming or prone to abuse; however, while buspirone is useful for generalized anxiety, it is not helpful for panic attacks or obsessive-compulsive states.

Sometimes, low doses of the older tricyclic agents, such as doxepin 15-25 mg/day, may be useful for generalized anxiety in patients who are not good candidates for benzodiazepines. If you want more details about available medications for mood and anxiety disorders, you may want to call the NIMH Depression Awareness program.

Answer. The first step in “pulling yourself out of this” is to stop pulling alone. You need to get professional help right away.

First of all, I’m not clear what you mean when you say the medications aren’t working. Are you still taking leftover Paxil and Ritalin, or has a new doctor prescribed other medications? In any case, you are clearly in need of a different approach.

It is very common for people with serious depression to feel “immobilized” and unable to work. Of course, it is important to rule out medical causes for this before assuming it is due to depression. So you probably need a thorough physical by a general physician, followed (if appropriate) by referral to a psychiatrist. If you lack insurance, or other means of paying for treatment, I would suggest you speak with a clinical social worker to see what your options are, vis-а-vis some form of temporary disability benefits.

Alternatively, try calling either the National Alliance for the Mentally Ill (NAMI)  or the National Depressive and Manic-Depressive Association  for support and advice on your predicament. When you are feeling a little more energetic, you may also be interested in the book Feeling Good by Dr. David Burns. Good luck, and don’t give up!